Recent Developments in the Synthesis of Triazoles and Their Applications in Antibacterial Drug Discovery

Abstract

Antibiotic abuse has become a global threat to public health concerns and has caused the emergence of powerful multidrug-resistant pathogens. These organisms have developed complex mechanisms to counter even the most advanced antibiotics of present times. Consequently, the search for novel potent antibacterial agents has gained immense traction. Triazole, a versatile nitrogen-containing heterocyclic moiety surpasses other pharmacophores in terms of chemotherapeutic and broad-spectrum antibacterial properties. Thus, this account highlights the recent development in synthetic methodologies for developing various small molecules comprising triazole functionalities showcasing potent antibacterial applications.

Biographical Sketches

Dr. Sushil K. Maurya obtained his Ph.D. from the CSIR-National Chemical Laboratory, Pune, India. Then he pursued postdoctoral studies at Brandeis University, USA (2007–2008) and the University of Leeds, UK as a Marie Curie Fellow (2008–2010). He was a visiting scientist in the group of Prof. Erhard Kemnitz in the Department of Chemistry, at Humboldt University, Germany. After working in Wockhardt Ltd., India for about 4 years, he began his academic career at the CSIR-Institute of Himalayan Bioresource Technology (CSIR-IHBT), Palampur in February 2015. He is currently an associate professor in the Department of Chemistry, University of Lucknow, India working on catalysis, medicinal chemistry, and organic synthesis.

Deepti Pal completed her M.Sc. from SSMS & PS College, Dr. Rammanohar Lohia Avadh University, Faizabad, India, in 2023. She is currently pursuing her Ph.D. under the supervision of Dr. Sushil K. Maurya at the University of Lucknow, Lucknow, India. Her research interest is in medicinal chemistry and synthetic organic chemistry with an emphasis on drug conjugates and click chemistry.

Shruti Yadav obtained her M.Sc. in Chemistry from Isabella Thoburn College, University of Lucknow, Lucknow in 2023. In the following year, she joined the research group of Dr. Sushil K. Maurya as a Ph.D. candidate in the Department of Chemistry at the University of Lucknow. Her research focuses on the development of catalytic methods for the synthesis of amines and pharmaceutically relevant compounds.

Abhishek Kumar Verma obtained his M.Sc. in Chemistry from the University of Lucknow, Lucknow, India, in 2020. Currently, he is pursuing his Ph.D. in Dr. Sushil K. Maurya’s research group at the University of Lucknow, Lucknow, India. His primary research is focused on the development of catalytic methods for efficient chemical transformations particularly in the synthesis of amines and their derivatives.

Introduction

In the wake of severe overuse and misuse of antibiotics, a significant increase in the number of antimicrobial-resistant (AMR) strains of bacteria has been seen across the world which has now become a global health concern. Several studies in recent times have also emphasized the incessant use of antibiotics in the treatment protocol for SARS-CoV-2 (COVID-19) to treat co-morbidities and secondary infections, as an inevitable reason for the current increase in AMR strains.[1a] The slow development process of novel antibacterial therapeutics having unconventional modes of action does not seem to outpace the widespread rise of antibacterial-resistant pathogens. The World Health Organization (WHO) classified Entrococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE­) bacteria as critical threat pathogens and none of the novel lead compounds seem to be potentially active against them.[1`] [c] [d] These grim conditions urgently require newer potent derivatives or chemical scaffolds that could effectively combat this rapidly growing menace.

Ciprofloxacin, a second-generation fluoroquinolone, is a broad-spectrum antibiotic (Figure [1]), that is used to treat bacterial infections ranging from cystitis, sinusitis, and prostatitis to urinary tract infections, etc. It works by inhibiting the DNA gyrase/topoisomerase that prevents the resealing of bacterial DNA.[2] [3] This molecule could be derivatized into more potent molecules that are effective against resistant pathogens by modifying the C-7 position in its structure. It has been well established, in drug discovery, that structural changes in the drug molecules could lead to potential increase in the effectiveness of a drug against specific pathogens.[4]

A popular pharmacophore that could be synergistically linked with ciprofloxacin is the 1,2,3-triazole ring system.[5] This moiety is conventionally prepared by Huisgen 1,3-dipolar cycloaddition of azides and alkynes through a copper-catalyzed click reaction (Figure [2]). 1,2,3-Triazoles are an integral component of cephalosporin, tazobactam, and ceftazidime. Its unique physicochemical properties allow various noncovalent interactions with different biological targets, displaying the ability of being both a hydrogen bond donor and acceptor. Further, it serves the dual purpose of being a bioisosteric replacement of the amide or other nitrogen-containing aromatic heterocycles and a highly effective bridging group in producing a competent bifunctional drug.[6] [7] [8] Pleasingly, given its multifaceted roles in medicinal chemistry, we have been constantly seeking to derive novel applications of the triazole group in building effective therapeutics and related compounds.[9]

Synthesis of Triazole Hybrids

Özil and co-workers synthesized novel triazole compounds incorporating an isatin moiety by reacting isatin (1a) and 5-nitroisatin (1b) with 4-amino-1,2,4-triazoles 2a–g either in an oil bath or with microwave irradiation.[10] The reaction in an oil bath resulted in moderate yields. Moreover, performing the reaction under microwave irradiation in ethanol (containing glacial acetic acid) in a closed vessel with control pressure for 3–5 min at 300 W at 110 °C resulted in reduced reaction time for the formation of Schiff bases 3a–g, 4a–g with an improved yield (Scheme [1]). The disappearance of the NH₂ signal in compounds 2a–g was observed, which shows the formation of 3a–g and 4a–g. The synthesized compound 3a–g and 4a–g were evaluated for antimicrobial properties against four strains, Escherichia coli ATCC 25922, P. aeruginosa ATCC 27853, S. aureus ATCC 25923, and B. subtilis ATCC 6633, and four yeast strains, C. albicans ATCC 60193, C. parapsilosis ATCC 22019, C. kefyr ATCC 46764, and C. glabrata ATCC 66032. Among the tested compounds, 3g exhibited significant antibacterial activity against S. aureus ATCC 25923 and B. subtilis ATCC 6633 with MIC values of 8 and 16 μg mL^–1, respectively. The antimicrobial activity of the compound was assessed using two techniques, first the agar-well diffusion method for measuring the zone of inhibition (ZOI) after incubating the plates for 18 h at 35 °C. Second, the broth micro-dilution method for determining the MIC (minimum inhibitory concentration) values. Furthermore, compounds 4a, 4b, and 3b showed moderate antifungal activity, indicating their potential for pharmacological development. The remaining compounds showed antimicrobial activity within an MIC range of 62 to 500 μg mL^–1.

Zhou and co-workers synthesized a series of clinafloxacin-1,2,4-triazole hybrids (Scheme [2]).[11] The 1,2,4-triazol-1-yloxirane reactant 8 was generated starting from the acetylation of substituted benzenes 5a–g with chloroacetyl chloride resulting in 2-chloroacetophenones 6a–g in 85–95% yield. Further, N-alkylation of 6a–g with 1,2,4-triazole in acetonitrile using potassium carbonate produced a range of 2-triazol-1-ylethanones 7a–g in satisfactory yields (78–85%). Epoxidation of compounds 7a–g in toluene using TMSI (trimethylsulfoxonium iodide) and 20% sodium hydroxide at 60 °C resulted in the formation of 1,2,4-triazol-1-yloxiranes 8a–g. Finally, reaction of clinafloxacin with oxiranes 8a–g in ethanol at 70 °C using sodium hydrogen carbonate as base resulting in clinafloxacin-1,2,4-triazole hybrids 9a–g. Compound 8a showed good antimicrobial activity due to the presence of the oxirane moiety. Compounds 9a, 9c, 9e, and 9g show excellent activity due to the presence of fluorine in the benzyl group. The results indicate that the 2,4-difluorophenyl moiety plays an important role in the antibacterial and antifungal profile and is shown in compound 9g. The target compounds 9a and 9c–g show biological activity against methicillin-resistant Staphylococcus aureus (MRSA) with low minimum inhibitory concentration (MIC).

Kamal and co-workers developed triazoles-linked to nitrofurans and evaluated their antibacterial and antimicrobial activities.[12] The synthesis began by reacting terminal alkyne 10 with a range of substituted benzyl azides 11a–j using click chemistry to give a series of triazole derivatives 12a–j in good yields (79–92%) (Scheme [3]). All nitro-triazole compounds showed antibacterial activity against Gram-positive bacteria, and compounds containing electron-withdrawing substituents such as nitro, fluoro, chloro, and trifluoromethyl showed enhanced activity, while 12b with a nitro group at the meta-position has slightly better activity. Conversely, the presence of the methoxy group does not significantly influence antibacterial activity. MIC and minimum bactericidal concentration (MBC) values of the compounds ranged from 1.17 to 75 μg mL^–1. Among all the tested derivatives compounds 12a, 12b, 12e, 12f, and 12h exhibited the highest antibacterial activity with MIC values of 1.17 μg mL^–1 against various bacterial strains. Additionally, compounds 12b, 12d, 12e, and 12j demonstrated selectivity against Gram-positive pathogenic bacteria and displayed good bactericidal and inhibitory effects against these strains. The synthesized compounds exhibited promising antibacterial activity against resistant strains of MRSA and biofilm formation. However, none of the synthesized compounds were active against the Gram-negative bacterial strain. The tested compounds showed promising antimicrobial activity against MRSA strains and they were found to be inactive against vancomycin resistant Enterococcus (VRE). The maximal anti-biofilm activity of each compound corresponded to its antibacterial activity against the strain S. aureus MLS-16 MTCC 2940 with IC₅₀ < 10 μg mL^–1. The therapeutic capabilities of the synthesized conjugates were tested for their cytotoxicity against two mammalian cell lines MRC-5 (normal lung cell line) and VERO (normal monkey kidney cell line) and it was found that 12f, 12i, 12b, and 12e showed 50% less cytotoxic effect than ciprofloxacin against mammalian cell lines.

Dilmaghani and co-workers studied the glycosylation of 1,2,4-triazole-5-thiones using per-acetylated β-pyranosyl bromides in the presence of K₂CO₃ (Scheme [4]).[13] Initially, d-galactosyl bromide 13 and d-glucosyl bromide 14 were synthesized. Subsequently, 1,2,4-triazole-5(4H)-thiones 15a–f were prepared and reacted with 13 and 14 to produce target glycosylated derivatives 16a–f and 17a–f. The synthesized compounds exhibited varying inhibitory zones against different strains of yeast and bacteria. However, P. aeruginosa and E. coli (Gram-negative), as well as E. faecalis (Gram-positive), showed resistance to all tested compounds. Conjugates from 15, 16, and 17 series especially 15d, 15f, 16d–f, 17a, and 17f displayed strong antibacterial activity against A. calcoaceticus showing greater potency than standard antibiotics such as ampicillin and trimethoprim/sulfamethoxazole. On the other hand, S. aureus was resistant against all derivatives from the series 15, 16, and 17. C. tropicalis exhibited sensitivity towards series 15 except 15f. Among the three sets, series 16 demonstrated the highest antimicrobial activity. In particular, thioglycoside derivatives of 1,2,4-triazole-5-thiones of series 16 and 17 demonstrated superior efficacy against A. calcoaceticus compared to their parent 1,2,4-triazole-5-thiones 15a–f. This finding underscores the significance of glyco-conjugation in enhancing the antiproliferative activity of antibiotic agents, emphasizing its potential for advancing drug design and improving bioactivity. Structural analysis of these compounds revealed that their antibacterial activity against A. calcoaceticus was significantly enhanced when a 2-furyl or phenyl group replaced the m-nitrophenyl group (Ar), and when p-bromophenyl group substituted the phenyl group (Ar¹).

In 2014, Zhou and co-workers synthesized novel 1,2,3-triazoles derived from d-glucose incorporating various substituted phenyl rings.[14] The introduction of the glucose moiety enhanced water solubility and improved artificial receptor-guest interactions in molecular recognition. These advantages encouraged researchers to explore sugar-containing polyhydroxyl groups in drug design. Zhou and co-workers synthesized d-glucose-derived 1,2,3-triazoles 20–22 by firstly preparing aryl azides from commercially available arylamines using tert-butyl nitrite and NaN₃ in t-BuOH. Compound 19 was obtained by propargylation of methyl 4,6-O-benzylidene-α-d-glucopyranoside with propargyl bromide in anhydrous THF (Scheme [5]). Cycloaddition of 19 with aryl azides using CuSO₄ and sodium ascorbate in t-BuOH/H₂O at room temperature yielded 1,4-disubstituted triazoles 20a–k (78–97.4%). The 4,6-O-benzylidene groups were deprotected with 5% HCl, followed by solvent evaporation and petroleum ether washing, affording pure hydrochloride salts 21a–k and finally neutralization with 25% NH₄OH gave compounds 22a–k. The antimicrobial activity of these compounds was systematically evaluated against a range of pathogens, including S. aureus, E. coli, B. subtilis, B. proteus, P. aeruginosa, C. albicans, and A. fumigatus, with fluconazole and chloramphenicol as reference drugs. Among the synthesized derivatives, 22c featuring a chloro substituent at the meta-position displayed potential antibacterial activity against S. aureus with an MIC₅₀ value of 27.8 μM comparable to chloramphenicol. Moreover, 22f–h and 22k along with their corresponding hydrochloride salts, exhibited the most potent antimicrobial activity. These findings demonstrated the influence of benzene ring substituents on the antibacterial efficacy of glucose-derived 1,2,3-triazoles highlighting their potential as promising antibacterial agents.

Pal and co-workers focused on synthesizing a series of novel benzoxepine-1,2,3-triazole hybrids by reacting azides 23 with a range of terminal alkynes using click chemistry with excellent yields (Scheme [6]).[15] The synthesis involved the preparation of azides 23 starting from 3,4-dihydrobenzoxepin-5(2H)-ones by Vilsmeier–Haack–Arnold reaction to give 5-chloro-2,3-dihydrobenzoxepine-4-carbaldehydes that were then exposed to reduction and chlorination using SOCl₂ leading to 5-chloro-4-(chloromethyl)-2,3-dihydrobenzoxepines; these chlorinated derivatives were further reacted with KI and NaN₃ to furnish azides 23.[15] The terminal alkynes 24 were prepared by reacting propargyl bromide with various hydroxyl-containing substrates, including 8-hydroxyquinoline, 7-hydroxy-2H-chromen-2-one, 7-hydroxy-4-methyl-2H-chromen-2-one. The synthesized azides 23 were coupled with various terminal alkynes 24 resulting in benzoxepine-1,2,3-triazole hybrids 25 (Scheme [6]). The synthesized compounds were tested for their antibacterial properties against two Gram-positive bacteria S. aureus and Klebsiella species and two Gram-negative bacteria P. aeruginosa and E. coli. The antibiotic pefloxacin was used as a positive reference to determine the sensitivity of the microorganisms tested at a concentration of 0.04 mg/50 μL. The synthesized compounds were tested for their cytotoxicity against colon cancer cell line HCT15 and lung cancer cell line NCI-H226.

Narsaiah and co-workers combined the 1,2,3-triazole moiety and pyrido[2,3-d]pyrimidines to give a single scaffold, 29a–h and 30a–e, thus enhancing the properties of the synthesized derivatives (Scheme [7]).[16] Conjugated pyrido[2,3-d]pyrimidine hybrid molecules were thus used to create a unique series of 1,2,3-triazole-functionalized pyrimidine hybrid molecules linked with an O- or N-linker. The target compounds 29a–h and 30a–e were synthesized from 2-substituted 7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-ones 26a–d that were synthesized by a multistep route using 4-ethoxy-1,1,1-trifluorobut-3-en-2-one and ethyl 3-amino-3-ethoxyacrylate. Compounds 26a–d were then reacted with propargyl bromide in acetone and K₂CO₃ as a base to produce N-propargylated and O-propargylated derivatives 27a–d and 28c,d, respectively. These derivatives were then subjected to 1,3-dipolar cycloaddition reactions with various alkyl azides, 2-azido-N-substituted aryl acetamides, and substituted aryl azides in anhydrous tetrahydrofuran at room temperature catalyzed by CuI under Sharpless conditions to smoothly yield 1,4-disubstituted 1,2,3-triazole-functionalized pyridopyrimidines 29a–h and 30a–e (Scheme [7]). Further, these derivatives were evaluated using nocodazole as the standard against four human cancer cell lines: MDA MB 231 (breast cancer), PANC1 (pancreatic cancer), A549 (lung cancer), and HeLa (cervical cancer). All the synthesized molecules showed excellent activity but compounds 29d and 29h showed greater efficiency against PANC1 and A549. Structure versus activity analysis showed difference in activities when the C-2 carbon and the triazole ring were substituted. The triazole ring of compounds 29a and 30a has an amide (-CONH-) functional group which assists in hydrogen bonding and is expected to boost activity. Three Gram-negative bacteria E. coli, K. pneumoniae, and P. aeruginosa and three Gram-positive bacteria B. licheniformis, S. pneumoniae, and S. aureus were used to test antibacterial properties where, 29d showed excellent activity against all the strains and 30c was potent for all the Gram-positive strains.

Agarwal and co-workers focused on the synthesis of new 1,2,3-triazole-ciprofloxacin conjugates (Scheme [8]).[17] Starting with ciprofloxacin hydrochloride, free ciprofloxacin (31) was generated. Reaction of 31 with propargyl bromide in the presence of NaHCO₃ gave N-propargyl ciprofloxacin propargylic esters 32 that were subjected to a Cu-catalyzed azide-alkyne [3+2]-cycloaddition reaction with aryl azides to yield 1,2,3-triazole-ciprofloxacin conjugates 33a–r (Scheme [8]). Compounds 33h, 33j, and 33m containing electron-withdrawing groups, influenced the antibacterial activity against all Gram-negative and Gram-positive bacteria. Interestingly, 4-ethyl and 4-pentyl substitutions were unable to inhibit the bacterial activity. In light of this, it was postulated that C4 of the phenyl group plays a significant role in antimicrobial activities and is greatly impacted by strong electron-withdrawing groups. Compounds 33m and 33j were most potent against all examined pathogens. S. aureus and P. aeruginosa bacterial activity was inhibited by all synthesized derivatives, except molecules bearing electron-donating groups, than the parent medication ciprofloxacin. The hemolytic activity of all compounds showed 1–30% hemolysis. This suggests that the toxicity of these compounds to human blood cells is low.

Basavoju and co-workers synthesized novel triazole substituted pyrazolyl-methylenehydrazinyl-5-arylidenethiazolidinone derivatives 38a–n to 39a–l containing pyrazole scaffolds with various substitutions (Scheme [9]).[18] Starting from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde with 1,2,4-triazole (34a) or benzotriazole (34b) gave triazolyl-substituted pyrazoles 35a and 35b. Further, condensation of 35a and 35b with thiosemicarbazide in the presence of a catalytic amount of glacial acetic acid yielded 1-(pyrazolylmethylene)semicarbazides 36a and 36b. Refluxing 36a and 36b with ethyl chloroacetate gave thiazol-4(5H)-ones 37a and 37b that subsequently reacted with various substituted benzaldehydes in a Knoevenagel condensation in methanol with a catalytic amount of piperidine at reflux for 3–5 hours to yield 5-arylidene derivatives 38a–n and 39a–l (Scheme [9]). The produced derivatives were screened for in vitro antibacterial activity against both Gram-positive (B. subtilis, B. megaterium) and Gram-negative (E. coli, P. aeruginosa) bacteria using streptomycin as the standard reference drug. MCF-7 and HeLa cell lines were used for in vitro cytotoxic activity. The structure-activity relationship (SAR) analysis of the derivatives based on their zone of inhibition and cell growth inhibition, highlighting the influence of substitution on 5-benzylidene ring, revealed that compounds 38h, 38i, 38k, 39b, and 39h exhibited significant antibacterial activity, while compounds with electron-withdrawing groups 38i and 38k demonstrated strong efficacy against both bacterial strains. In contrast, compound 38c featuring a 4-chloro group, showed moderate activity. Compounds 38b and 39b containing an electron-releasing group (4-Me) displayed good activity compared to the other substitutions and the unsubstituted parent compounds. Regarding cytotoxicity, compounds 38c, 38l, and 38f showed effective inhibition of human breast cancer cell line MCF-7 whereas 38b and 38c inhibited the human cervical cancer cell line HeLa.

In 2018, we developed a sustainable and efficient method using copper(I) iodide nanoparticles (CuI-NPs) for synthesizing 1,4-disubstituted 1,2,3-triazole pharmacophores (Scheme [10]).[19] The key motivation behind this work was the need for selective and environmentally friendly methods for synthesizing bioactive molecules, particularly triazoles, which have significant pharmaceutical relevance. Cross-coupling reactions between alkynes and amines catalyzed by CuI nanoparticles were used to synthesize tertiary aminopropenoates. The protocol was applied to various terminal and internal alkynes along with aliphatic, cyclic, and heterocyclic amines to obtain the desired enamines. This methodology was further employed to synthesize a potent scaffold, 1,4-disubstituted 1,2,3-triazoles 42, using differently functionalized alkynes 40 and aryl azides 41 (Scheme [10]). The method demonstrated excellent compatibility with various functional groups, heteroatom-containing alkynes, and sterically hindered azides, resulting in a high yields of compounds 42a, 42b, and 42c. Moreover, the catalyst maintained its performance for up to six cycles, highlighting its durability and cost-effectiveness, making it a valuable tool for green and scalable synthetic methodologies.

Ma and co-workers reported the synthesis of 1H-1,2,3-triazole-containing 3-methoxybenzamide (3-MBA) analogues by isosteric replacement of the amide with 1H-1,2,3-triazoles leading to the identification of unexpected and potent antibacterial activity (Figure [3]).[20] The synthesis of a range of molecules by varying small polar substituents and other modifications resulted in a series of compounds containing triazoles (series A and C), non-fluorinated compounds (series B), and tetrazole (series D). Besides the above modifications, the heteroatoms were incorporated in the five-membered ring (series E1, F1, and G1) resulting in more compounds. Some triazole compounds were synthesized by nitromethane and p-TsOH-mediated cycloaddition using aldehydes via a two-step protocol. All the compounds corresponding to different series were tested against four Gram-positive and two Gram-negative strains. Among different series non-fluorinated series B, triazole analogues 44 were more potent. Interestingly, these compounds were more active than their amide and tetrazole analogues. Further, introducing a O-heteroatom to replace nitrogen in the triazole does not yield favorable results. This inactivity may be attributed to the absence of a polar N–H in the triazole group. Compounds bearing linear alkoxy group 44 were more active than those bearing branched one 45. Among various triazoles explored for the study, the compounds bearing alkoxy side chains were the most active which may be attributed to the limited space available at the binding site which may not be sufficient to accommodate rigid phenyl or heterocyclic side chains. A different mode of action is proposed for these molecules which opens new opportunities for further evaluation.

Series A, B, and F structures of the most potent compounds, i.e., 43, 44, 45, and 46, are shown in Figure [3].

Hurtado and co-workers focused on the synthesis of Co(II) and Cr(III) complexes with triazole-based ligands; the study also involved the synthesis of 3,5-bis(1,2,4-triazol-1-ylmethyl)toluene (49) as a ligand (Scheme [11]).[21] The synthesis of ligand 49 was facilitated by phase-transfer catalysis, thus reaction of 1,3-bis(bromomethyl)toluene with 1H-1,2,4-triazole under an inert atmosphere (nitrogen) using anhydrous toluene and TBAB at 85 °C for 48 h gave 3,5-bis(1,2,4-triazol-1-ylmethyl)toluene (49) in 67% yield. Six complexes were synthesized by a standardized procedure, wherein the ligand solution of 49, 1,3-bis(1,2,4-triazol-1-ylmethyl)benzene, or 2,6-bis(1,2,4-triazol-1-ylmethyl)pyridine in acetone was reacted with a cobalt or chromium salt solution in acetone. The biological evaluation of the synthesized compounds illustrates that complexes 49a, 49b, and 49c exhibit potent antibacterial activity against C. tropicalis. Furthermore, antifungal assays revealed that the compounds were effective against at least one strain with moderate MIC values in comparison to reference drug amphotericin B. The synthesized chromium complex shows better antifungal activity than cobalt complexes due to azoles. Some complexes of Co(II) and Cr(III) functioned as electrolytes due to chloride as counterions. From infrared spectroscopy, a band shift relative to free ligands is observed. The biological activity of the ligand and the complexes were evaluated against all the strains in three replicates. No antimicrobial activity was found on combination of ligand and metal salts. Through broth microdilution method (MIC; μg mL^–1) and colorimetric method (CC₅₀; μg mL^–1) the antibacterial, antifungal, and cytotoxic activities were calculated.

Dwivedi and co-workers focused on developing new hybrid molecules containing bioactive pharmacophores (Scheme [12]).[22] The synthesis of 1,2,4-triazole condensed azetidine derivatives 56a–j began with the reaction of ibuprofen (50) with ethanol to form ethyl ester 51, followed by treatment with hydrazine hydrate to obtain carbohydrazide 52. Treatment of the carbohydrazide 52 with CS₂ in a basic medium gave carbothioamides 53 that were cyclized with hydrazine hydrate to give 4-amino-1,2,4-triazole-5-thione 54. Subsequent refluxing of 54 with various substituted aldehydes under acidic conditions resulted in the benzylidene derivatives 55a–j. Finally, the reaction of 55a–j with chloroacetyl chloride yielded the 3-chloroazetidin-2-ones 56a–j. The antibacterial assay performed showed that compound 56c has greater antibacterial activity against both Gram-positive and Gram-negative bacteria using cefotaxime as reference standard. The broad range of antibacterial properties of 56e are primarily attributed to its high electron density on the triazole nucleus and phenyl-substituted azetidine ring. Thus, the capacity of the molecule to fight bacteria is enhanced by inserting an azetidine nucleus. The strong antibacterial activity of 56c was confirmed by fluorescence spectral studies against two bacterial strains, P. aeruginosa and S. aureus. Furthermore, molecular docking studies were performed on the derived compounds against the protein DNA gyrase (Protein Data Bank ID: 3U2D). The results indicated that amino acid 257HIS played a crucial role in binding of the most active compounds. Good docking values and molecular interaction were exhibited by 56c, 56d, and 56e. The noteworthy observation was that while all the compounds shared a similar core structure, their binding site and interactions with the target enzymatic protein exhibited slight variations. Compounds 56c and 56e containing chloro and bromo groups at the para position had docking scores of –12.04 kcal mol^–1 and –11.75 kcal mol^–1, respectively, thus displaying a better docking score than 56d with a bromo group in the ortho position. According to the drug-likelihood analysis, 56c and 56d successfully met Lipinski’s rule of five (Ro5), highlighting their potential as drug candidates for bacterial therapy.

Lv and co-workers developed a new framework using the ester group as a linker and pyrazole as a primer, incorporating a triazole moiety.[23] A series of novel triazole-containing pyrazole ester derivatives 60 were synthesized following the synthetic route in Scheme [13]. Initially, a substituted phenylhydrazine was dissolved in ethanol and ethyl acetoacetate was added to give a 1-arylpyrazol-5(4H)-one. Vilsmeier–Haack reaction of 1-arylpyrazol-5(4H)-ones gave 1-aryl-5-chloropyrazol-4-carbaldehydes 57a–d. Subsequent oxidation of carbaldehydes 57a–d with potassium permanganate gave the carboxylic acids 58a–d. 1-Aryl-1,2,4-triazol-3-ols 59a–d were obtained through the reaction of phenylhydrazine hydrochloride and urea under acidic conditions using formic acid. The final target compounds 60a–m were obtained by reacting 58a–d and 59a–d. The biological evaluation of the target derivatives revealed that 60d exhibited significant antibacterial properties against S. gallinarum, E. coli, L. monocytogenes, and S. aureus in comparison to standard ciprofloxacin. The SAR analysis indicated that electron-donating substituents at the R¹ and R² positions enhanced antibacterial potency, whereas electron-withdrawing groups decreased the activity. Additionally, 60d also showed the most potent inhibitory activity against topoisomerase II and topoisomerase IV. Further, molecular docking studies supported its potential as a possible topoisomerase II inhibitor, highlighting its promise as a lead compound for antibacterial drug development.

In a study focusing on the production of novel triazole hybrids incorporating semicarbazone moieties and evaluating their in vitro antioxidant and antimicrobial potency,[24] Aouadi and co-workers successfully synthesized 4-(1,2,3-triazol-4-ylmethoxy)benzaldehydes 63a–f, which were subsequently converted into heterocyclic semicarbazone derivatives 64a–f via single-step condensation using NaOAc and commercially available semicarbazide hydrochloride in ethanol (Scheme [14]). The antioxidant potential of the synthesized 1-[4-(1,2,3-triazol-4-ylmethoxy)benzylidene] semicarbazides 64 was assessed through multiple assays, including the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay using reference standard BHT (butylhydroxytoluene), ABTS (2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) free radical assay using positive control trolox, and ferric reducing power assay using ascorbic acid as a standard. Among all the tested compounds, 64c and 64e exhibited significant antioxidant efficacy across all the assays. Further, in vitro antimicrobial and antifungal evaluations demonstrated that 64c exhibited the highest antifungal activity against F. oxysporum. While 64c and 64e displayed potent antibacterial effects against S. entertidis, M. luteus, S. aureus, and B. cereus. It was seen that the synthesized compounds were bacteriostatic and fungistatic when their MIC values were less than those of their MBC and minimum fungicidal concentration (MFC) values. Also, the compounds were categorized as bactericidal and fungicidal, when the MBC/MIC and MFC/MIC ratio was ≤ 2.0. Structure-property-activity relationship (SPARs) analysis suggested that the biological activity of these molecules was influenced by the presence of the 1,2,3-triazole moiety and its various substituents. Notably, the incorporation of 2-methyl groups at the ortho-position of the aromatic ring enhanced the activity likely due to hyperconjugative stabilization in compound 64c. Additionally, the lipophilicity values of synthesized derivatives were all below 5 suggesting their good oral bioavailability.

Building on the broad biological applications of triazole and isoxazole scaffolds, Azam, Abid, and co-workers synthesized novel antibacterial agents in the form of isoxazole-triazole conjugates via click chemistry and explored their biological activity (Scheme [15]).[25] Several novel isoxazole-1,2,3-triazole conjugates 72a–q were synthesized successfully. The synthetic route began with the oxalylation of commercially available precursor 4-chloroacetophenone (65) with diethyl oxalate (66) in the presence of sodium ethoxide to give ethyl 4-(4-chlorophenyl)-2-hydroxy-4-oxobut-2-enoate (67) that was subsequently subjected to a [3+2] cyclocondensation reaction with hydroxylamine hydrochloride in ethanol to afford ethyl isoxazole-3-carboxylate 68, which was then converted into the corresponding acid 69. Further propargylation of 69 in acetonitrile yielded propargyl isoxazole-3-carboxylate 70. Finally, the target compounds 72a–q were obtained in high to excellent yields via Cu(I)-catalyzed [3+2] cycloaddition reaction between azide 71a–q and the propargyl isoxazole-3-carboxylate 70 (Scheme [15]). Antimicrobial screening of these conjugates was evaluated against two Gram-positive (S. pneumoniae, E. faecalis) and four Gram-negative strains (P. aeruginosa, S. typhimurium, K. pneumoniae, E. coli). The activity varied based on substitutions on the phenyl ring, with compounds 72a–b, 72d–f, 72m, 72o, and 72q exhibiting moderate to significant activity against the bacterial strains. Compound 72b displayed enhanced inhibitory activity against P. aeruginosa, S. typhimurium, S. pneumoniae, and E. coli as indicated in its IC₅₀ values (Scheme [15]). Notably, compound 72e selectively inhibited K. pneumoniae, P. aeruginosa, and S. pneumoniae due to the presence of a fluorine substituent at the para position whereas, chlorine substitution at the meta-position in 72m conferred broad-spectrum antibacterial activity. Importantly, 72b and 72m exhibited no cytotoxicity against human HEK293 cells even at higher concentrations. Given the critical role of biofilm formation in bacterial pathogenicity, the ability of the synthesized compounds to inhibit biofilm production was assessed using XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) semi-quantitative reduction assay. The results revealed that 72m significantly inhibited biofilm formation in S. pneumoniae and E. faecalis. Multi-spectroscopic techniques and molecular docking studies further demonstrated that 72m intercalates within the minor groove of bacterial DNA, suggesting a possible mechanism of action for its antibacterial activity.

Our group constantly strives to develop protocols for new molecules using the click chemistry approach. Our study employed CuI nanoparticles as a catalyst in a solvent mixture of MeCN/H₂O at 70 °C, facilitating the conjugation of ciprofloxacin methyl ester and other complex small molecules via triazole formation (Scheme [16]).[26] Various synthesized N-propargyl ciprofloxacin reacted with azides using this protocol to give a range of substituted 1,2,3-triazoles (a-i). The substrate scope of the 1,4-disubstituted 1,2,3-triazoles was explored yielding excellent results. Phenylacetylene derivatives with electron-withdrawing groups had superior activity. Additionally, 1,3-diethynylbenzene selectively yielded either mono- or disubstituted products. Alkynes bearing different functional groups including electron-withdrawing and electron-donating groups, halogen, and hydroxy groups were well tolerated. Notably, alkynes bearing both aliphatic and aromatic heteroatom and bulky groups, were efficiently converted into the desired bioactive heterocyclic molecules. Further, we synthesized triazoles derived from natural products, like vasicinone and tocopherol, and drug molecules, like paracetamol and aspirin, through their reaction with benzyl azide producing the corresponding products in higher yields. Additionally, the reaction of these alkynes with ciprofloxacin methyl ester produces the desired products. However, modification to ciprofloxacin resulted no significant improvement in antibacterial activity. The study explored the range of functionalized triazoles from amino acid derived azides with ciprofloxacin-based alkynes. Subsequent methyl ester hydrolysis yielded dicarboxylic acid derivatives. The antibacterial activity of the synthesized compound was evaluated against ESKAPE pathogens. The conjugates of a triazole with aromatic moieties showed an irrelevant effect on antibacterial activity, while heterocyclic systems also showed no significant impact on antibacterial properties. However, amino acid conjugates showed a better antibacterial efficiency, and after hydrolysis of amino acid the activity improved more. The MIC values of these compounds were ≤ 8 μg mL^–1 against at least one bacterial strain. From the study it was found that most compounds showed no hemolysis at 100 μg mL^–1 concentration, except compound bh which showed hemolysis by 14%. 50% of compounds showed better safety index than ciprofloxacin was found in mammalian toxicity studies.

Kantevari and co-workers synthesized usnic acid enaminone conjugated triazoles through click chemistry (Scheme [17]).[27] Firstly, reaction of (+)-usnic acid with propargylamine in absolute ethanol and triethylamine at 85 °C resulting in N-propargyl usnic acid enaminone 74. The required azides were synthesized through three different methods. Aryl azides 75(1–26) were prepared via α-bromination of aryl methyl ketones, followed by nucleophilic substitution with sodium azide. Secondly, saccharin-based azide 75(27) was synthesized by reacting saccharin sodium salt with 1,2-dibromoethane in DMF through nucleophilic substitution reaction followed by azide substitution. Whereas N-substituted piperazines azides 75(28–35) were synthesized through N-acylation, azidation and in some cases additional bromination step to enhance reactivity. The desired product was synthesized through click chemistry by reacting the compound 74 with the previously generated range of azides in t-BuOH/H₂O (1:1) with sodium l-ascorbate as a catalyst yielding triazole derivatives 76–110 in good yields (Scheme [17]). The structure-activity relationships (SAR) were analyzed for the compounds 76–110 against Mtb H37Rv. Compound 102 with an O-sulfobenzimidinyl group (saccharin) was active with a MIC value of 2.5 μM. Product 82 and 93 showed significant antitubercular activity with MIC values of 5.4 μM and 5.3 μM, respectively. The compound 82 showed higher antimicrobial activity compared to other products (Scheme [17]). The antibacterial activity of the synthesized compounds was also tested against Gram-positive and Gram-negative bacterial strains, using the agar well diffusion method and broth microdilution assay. Compounds 84 and 94 demonstrate higher antibacterial activity against B. subtilis with MIC values of 41 and 90.7 μM. Compound 102 emerged as the most potent antitubercular agent with 2.8-fold bacterial reduction.

Nagaraj and co-workers synthesized a heterocyclic hybrid of isoxazole and triazole and studied their antibacterial activity using the broth dilution method (Scheme [18]).[28] The synthesis began with the preparation of an intermediate 1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethan-1-one (113), which was obtained from the reaction between phenyl azide (111) and acetylacetone (112). Further, condensation of 113 in a solution of ethanol with aryl aldehyde, and potassium hydroxide at 5–10 °C yielded 114a–h. Subsequently, compound 114 was dissolved in ethanol and reacted with hydroxylamine hydrochloride and sodium acetate in acetic acid, which was then refluxed, neutralized with NaOH, and extracted with ether to give a crude product that was purified to obtain the final 115a–h (Scheme [18]). The antibacterial activity of compounds 115a–h was studied against Gram-positive bacteria B. subtilis, S. aureus, and M. luteus and Gram-negative bacteria, P. vulgaris, S. typhimurium, and E. coli. The result demonstrated that compounds 115b and 115c showed equal antibacterial activity against Gram-positive bacteria compared to the reference drug ampicillin.

Since the outbreak of COVID-19, the search for efficient antivirals and antibacterial treatments has gained the attention of medicinal chemists, especially fluoroquinolones due to their wide-range applications.[29] In silico molecular docking analysis demonstrated that ciprofloxacin and moxifloxacin can effectively interact with the primary protease of COVID-19. Structural modifications at the C-7 position were found to significantly influence the pharmacokinetic properties, molecular permeability, and target enzyme interactions, particularly with DNA gyrase. In this study, Sidorenko and co-workers synthesized new 1,2,3-triazole-substituted derivatives of the fluoroquinolone group of ciprofloxacin and norfloxacin in vitro and evaluated their interactions through molecular docking analysis. Reaction of nitrile 116 and phenyl azide 117 with sodium methoxide as a catalyst gave target compounds 118a,b and 119c–119k in 37–68% yield (Scheme [19]). Molecular docking analysis revealed negative scoring function values, confirming the thermodynamic binding probability of the hybrid complexes. After evaluation of the antimicrobial activity of the synthesized compounds against bacterial and fungal strains: S. aureus (ATCC25923), E. coli (ATCC25922), B. subtilis (ATCC6633), P. aeruginosa (ATCC27853), and C. albicans (NCTC885-653), 119c emerged as the most potent antibacterial agent.

Abdel-Latif and co-workers synthesized benzothiazolopyridine and its derivatives by reacting benzothiazol-2-ylacetonitrile (120) with 4-chlorobenzaldehyde to give 2-(benzothiazol-2-yl)-3-(4-chlorophenyl)acrylonitrile which served as a key precursor for further modifications (not shown).[30] Modifications occurred via Michael addition between the active methylene CH₂ group of indanedione and an induced double bond in 2-(benzothiazol-2-yl)-3-(4-chlorophenyl)acrylonitrile, resulting in an imine Michael adducts intermediate. This intermediate underwent further conversion into an enamine, which on intermolecular cyclocondensation affords the benzothiazolopyridine derivative. Additional derivatives were synthesized through a similar procedure by substituting indanedione with thiobarbituric acid, malononitrile, or phenyl isothiocyanate leading to fused benzothiazolopyridine derivatives. Reaction of benzothiazol-2-ylacetonitrile (120) with 4-chlorobenzenediazonium chloride gave a benzotriazolyl(cyano)methylene)hydrazine 121 that was treated with hydrazine hydrate to give triazolyl-benzothiazole 122 (Scheme [20]). Attempts to synthesize pyrimidine-containing compounds from triazolyl-benzothiazole 122 using ethyl cyanoacetate in glacial acetic acid did not give the desired compound, but instead gave bis(benzothiazolyl-triazolyl)amine 123. The reaction of phthalic anhydride with benzothiazolyl-triazole derivative 122 with phthalic acid gave a 4-phthalimido derivative (not shown) while reaction with 2-cyano-2-(3,5-dimethylpyrazol-1-yl)acetamide resulted in cyanoacetylation to give 124. Further reaction of cyanoacetamide derivative 124 with 4-anisaldehyde or phenyl isothiocyanate resulted acrylamide derivatives 125 and 126, respectively. On reaction of compound 126 with phenacyl bromide the thiophene was not formed and instead a triazolopyrimidine 127 was formed. The mass spectrometric analysis reveals a molecular ion peak at m/z 530 which is identical to molecular weight of compound 126 confirming that phenacyl bromide was not involved in the reaction. The biological activities were observed in the order of 125 > ascorbic acid > 124 for their antioxidant potential using DPPH colorimetric assay. The compounds were tested against two Gram-positive bacteria B. cereus and S. aureus and two Gram-negative bacteria P. aeruginosa and E. coli using the agar well diffusion assay. The compounds showed no antibacterial properties against Gram-negative bacteria. Among the synthesized compounds, 125 showed the most potent antibacterial activity against Gram-positive bacteria. The antioxidant result might be reversed through (SARs). The mode of action and structure of the researched product were confirmed by spectral data.

In 2023, Al-Taweel and co-workers reported the synthesis of six novel ciprofloxacin-1,2,3-triazole hybrids by reacting ciprofloxacin derivatives with various aryl azides via a 1,3-dipolar cycloaddition (Scheme [21]).[31] This synthetic protocol was metal- and alkyne-free, utilizing anhydrous K₂CO₃ to circumvent copper ion toxicity. The reaction between ciprofloxacin derivative 128 and organic azide 129 in dry DMSO with dry K₂CO₃ as a base gave ciprofloxacin-1,2,3-triazole hybrids 130a–f via an enolate-click reaction. A mechanism was proposed (Scheme [22]), where the enolate 131 is initially produced by the reaction of carbonate, a base, and a β-keto amide. Next, [3+2] enolate-azide cycloaddition gives triazoline 132 that undergoes rapid elimination of water leading to 133. The antitumor screening was conducted using the human lung carcinoma cell line (A549), human glioblastoma (U-87 MG), human dermal fibroblast (HDF, human dermal cell line), and breast cancer (MCF7) cell line. Among the tested compounds, hybrids 130a and 130b exhibited significant antiproliferative activity. Additionally, these compounds demonstrated the ability to neutralize DPPH and ABTS radicals. The antibacterial assay revealed weak to moderate antibacterial activity, which was influenced by the electronic effect of the substituents on phenyl triazole-ciprofloxacin hybrids. Notably, the para-substituted phenyl-triazole derivative exhibited broad-spectrum antibacterial activity, with selectivity towards Gram-positive bacteria, including S. aureus (ATCC 10145), B. cereus (ATCC 11778), and B. subtilis (ATCC 6633) (Scheme [21]).

Sustainable precursors and substrates play an important role in developing environmentally friendly approaches for organic transformations. Jannet, Othman, and co-workers synthesized novel oleanolic acid-phthalimidine conjugates that contained a 1,2,3-triazole framework within the structure (Scheme [23]).[32] The synthesis began with the preparation of key precursors. Initially, an azidoacetyl derivative of the triterpene oleanolic acid was synthesized. Various N-propargylated isoindolinones and phthalimidines were prepared. The treatment of azidoacetyl derivative 134 with propargylated phthalimidines of isoindolinones derivatives through Cu(I)-catalyzed azide-alkyne Huisgen 1,3-cycloaddition led to the formation of 1,2,3-triazole conjugates 135 (Scheme [23]). The non-selective cycloaddition led to the successful formation of the compound in good yield. The presence of hydroxy, acetoxy, and sulfonyl groups in the synthesized molecules had an enhancing effect on the antibacterial activity of the molecule. The antibacterial activity of newly synthesized compounds was evaluated against two Gram-positive and two Gram-negative bacteria using tetracycline and chlorhexidine as standard references. Oleanolic acid was active against S. aureus, S. typhimurium, and P. aeruginosa but inactive against L. monocytogenes. 135m exhibited the highest antibacterial activity with 135h exhibiting significant potency due to the presence of hydroxyl functional groups. Additionally, 135d, 135g, and 135h showed good antibacterial activity. Through molecular docking studies it was found that binding of substrate and protein was through hydrogen bonding and hydrophobic interaction. Furthermore, the quantitative structure-activity relationship (QSAR) model justifies the good binding score and the antibacterial activities of the synthesized compounds.

Veerapur, Netravati, and Basavaraja synthesized novel benzofuran-1,2,4-triazole hybrids starting from 5-nitrosalicylaldehyde (136) which underwent condensation with phenacyl bromide under the optimized conditions to give 2-benzoyl-5-nitrobenzofuran-3-amine (137). This intermediate served as a precursor for the synthesis of the 1,2,4-triazole scaffold (Scheme [24]).[33] 2-Benzoyl-5-nitrobenzofuran-3-amine (137) was reacted with acetyl chloride and benzoyl chloride to give 138a and 138b, respectively. These intermediates were then reacted with hydrazine hydrate in absolute ethanol to produce 139a,b. The desired molecules 140a,b were synthesized by refluxing 139a,b with formic acid (Scheme [24]). The antibacterial, antifungal and antimicrobial activity of the synthesized compounds 138–140a,b was evaluated in comparison to penicillin and streptomycin; they showed excellent antibacterial activity against S. aureus, S. epidermidis, E. coli, and P. aeruginosa. In comparison to griseofulvin, 138–140a,b showed significant antifungal activity against C. albicans and A. niger. Additionally, molecular docking studies were conducted to investigate the antimicrobial activity of 138–140a,b (Scheme [24]). The analysis revealed that these compounds, having inhibitory properties, displayed interactions with amino acids in active pockets within the lutamine amide transferees domains, justifying their activity as antimicrobial agents.

Agarwal and co-workers employed click chemistry to synthesize the triazole derivatives of ciprofloxacin, specially modifying the C-3 carboxylic group (Scheme [25]).[34] Firstly they freed ciprofloxacin from ciprofloxacin hydrochloride using 5% aqueous solution of NaHCO₃. Subsequently, the amine functionality of the piperazine ring was selectively protected using Boc-anhydride, acyl chloride, or benzoyl chloride and then these intermediates were reacted with propargyl bromide at 100 °C in the presence of NaHCO₃ resulting in propargylated products 144, 145, and 146 (Scheme [25]). The final triazole-containing compounds were synthesized through copper-catalyzed [3+2]-cycloaddition reactions between the propargylated products (alkynes) 144, 145, and 146 with a range of substituted aromatic azides 147a–f which led to the formation of triazole-linked ciprofloxacin analogues. Additionally, compounds 144 and 148a–f underwent deprotection after dissolving them in a mixture of dichloromethane and trifluoroacetic acid resulting in the deprotected compounds 149a–f. The antibacterial activity of the synthesized compound was assessed against Gram-positive and Gram-negative bacterial strains. The compound 145 with acetyl group demonstrated MICs of 6.25 and 0.391 μg mL^–1 against S. aureus and E. coli, 146 having a benzoyl group showed MIC of 12.5 μg mL^–1 against A. baumannii, 149b with the 4-bromophenyl group displayed high binding efficiency against S. aureus and E. coli with MIC of 0.391 and 0.195 μg mL^–1, 149c with 4-chlorophenyl was found effective against S. aureus and A. baumannii with MIC value of 1.56 and 12.5 μg mL^–1, 149d with 3-chlorophenyl group exhibited MIC of 0.391 μg mL^–1 against S. aureus and MIC of 0.781 μg mL^–1 against P. aeruginosa, and lastly, 149e with a 4-(trifluoromethoxy)phenyl group with MIC of 6.25 μg mL^–1 against S. aureus. Some compounds did not show any activity. The inhibition of DNA gyrase was studied using in silico docking studies and in vitro assays on several ciprofloxacin-linked 1,2,3-triazole compounds and found 149, 149a, 149b, 149c, and 151e to be the most potent inhibitors of DNA gyrase, suggesting future developments in the defense against upcoming antibiotic resistance.

Conclusion

Antimicrobial resistance (AR) against current antibiotics is a growing concern and needs to be addressed urgently. Several strategies are employed to tackle the problem. The development of new small molecules and drug conjugates is among those strategies. Huisgen 1,3-dipolar cycloaddition of azides and alkynes through a click reaction is one of the powerful strategies to develop small molecules and drug conjugates by varying coupling partners. In this account, several approaches utilizing click reaction for the synthesis of a range of new chemical entities (NCEs) are discussed. The various synthesized molecules were evaluated for Gram-negative and Gram-positive pathogens to obtain next-generation therapeutic molecules.

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1a Murray CJ. L, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, Han C, Bisignano C, Rao P, Wool E. Lancet 2022; 399: 629
  CrossrefPubMedSearch in Google Scholar
• 1b Miethke M, Pieroni M, Weber T, Brönstrup M, Hammann P, Halby L, Arimondo PB, Glaser P, Aigle B, Bode HB. Nat. Rev. Chem. 2021; 5: 726
  PubMedSearch in Google Scholar
• 1c Koya SF, Ganesh S, Selvaraj S, Wirtz VJ, Galea S, Rockers PC. Lancet Reg. Health - Southeast Asia 2022; 4: 100025
  PubMedSearch in Google Scholar
• 1d Hsu J. BMJ 2020; 369: m1983
  PubMedSearch in Google Scholar
• 2 Sharma PC, Jain A, Jain S. Acta Pol. Pharm. 2009; 66: 587
  PubMedSearch in Google Scholar
• 3 Tse-Dinh YC. Infect. Disord.: Drug Targets 2007; 7: 3
  PubMedSearch in Google Scholar
• 4a Chu DT, Fernandes PB. Antimicrob. Agents Chemother. 1989; 33: 131
  PubMedSearch in Google Scholar
• 4b Tian G, Song Q, Liu Z, Guo J, Cao S, Long S. Eur. J. Med. Chem. 2023; 259: 115603
  PubMedSearch in Google Scholar
• 5 Maurya SK, Gollapalli DR, Kirubakaran S, Zhang M, Johnson CR, Benjamin NN, Hedstrom L, Cuny GD. J. Med. Chem. 2009; 52: 4623
  PubMedSearch in Google Scholar
• 6 Guan Q, Xing S, Wang L, Zhu J, Guo C, Xu C, Zhao Q, Wu Y, Chen Y, Sun H. J. Med. Chem. 2024; 67: 7788
  PubMedSearch in Google Scholar
• 7 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2569
  Search in Google Scholar
• 8 Meanwell NA. J. Med. Chem. 2011; 54: 2529
  CrossrefPubMedSearch in Google Scholar
• 9a Maurya SK, Rana R. Beilstein J. Org. Chem. 2017; 13: 1106
  CrossrefPubMedSearch in Google Scholar
• 9b Kumar R, Pathania V, Kumar S, Kumar M, Nandanwar H, Maurya SK. Bioorg. Med. Chem. Lett. 2023; 88: 129308
  PubMedSearch in Google Scholar
• 10 Özil M, Menteşe E, Yılmaz F, İslamoğlu F, Kahveci B. J. Chem. Res. 2011; 35: 268
  Search in Google Scholar
• 11 Wang Y, Damu GL. V, Lv J.-S, Geng R.-X, Yang D.-C, Zhou C.-H. Bioorg. Med. Chem. Lett. 2012; 22: 5363
  PubMedSearch in Google Scholar
• 12 Kamal A, Hussaini SM, Faazil S, Poornachandra Y, Narender Reddy G, Kumar CG, Rajput VS, Rani C, Sharma R, Khan IA. Bioorg. Med. Chem. Lett. 2013; 23: 6842
  PubMedSearch in Google Scholar
• 13 Dilmaghani KA, Pur FN, Jazani NH, Alavi A, Niknam Z, Mirfakhraee F. Phosphorus, Sulfur, Silicon Relat. Elem. 2013; 189: 81
  Search in Google Scholar
• 14 Zhang H.-Z, Wei J.-J, Vijaya Kumar K, Rasheed S, Zhou C.-H. Med. Chem. Res. 2014; 24: 182
  Search in Google Scholar
• 15 Kuntala N, Telu JR, Banothu V, Nallapati SB, Anireddy JS, Pal S. MedChemComm 2015; 6: 1612
  CrossrefSearch in Google Scholar
• 16 Naresh Kumar R, Jitender Dev G, Ravikumar N, Krishna Swaroop D, Debanjan B, Bharath G, Narsaiah B, Nishant Jain S, Gangagni Rao A. Bioorg. Med. Chem. Lett. 2016; 26: 2927
  PubMedSearch in Google Scholar
• 17 Kant R, Singh V, Nath G, Awasthi SK, Agarwal A. Eur. J. Med. Chem. 2016; 124: 218
  PubMedSearch in Google Scholar
• 18 Pogaku V, Eslavath RK, Dayakar G, Singh SS, Basavoju S. Res. Chem. Intermed. 2017; 43: 6079
  Search in Google Scholar
• 19 Nayal OS, Thakur MS, Kumar M, Shaifali, Upadhyay R, Maurya SK. Asian J. Org. Chem. 2018; 7: 776
  Search in Google Scholar
• 20 Bi F, Ji S, Venter H, Liu J, Semple SJ, Ma S. Bioorg. Med. Chem. Lett. 2018; 28: 884
  PubMedSearch in Google Scholar
• 21 Murcia RA, Leal SM, Roa MV, Nagles E, Muñoz-Castro A, Hurtado JJ. Molecules 2018; 23: 2013
  PubMedSearch in Google Scholar
• 22 Dhall E, Jain S, Mishra A, Dwivedi J, Sharma S. J. Heterocycl. Chem. 2018; 55: 2859
  Search in Google Scholar
• 23 Chu MJ, Wang W, Ren ZL, Liu H, Cheng X, Mo K, Wang L, Tang F, Lv XH. Molecules 2019; 24: 1311
  PubMedSearch in Google Scholar
• 24 Brahmi J, Bakari S, Nasri S, Nasri H, Kadri A, Aouadi K. Mol. Biol. Rep. 2019; 46: 679
  PubMedSearch in Google Scholar
• 25 Habib F, Alam S, Hussain A, Aneja B, Irfan M, Alajmi MF, Hasan P, Khan P, Rehman MT, Noman OM, Azam A, Abid M. J. Mol. Struct. 2020; 1201: 127144
  CrossrefSearch in Google Scholar
• 26 Upadhyay R, Kumar R, Jangra M, Rana R, Nayal OS, Nandanwar H, Maurya SK. ACS Comb. Sci. 2020; 22: 440
  PubMedSearch in Google Scholar
• 27 Bangalore PK, Vagolu SK, Bollikanda RK, Veeragoni DK, Choudante PC, Misra S, Sriram D, Sridhar B, Kantevari S. J. Nat. Prod. 2020; 83: 26
  PubMedSearch in Google Scholar
• 28 Nagaraj A, Rana N, Aparna M, Raghaveer S. J. Adv. Sci. Res. 2021; 12: 149
  Search in Google Scholar
• 29 Hryhoriv H, Mariutsa I, Kovalenko SM, Georgiyants V, Perekhoda L, Filimonova N, Geyderikh O, Sidorenko L. Sci. Pharm. 2021; 90: 2
  Search in Google Scholar
• 30 Arafat M, Abdel-Latif E, El-Taweel FM, Ayyad S.-EN, Mohamed KS. Bull. Chem. Soc. Ethiop. 2022; 36: 451
  Search in Google Scholar
• 31 Al-Taweel S, Al-Saraireh Y, Al-Trawneh S, Alshahateet S, Al-Tarawneh R, Ayed N, Alkhojah M, Al-Khaboori W, Zereini W, Al-Qaralleh O. Heliyon 2023; 9: e22592
  PubMedSearch in Google Scholar
• 32 Lahmadi G, Horchani M, Dbeibia A, Mahdhi A, Romdhane A, Lawson MA, Daïch A, Harrath HA, Jannet BH, Othman M. Molecules 2023; 28: 4655
  PubMedSearch in Google Scholar
• 33 Veerapur SB, Netravati NL, Basavaraja KM. Res. J. Chem. Environ. 2023; 27 (03) 20
  Search in Google Scholar
• 34 Patel UK, Tiwari P, Tilak R, Joshi G, Kumar R, Agarwal A. RSC Adv. 2024; 14: 17051
  PubMedSearch in Google Scholar

Corresponding Author

Publication History

Received: 08 December 2024

Accepted after revision: 27 February 2025

Article published online:
23 April 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

• References

• 1a Murray CJ. L, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, Han C, Bisignano C, Rao P, Wool E. Lancet 2022; 399: 629
  CrossrefPubMedSearch in Google Scholar
• 1b Miethke M, Pieroni M, Weber T, Brönstrup M, Hammann P, Halby L, Arimondo PB, Glaser P, Aigle B, Bode HB. Nat. Rev. Chem. 2021; 5: 726
  PubMedSearch in Google Scholar
• 1c Koya SF, Ganesh S, Selvaraj S, Wirtz VJ, Galea S, Rockers PC. Lancet Reg. Health - Southeast Asia 2022; 4: 100025
  PubMedSearch in Google Scholar
• 1d Hsu J. BMJ 2020; 369: m1983
  PubMedSearch in Google Scholar
• 2 Sharma PC, Jain A, Jain S. Acta Pol. Pharm. 2009; 66: 587
  PubMedSearch in Google Scholar
• 3 Tse-Dinh YC. Infect. Disord.: Drug Targets 2007; 7: 3
  PubMedSearch in Google Scholar
• 4a Chu DT, Fernandes PB. Antimicrob. Agents Chemother. 1989; 33: 131
  PubMedSearch in Google Scholar
• 4b Tian G, Song Q, Liu Z, Guo J, Cao S, Long S. Eur. J. Med. Chem. 2023; 259: 115603
  PubMedSearch in Google Scholar
• 5 Maurya SK, Gollapalli DR, Kirubakaran S, Zhang M, Johnson CR, Benjamin NN, Hedstrom L, Cuny GD. J. Med. Chem. 2009; 52: 4623
  PubMedSearch in Google Scholar
• 6 Guan Q, Xing S, Wang L, Zhu J, Guo C, Xu C, Zhao Q, Wu Y, Chen Y, Sun H. J. Med. Chem. 2024; 67: 7788
  PubMedSearch in Google Scholar
• 7 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2569
  Search in Google Scholar
• 8 Meanwell NA. J. Med. Chem. 2011; 54: 2529
  CrossrefPubMedSearch in Google Scholar
• 9a Maurya SK, Rana R. Beilstein J. Org. Chem. 2017; 13: 1106
  CrossrefPubMedSearch in Google Scholar
• 9b Kumar R, Pathania V, Kumar S, Kumar M, Nandanwar H, Maurya SK. Bioorg. Med. Chem. Lett. 2023; 88: 129308
  PubMedSearch in Google Scholar
• 10 Özil M, Menteşe E, Yılmaz F, İslamoğlu F, Kahveci B. J. Chem. Res. 2011; 35: 268
  Search in Google Scholar
• 11 Wang Y, Damu GL. V, Lv J.-S, Geng R.-X, Yang D.-C, Zhou C.-H. Bioorg. Med. Chem. Lett. 2012; 22: 5363
  PubMedSearch in Google Scholar
• 12 Kamal A, Hussaini SM, Faazil S, Poornachandra Y, Narender Reddy G, Kumar CG, Rajput VS, Rani C, Sharma R, Khan IA. Bioorg. Med. Chem. Lett. 2013; 23: 6842
  PubMedSearch in Google Scholar
• 13 Dilmaghani KA, Pur FN, Jazani NH, Alavi A, Niknam Z, Mirfakhraee F. Phosphorus, Sulfur, Silicon Relat. Elem. 2013; 189: 81
  Search in Google Scholar
• 14 Zhang H.-Z, Wei J.-J, Vijaya Kumar K, Rasheed S, Zhou C.-H. Med. Chem. Res. 2014; 24: 182
  Search in Google Scholar
• 15 Kuntala N, Telu JR, Banothu V, Nallapati SB, Anireddy JS, Pal S. MedChemComm 2015; 6: 1612
  CrossrefSearch in Google Scholar
• 16 Naresh Kumar R, Jitender Dev G, Ravikumar N, Krishna Swaroop D, Debanjan B, Bharath G, Narsaiah B, Nishant Jain S, Gangagni Rao A. Bioorg. Med. Chem. Lett. 2016; 26: 2927
  PubMedSearch in Google Scholar
• 17 Kant R, Singh V, Nath G, Awasthi SK, Agarwal A. Eur. J. Med. Chem. 2016; 124: 218
  PubMedSearch in Google Scholar
• 18 Pogaku V, Eslavath RK, Dayakar G, Singh SS, Basavoju S. Res. Chem. Intermed. 2017; 43: 6079
  Search in Google Scholar
• 19 Nayal OS, Thakur MS, Kumar M, Shaifali, Upadhyay R, Maurya SK. Asian J. Org. Chem. 2018; 7: 776
  Search in Google Scholar
• 20 Bi F, Ji S, Venter H, Liu J, Semple SJ, Ma S. Bioorg. Med. Chem. Lett. 2018; 28: 884
  PubMedSearch in Google Scholar
• 21 Murcia RA, Leal SM, Roa MV, Nagles E, Muñoz-Castro A, Hurtado JJ. Molecules 2018; 23: 2013
  PubMedSearch in Google Scholar
• 22 Dhall E, Jain S, Mishra A, Dwivedi J, Sharma S. J. Heterocycl. Chem. 2018; 55: 2859
  Search in Google Scholar
• 23 Chu MJ, Wang W, Ren ZL, Liu H, Cheng X, Mo K, Wang L, Tang F, Lv XH. Molecules 2019; 24: 1311
  PubMedSearch in Google Scholar
• 24 Brahmi J, Bakari S, Nasri S, Nasri H, Kadri A, Aouadi K. Mol. Biol. Rep. 2019; 46: 679
  PubMedSearch in Google Scholar
• 25 Habib F, Alam S, Hussain A, Aneja B, Irfan M, Alajmi MF, Hasan P, Khan P, Rehman MT, Noman OM, Azam A, Abid M. J. Mol. Struct. 2020; 1201: 127144
  CrossrefSearch in Google Scholar
• 26 Upadhyay R, Kumar R, Jangra M, Rana R, Nayal OS, Nandanwar H, Maurya SK. ACS Comb. Sci. 2020; 22: 440
  PubMedSearch in Google Scholar
• 27 Bangalore PK, Vagolu SK, Bollikanda RK, Veeragoni DK, Choudante PC, Misra S, Sriram D, Sridhar B, Kantevari S. J. Nat. Prod. 2020; 83: 26
  PubMedSearch in Google Scholar
• 28 Nagaraj A, Rana N, Aparna M, Raghaveer S. J. Adv. Sci. Res. 2021; 12: 149
  Search in Google Scholar
• 29 Hryhoriv H, Mariutsa I, Kovalenko SM, Georgiyants V, Perekhoda L, Filimonova N, Geyderikh O, Sidorenko L. Sci. Pharm. 2021; 90: 2
  Search in Google Scholar
• 30 Arafat M, Abdel-Latif E, El-Taweel FM, Ayyad S.-EN, Mohamed KS. Bull. Chem. Soc. Ethiop. 2022; 36: 451
  Search in Google Scholar
• 31 Al-Taweel S, Al-Saraireh Y, Al-Trawneh S, Alshahateet S, Al-Tarawneh R, Ayed N, Alkhojah M, Al-Khaboori W, Zereini W, Al-Qaralleh O. Heliyon 2023; 9: e22592
  PubMedSearch in Google Scholar
• 32 Lahmadi G, Horchani M, Dbeibia A, Mahdhi A, Romdhane A, Lawson MA, Daïch A, Harrath HA, Jannet BH, Othman M. Molecules 2023; 28: 4655
  PubMedSearch in Google Scholar
• 33 Veerapur SB, Netravati NL, Basavaraja KM. Res. J. Chem. Environ. 2023; 27 (03) 20
  Search in Google Scholar
• 34 Patel UK, Tiwari P, Tilak R, Joshi G, Kumar R, Agarwal A. RSC Adv. 2024; 14: 17051
  PubMedSearch in Google Scholar