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DOI: 10.1055/a-2535-1306
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Small Molecules in Medicinal Chemistry

Bioactive Molecules via Morita–Baylis–Hillman Chemistry

Ch. N. S. Sai Pavan Kumar
b   Department of Chemistry, School of Applied Science and Humanities, Vignan’s Foundation for Science, Technology and Research, Vadlamudi, Guntur 522213, Andhra Pradesh, India
c   Department of Chemistry, Vignan Degree & P.G. College, Palakaluru Road, Guntur 520 009, Andhra Pradesh, India
,
Vaidya Rao Jayathirtha
a   Organic Synthesis and Process Chemistry Department, AcSIR-Ghaziabad, CSIR-Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad – 500007, Telangana, India
› Author Affiliations
 


Abstract

Morita–Baylis–Hillman (MBH) chemistry was applied to the synthesis of a variety of new chemical entities and their bioactivity was evaluated. Various substances synthesized via MBH chemistry have: antimalarial, anti-inflammatory, antidiabetic, antimicrobial, antitubercular, and anticancer activity and also act as phosphodiesterase inhibitors. There are a few instances animal model and biology studies explored. Several hits and lead molecules are identified and their IC50 values listed. The simplicity of Morita–Baylis–Hillman chemistry provides a realistic, impactful option for the pharma industry.

1 Introduction

2 Antimalarial Activity

3 Anti-inflammatory Activity of MBH Adducts Coupled to Heterocycles

4 Antidiabetic Activity of Epalrestat Analogues Derived from MBH Adducts

5 Antimicrobial Activity

6 Antitubercular Activity of N-Cinnamyl-isatins

7 Inhibitors of Phosphodiesterase-3 (PDE3); Cardiotonic Agents

8 Anticancer Activity

9 Asymmetric Morita–Baylis–Hillman Reactions

10 Conclusion


#

Biographical Sketches

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Ch. N. S. Sai Pavan Kumar received his postgraduate degree (M.Sc.) in organic chemistry from Andhra University and his Ph.D. (Prof V. Jayathirtha Rao) at IICT-Hyderabad, India in 2012. He was an post-doctoral researcher in the lab of Prof. Rong-Jie Chein at Academia Sinica, Taipei, Taiwan from 2012–2015. Presently, he is an Associate Professor in Vignan’s Foundation for Science, Technology & Research, Deemed to be University, Guntur. His research interests are the total synthesis of natural products, synthesis of novel heterocycles with pharmacological activity, and new synthetic methodologies. He has 5 research scholars at present under his supervision and 4 students have been awarded their Ph.D. He has published >40 papers in reputed international journals like Organic Letters, RSC Advances, MedChemComm, Journal of Molecular Liquids etc., 1 patent, and 6 book chapters.

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V. Jayathirtha Rao has obtained his Ph.D. (Prof. V. Ramamurthy) in 1983 from the Department of Organic Chemistry, Indian Institute of Science, Bengaluru, India; Post Doctorate (Prof. R. S. H. Liu) 1983–1984 at University of Hawaii, Honolulu, USA; Research Associate (Prof. Koji Nakanishi) 1985–1986 at Columbia University, New York, USA. He was Head, Deputy Director and Chief Scientist of Fluoro Agro Chemicals Division of Indian Institute of Chemical Technology, Hyderabad, CSIR-IICT, Hyderabad. He was an Alexander von Humboldt Fellow, Germany. He was a visiting scientist at Tulane University, USA (1996–1997), University of Miami, Coral Gables, USA (2006–2007), and also at Queensland University, Australia (2015). He was honored with Fellow of the Royal Society of Chemistry (FRSC) (London) in 2008. He has acted as Judge in the PCB-Appellate Authority, Hyderabad. His research interest include: (1) organic materials for applications in solar cells, light emitting devices, optical sensors, NLO compounds, NIR compounds; (2) synthesis of heterocycles for bioevaluation in medicinal chemistry; (3) organic photochemistry; (4) method development for APIs in analytical studies; and (5) process development and technology. He has published >250 publications, >80 patents, >25 processes, 6 book chapters, 2 books, and 3 reviews and he has 4 processes demonstrated. He has trained ~52 Ph.D. students and >200 Master students for his credit.

1

Introduction

The catalyst-mediated carbon–carbon (C–C) bond-coupling process involving an activated alkene (nucleophilic substance) and a carbonyl compound (aldehyde, ketone, imine, etc.) leading to a super functionalized molecule is termed the Morita–Baylis–Hillman (MBH) reaction. First reported by Morita and co-workers[1] in 1968 and later, in 1972, Baylis and Hillman[2] patented BH chemistry. Several reviews have been published on the MBH reaction and a few are given here.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] A simple reaction pathway for the MBH reaction using DABCO, methyl acrylate, and an arylaldehyde is depicted in Scheme [1]. Activated alkene I interacts with catalyst DABCO II to form a zwitterion III (Scheme [1]). Then the formed zwitterion III undergoes coupling with arylaldehyde IV forming a C–C bond to generate zwitterion V. Intramolecular proton transfer takes place within the zwitterion V, leading to zwitterion VI, which collapses to give the MBH adduct VII and the catalyst DABCO is regenerated (Scheme [1]). The mechanism of the Morita–Baylis–Hillman reaction is more complex than depicted in Scheme [1] and remains the subject of investigation.[13] [14] [15] [16] The Morita–Baylis–Hillman reaction mechanism has also been the subject of computational studies.[17] Mechanisms are always debatable and MBH reaction is no exception. Chiral catalysts (chiral tertiary amines and phosphines) were employed to generate MBH adducts in enantiomeric excess and several chiral catalysts are given in a review article.[9] Further, MBH adducts were submitted to asymmetric chemical transformations with good selectivity using chiral Lewis bases.[9] Lipase enzymes were utilized to resolve MBH acetylated adducts in a successful way by achieving 50% to 90% ee.[18]

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Scheme 1 A simplified mechanism of the Morita–Baylis–Hillman reaction

There is a continuous global effort to discover organic molecules having biological activity in the human health sector research program. The MBH reaction is a classical named reaction in organic chemistry and can contribute to the synthesis of new bioactive molecules in a very simple way. The prominent features of the MBH reaction, like simple reaction conditions, readily available and cheap chemicals, 100% atom economy, ability to produce highly functionalized products, and control of stereochemistry and selectivity are attractive reasons for medicinal chemists to utilize and exploit this reaction to synthesize a variety of new chemical entities with pharmaceutical importance. MBH adducts carry functionalities like a double bond, electron-withdrawing group (ester, nitrile, keto, etc.), or hydroxyl group, and may also contain an aromatic residue in a crowded fashion and in limited space, which is an excellent opportunity for medicinal chemists to exploit and make newer chemical entities. Furthermore, the conversion of MBH adducts into the corresponding acetates, carbonates, and bromides by the further manipulation of these entities allows the generation of a variety of medicinally important compounds. The objective/aim of this account is to bring into focus the potential of the MBH reaction to lead to a variety of bioactive entities and also to comprehend our research observations in medicinally important publications. Emphasis will be on the hit molecules, lead molecules, and also data generated by animal studies using these MBH-derived bioactive molecules.

Now-a-days, various MBH-derived reaction products have been synthesized to evaluate them for their bioactivity, like antimalarial, antibacterial, antituberculosis, cardiovascular, cerebrovascular, anticancer, antidiabetic, antifungal, anti-inflammatory, antiallergic, etc. IC50 values generated on these bioactive molecules were used to identify them as hit and lead molecules. Lead molecules were discerned and taken forward to animal model studies. In this account, the focus is on the synthesis of MBH-derived products, their bioactivities, structure, and scaffold-derived relationship with bioactivity and animal model studies for lead compounds.


# 2

Antimalarial Activity

Malaria is a health problem particularly in poorer countries as per the statistical global healthcare information. Mosquitoes are involved in the transmission of this disease to humans. The drug resistance developed by Plasmaodium falciparum coupled with existing drugs efficacy has made the identification of good candidates for therapeutic purposes to treat malaria an important topic.

2.1

Antimalarial Activity of Pyridine-Based MBH Adducts

Chloroquine is a quinoline moiety containing a nitrogen heterocycle, and we utilized this structural feature to design MBH adducts for antimalarial activity (Schemes 2 and 3).

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Scheme 2 Synthesis of substituted 2-chloronicotinaldehydes

Several enamides 1 [19] [20] [21] [22] [23] [24] [25] were prepared and allowed to react under Vilsmeier–Haack conditions to make tetrasubstituted 2-chloro-3-nicotinaldehydes 2 (Scheme [2]).[26] [27] Phosphoryl chloride was replaced with diphosgene or triphosgene in the Vilsmeier–Haack reaction to improve yields and also to improve the ‘green chemistry’ criteria (Scheme [2]).

Some of the salient points of this chemistry are the formation of multiple bonds with cyclization and aromatization, as shown in Scheme [2]. Thus, the synthesized 2-chloro-3-nicotinaldehydes 2 were subjected to the MBH reaction with methyl acrylate or acrolein to give the MBH adducts 4.[28] [29] The formation of the MBH adducts 510 derived from 2-chloro-3-nicotinaldehydes (Scheme [3]) is interesting in terms of the reaction times and yields. An X-ray crystal structure was determined for compound 7. Six MBH adducts 510 of 2-chloro-3-nicotinaldehyde were examined for antimalarial activity.[29]

In vitro testing was carried out using chloroquine sensitive and chloroquine resistant Plasmodium falciparum and chloroquine used as standard. IC50 and IC90 values were determined for compounds 510 employing shizant maturation inhibition and total parasite growth inhibition assay and the results are given in Scheme [3]. The IC50 and IC90 numbers are in the range of μg mL–1 indicating comparable activity,[29] particularly for compounds 6, 7, and 8. More interestingly these compounds exhibited good activity on chloroquine resistant Plasmodium falciparum. A limited SAR was discussed making use of substitutions present on the pyridine moiety.[29]

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Scheme 3 Synthesis of MBH adducts derived from substituted 2-chloronicotinaldehydes and their IC50 values towards antimalarial activity

# 2.2

Antimalarial Activity of Quinoline-Based MBH Adducts

We have also reported the synthesis of various 2-chloroquinoline-3-carbaldehydes 13 by reacting substituted anilides 11 under Vilsmeier–Haack reaction conditions (Scheme [4]).[30] In this way, 21 2-chloroquinoline-3-carbaldehydes 13 were synthesized and converted into the corresponding MBH adducts (Scheme [4]). X-ray crystal structures were determined for compounds 15 and 26.

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Scheme 4 Synthesis of substituted 2-chloroquinoline-3-carbaldehydes and their corresponding MBH adducts with IC50 values towards antimalarial activity

All MBH adducts prepared were subjected to studies of their in vitro antimalarial activity (chloroquine as standard) and IC50 and IC90 (μg mL–1) values were evaluated.[30] Substantial antimalarial activity was noted for several of these compounds (Scheme [4]). Substitution on the quinoline ring contributes towards antimalarial activity.

The data generated in Sections 2.1 and 2.2 led to the identification of several hit molecules and allowed these to be converted into lead molecules.


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# 3

Anti-inflammatory Activity of MBH Adducts Coupled to Heterocycles

‘Inflammation’ can be defined in a simple way as the response of a part of the body to injury or infection (immune response) that is characterized by swelling, heat, redness, edema, and pain. Inflammation occurs when the physiological action is triggered by the oxygenation of arachidonic acid involving the cyclooxygenase (COX) enzyme leading to the production of prostaglandins, prostacyclin, and thromboxanes and these are responsible for inflammation.[31] [32] There are two forms of cyclooxygenase that exist in the human body, COX-1 and COX-2. Therefore, inhibiting the COX enzyme will stop the production of prostaglandins, prostacyclin, and thromboxanes responsible for inflammation, and thus this has therapeutic importance. Aspirin, ibuprofen, and diclofenac are non-selective inhibitors towards COX-1 and COX-2 and are also marketed as generic medicines. These medicines create gastroenteric problems leading to ulcer formation in the stomach.[33] Celecoxib,[34] valdecoxib,[35] [36] and rofecoxib[37] are marketed medicines that act as selective inhibitors for COX-2 (Figure [1]), but they have adverse problems like interfering with the cardiac and cardiovascular systems. Therefore, these observations provided motivation to discover newer chemical entities that act as COX-2 inhibitors to control the inflammation process.

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Figure 1 Specific inhibitors for COX-2

The different types of heterocycle present in the celecoxib (pyrazole), valdecoxib (isoxazole), and rofecoxib (lactone) are shown in Figure [1], indicating that one can try to make chemical entities with different heterocyclic systems. We have used MBH-derived bromide 31 and formed a C–S bond between pyrimidine-2-thiol, oxazole-2-thiol, thiazole-2-thiol, and 1,2,4-triazole-3-thiol moieties, leading to new chemical entities (Scheme [5]). We synthesized 20 new molecules using coupling with MBH bromide derivatives 31 to form a C–S bond with different heterocycles (Scheme [5]).[38]

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Scheme 5 Synthesis of MBH bromide and heterocycle-thiol coupled products as anti-inflammatory compounds
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Figure 2 Selected heterocycles synthesized with IC50 numbers for COX-2 inhibitory activity indicating lead molecules

All the compounds synthesized were subjected to COX-1 and COX-2 inhibitory activity using colorimetric enzyme assay using celecoxib as a standard for comparison. Figure [2] indicates the compounds with excellent IC50 values comparable to standard celecoxib. Compounds 3743 have very little active towards inhibiting COX-1, but displayed anti-inflammatory activity at micromolar concentrations with IC50 values for COX-2 inhibition ranging from 2.93 to 5.88 μM compared to celecoxib with IC50 2.66 μM. The compounds with selectivity towards COX-2 inhibition were used as lead molecules and further ADMET studies were undertaken.


# 4

Antidiabetic Activity of Epalrestat Analogues Derived from MBH Adducts

A person becomes diabetic when insulin secretion is affected or the physiological system is unable to assimilate glucose in the body.[39] Indeed, high levels of glucose in a physiological system poses many health-related problems, like retinopathy, nephropathy, neuropathy, cataracts, and cardiac problems. Researchers account diabetic-related health issues as involving various mechanisms of physiological routes.[40] [41] Glucose is reduced to sorbitol biochemically with the help of an enzyme called aldose reductase.[42] The produced sorbitol accumulates in the cells and affects oxidative stress and osmotic stress[43–45] leading to complications. Therefore it becomes very important to find aldose reductase inhibitors[46] [47] [48] [49] [50] as therapeutic agents to control diabetic related health issues. Interestingly epalrestat is the only medicine approved and marketed in Asia to deal with neuropathy. To this end, we decided to attempt to make new chemical entities effective in inhibiting aldose reductase enzyme to control the problems of diabetes.

The structure of epalrestat is given in Scheme [6]; its structure allows to modify or bring five changes to understand the structure-activity relationships (SAR). We kept the thiazole moiety and also the stereochemistry of the C=C bonds intact and introduced changes at the aryl group, the methyl group, and the end group and accordingly synthesized 39 analogues structurally related to epalrestat; the synthetic methods utilized are shown in Scheme [6].[51] A crystal structure for one of the target compounds determined.[51]

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Scheme 6 Synthesis of aldose reductase inhibitors

Glyceraldehyde to glycerol reaction catalyzed by the aldose reductase was employed with cofactor NADPH for measuring the inhibition activity. Measuring the UV-visible absorption of cofactor at different time intervals and in the presence of 39 compounds acting as inhibitors helped us to define the IC50 values. Out of 39 compounds, 5 compounds were found to be effective as aldose reductase inhibitors with comparable IC50 numbers (Figure [3]). Epalrestat was used as a standard in evaluating activity and also IC50 values. The 0.40 μM value for epalrestat was determined by us and the remaining two IC50 values (0.87 μM and 0.10 μM) were taken from the literature[51] for comparison. Molecular docking studies helped in binding of inhibitors at the site of activity. We have introduced structural changes into the epalrestat structure and achieved 5 molecules responding as well as the standard marketed medicine epalrestat. These results induce to take these observations to further to a higher level of investigation.


# 5

Antimicrobial Activity

5.1

Antimicrobial Activity of Quinolines Synthesized from MBH Adducts

WHO reports[52] [53] indicate the global status on the importance of antimicrobial agents for human healthcare and their present research activities. Present day research indicates that microbes very quickly develop resistance to antibiotics and this microbial resistance is a grave problem for researchers. This ‘microbial resistance’ has become a driving force to discover new and more effective antibiotics and also antifungal agents.[54] We will discuss some of our work in this area involving MBH chemistry.

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Figure 3 Aldose reductase inhibitor lead molecules and their IC50 values

The quinoline structure[55] known to contribute towards antibacterial activity and we selected them for antimicrobial studies; quinolines can be constructed by applying MBH chemistry (Scheme [7]). 2-Chloro-3-nicotinaldehydes 2 were converted into the corresponding MBH adducts 4 and 55 and these MBH adducts were acetylated to give 53 and 56 in excellent yields (Scheme [7]). MBH acetates 53 and 56 were then treated with nitroethane or ethyl cyanoacetate (Scheme [7]) in the presence of K2CO3 in DMF and upon heating provided quinolines 57, 58, and 59.[56] A plausible mechanism is also provided (Scheme [7]). A total of 15 quinolines were synthesized by this route and all subjected to in vitro antibacterial activity against 3 Gram-positive and 3 Gram-negative bacteria. Penicillin and streptomycin were used as standards and also for determining minimum inhibitory concentration (MIC).[56] All the quinolines exhibited antibacterial and antifungal activity differing in their MIC compared to the standards used. Particularly the quinolines 6064 showed excellent antibacterial activity towards Gram-positive or Gram-negative bacteria, comparable to the standards penicillin or streptomycin (Figure [4]). Antifungal activity determined for all the compounds was found to be satisfactory when compared to standard clotrimazole.[56]

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Scheme 7 Synthesis of quinoline derivatives via MBH acetates
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Figure 4 Quinoline derivatives exhibiting antibacterial activity comparable to standards penicillin or streptomycin

# 5.2

Antimicrobial Activity of Tetrazolones Coupled to MBH Adducts

MBH-derived tetrazolones[57] were synthesized for the purpose of evaluating their antibacterial and antifungal activities (Scheme [8]). The prepared MBH adducts 65 and 67 were converted into the corresponding bromides 66 and 68 differing in double bond stereochemistry (Scheme [8]). Tetrazolones 71 were prepared from an aryl isocyanate and trimethylsilyl azide (70) (Scheme [8]). The thus prepared tetrazolones 71 were reacted with MBH bromides 66 and 68 to synthesize target tetrazolones coupled with MBH bromides 72 and 73 (Scheme [8]). All of the 20 compounds synthesized were evaluated towards antibacterial and antifungal activity with a very good response. Out of 20 compounds, 8 compounds responded very well, and the identified hit molecules are given in Figure [5].

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Scheme 8 Synthesis of tetrazolones via MBH bromides
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Figure 5 Antimicrobial activities of tetrazolones: identified hits

The organisms used for the antibacterial study comprises both Gram-positive (B. subtilis, S. aureus) and Gram-negative (E. coli, E. aerogenes) by the agar well diffusion method, and ciproflaxacin (40 μg mL–1) used as a standard. All the tetrazolone compounds demonstrated a wide range of antibacterial activity with some variation. Of the 20 new tetrazolone compounds, 16 compounds exhibited strong activity against the Gram-positive bacteria B. subtilis. Notably, compounds 74, 77, and 80 displayed significant activity against this bacterium, with minimum zone of inhibition (MZI) >20 mm, while compounds 75, 76, 79, and 81 also showed considerable activity with MZI greater than 15 mm compared to ciprofloxacin, which had an MZI of 10 mm. These tetrazolone compounds also exhibited excellent activity against the Gram-positive bacteria S. aureus, with 5 compounds 74, 79, 80, and 81 showing an MZI greater than 20 mm in comparison to ciprofloxacin, which had an MZI of 22 mm. The synthesized compounds displayed moderate to strong activity against the Gram-negative bacteria E. coli and E. aerogenes. Compounds 76 and 77 exhibited a very high level of activity against E. coli, with MZI of 18 and 19 mm, respectively, while 75 and 79 demonstrated good activity. For E. aerogenes, compounds 74 and 79 exhibited as the most effective among all synthesized tetrazolones, with 19-mm zone of inhibition. Compounds 75 and 77 also demonstrating good activity against this bacteria.

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Scheme 9 Synthesis of benzothiazolopyrimidinones from MBH acetates

The in vitro antifungal activity was assessed against fungal strains such as A. niger and C. albicans using AHA medium; itraconazole at a concentration of 30 μg mL–1 served as the reference drug. The results from the antifungal screening indicated that compounds 74, 76, 77, and 81 exhibited excellent activity against A. niger with MZI values 16, 18, 16, and 16 mm, respectively, while 75 and 79 displayed moderate activity compared to itraconazole with MZI 17 mm. For the strain C. albicans, the most effective compounds were 75, 76, 77, and 81 with MZI values 19, 17, 18, and 17 mm, respectively, whereas 74, 78, and 79 showed moderate effectiveness compared to itraconazole drug which had an MZI of 20 mm.

According to this study, compounds 74, 75, 76, 77, and 79 have been identified as effective agents with a wide range of antibacterial and antifungal activities (Figure [5]). The notable variation in substitution at N4 of the tetrazolone ring plays a key role in these interesting results. Furthermore, the presence of a p-methoxy group on the N1-phenyl ring significantly enhances the activity, as evidenced by three of the hit compounds 75, 76, and 79 featuring this substitution.

The hit compounds shown substantial antimicrobial activity, act as metabolites that are resistant to breakdown by microbes, cannot be diluted easily, and have the ability to kill a broad spectrum of bacteria and fungi.


# 5.3

Antimicrobial Activity of Benzothiazolopyrimidinones

We have reported the synthesis of benzothiazolopyrimidinones 83 via MBH acetates (Scheme [9]) and evaluated their antimicrobial activity.[58] MBH adducts 30 were prepared from various aldehydes 29 and they were converted into their corresponding acetates 31. MBH acetates 31 were then reacted with aminothiazole 82 to undergo C–N coupling and followed by cyclization leading to various benzothiazolopyrimidinones 83. All the compounds were assayed for antimicrobial activity using streptomycin and itraconazole as standards. Out of 20 compounds synthesized only one compound 84 exhibited very good antimicrobial activity.[58]


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# 6

Antitubercular Activity of N-Cinnamyl-isatins

We have synthesized N-cinnamyl-isatin derivatives 87 from the corresponding MBH bromides 85 (Scheme [10]).[59] MBH bromides 85 were prepared in good yields and reacted with isatins 86 in the presence of base to make N-cinnamyl-isatin derivatives 87. All the 12 compounds synthesized were assayed against Micobacter tuberculosis to determine antitubercular activity. MIC values determined were found to be encouraging and three compounds were found to possess MIC values better than standards ethambutol and pyrazinamide and also as good as isoniazid. Interestingly compound 90 exhibited anticancer activity against three cell lines.[59]


# 7

Inhibitors of Phosphodiesterase-3 (PDE3); Cardiotonic Agents

Phosphodiesterases (PDEs) are enzymes that hydrolyzes cyclic-adenosine monophosphate (cAMP) or cyclic-guanosine monophosphate (cGMP) (Scheme [11]); cAMP and cGMP are known as intracellular secondary messengers in a given physiological system. cAMP and cGMP are known to have a role in vision, mitosis, and gene regulation, cell death, control of carbohydrates and lipids, hormonal secretions, and other processes. Because of the control by PDEs over cGMP or cAMP levels at a given site, this makes them attractive targets for discovering various therapeutic agents as PDE inhibitors in health care systems.[60] [61] [62] [63] [64] [65] [66] There are 11 types[64] of PDEs that have been identified, along with several isoforms[64–67] and they are distributed[60] in several important parts of the body. There is an interesting specificity noticed in these 11 PDEs available. PDE4, PDE7, and PDE8 specifically hydrolyze cAMP, whereas PDE5, PDE6, and PDE9 specifically hydrolyze cGMP. Furthermore, PDE1, PDE2, PDE3, PDE10, and PDE11 hydrolyze both cAMP and cGMP.

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Scheme 10 Synthesis of N-cinnamyl-isatin derivatives and their anti-TB activity

PDE3 is associated with cardiac muscles to control and modulate the levels of cAMP. A PDE3 inhibitor will be administered to a person facing problem of heart failure or myocardial infarction. The PDE3 inhibitor binds and executes its function by controlling cAMP/cGMP hydrolysis, thereby therapeutically increasing its concentration in myocardial muscle cells and allowing its function of myocardial contractility.[68] [69] These PDE3 inhibitors (amrinone and milrinone) are used under acute heart failure conditions, but long-term usage of these PDE3 inhibitors (amrinone and milrinone) increases cardiac mortality. Therefore, it is necessary to study the functioning of these PDE3 inhibitors for better efficacy, leading to reduced mortality and increased effective functioning[68] [69] of the heart. Some cases where thrombus formation in arteries taking blood to heart creates a problem of less oxygen supply to heart muscles and in some cases, thrombus formation completely blocks the way for blood supply. Under these conditions, therapeutic agents are required that can clear the thrombus formed to forward the way for blood circulation.[70] Another case, the inhibitor binds with PDE3A present in platelets and improves the concentration levels of cAMP within platelets thus avoiding platelet aggregation, which is problem because it forms thrombus in arteries. We have synthesized new molecules via MBH chemistry with PDE3 inhibition activity and their animal model studies indicate their effectiveness of action.

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Scheme 11 Biochemical route of ATP to cAMP to AMP
7.1

Pyridones as Inhibitors of Phosphodiesterase-3 (PDE3)

The 2-pyridone structure has significant biological activity, demonstrating antimicrobial, antitumor, antiviral, and psychotherapeutic activity and they are also used as cardiotonic agents. Milrinone, amrinone, and cilostazol are approved medicines used for the acute cardiac problems that bear a 2-pyridone moiety. We became interested in the synthesis of 2-pyridones by applying MBH chemistry; Scheme [12] illustrates the synthesis of various substituted pyridones 92 via MBH acetates 30 reacting with suitable enamino compounds 91 in the presence of NaH base.[71] The formation of the 2-pyridone involves several bond making and breaking processes and the proposed mechanism is shown Scheme [13]. The MBH acetate containing a nitrile group 93 (instead of an ester moiety) resulted in substituted 2-aminopyridines (Scheme [12]).[72]

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Scheme 12 Synthesis of substituted 2-pyridones and 2-aminopyridines via MBH chemistry
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Scheme 13 Mechanism of formation of 2-pyridones synthesized via MBH chemistry

Using the milrinone structure as a reference, we synthesized over 26 pyridone derivatives using our work involving MBH chemistry[71] and used them to conduct PDE3 inhibition studies.[73] The structure activity relationships (SAR) considered are given in Figure [6]. The 26 compounds synthesized covered all the replacements mentioned therein. The 4-pyridyl group at C5 is replaced by a methyl or ethyl ester group or cyano group. The methyl group at C6 is retained in some cases and also replaced by phenyl group. The cyano group at C3 is replaced with a substituted benzyl group. The core 2-pyridone without substitution at C4 is retained. In some compounds N1 is attached to an alkyl group or is part of a ring structure.[74] The 2-amino-pyridines synthesized following MBH chemistry (Scheme [12])[72] are in the process of evaluation to determine the PDE3 inhibition activity.

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Figure 6 Milrinone scaffold based structure activity relationships (SAR)

All the 26 compounds were assayed for PDE3 inhibition activity, where the PDE3 was isolated from the blood. Some of the compounds exhibiting very good inhibition are arranged with molecular structures (Figure [7]) as lead compounds. Figure [7] also provides IC50 values for the selected compounds indicating the PDE3 inhibition activity along with milrinone standard IC50 values.[75] [76] [77] [78] Computational analysis were carried out to find good correlation in docking the PDE3 binding site.[73] It was found out that by varying the structure upon substitutions on the pyridone core structure can provide lead compounds.

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Figure 7 Selected pyridines showing PDE3 inhibition activity; IC50 values are given

# 7.2

In Vivo Studies of Lead Compound Pyridone

Aspirin and clopidogrel are medicines used as blood anticoagulating agents to control ischemia with limited efficacy and side effects. Cilostazol is another medicine used to control aggregation process in blood leading to ischemia. Nevertheless, there is a requirement for newer anticoagulating agents with fewer side effects and improved efficacy. We have found lead compound pyridone 99 (Figure [7]) as a PDE3 inhibitor[73] and utilized it for studying an in vivo mouse model[79] to understand cerebral ischemia, biochemical routes of pathophysiology, and also efficacy of the pyridone 99.

A thrombus (clot or occlusion) was created artificially in an artery taking blood to a part of a mouse brain and this termed as ‘transient middle cerebral arterial occlusion (tMCAO).’ The introduction of tMCAO initiates ischemia and other effects as controlled by the part of the brain suffering from less oxygen. The pyridone 99 was injected into the mice effected by the tMCAO, after 60 min of tMCAO formation. Control experiments were performed using cilostazol (standard drug; Scheme [12]) and a blank without any compound. Various parameters were measured to assess the situation of mice effected with tMCAO and after treatment with pyridone 99. Mice brain effected tissue was analyzed for increase in the cAMP concentration and also decrease in the infarct volume as judged by the triphenyltetrazolium chloride dye fluorescence assay (comparing with the untreated experiment) indicating the effectiveness of the treatment with pyridine 99 and also that there were no cerebral hemorrhage occurring after pyridone 99 treatment. Evans blue injected into the tMCAO effected brain tissue indicated very little leakage of dye into the brain tissue and also edema formation, informing the blood brain barrier (BBB) situation is protected. Analysis of mice brain tissue effected by the tMCAO indicates higher levels phosphorylated protein kinase A, which in turn informs that low levels of formation of other proteins like TNF-α, IL-1β, and IL6, responsible for less or no inflammation after treatment with pyridone 99. Pyridone 99 was found to be effective in the reduction of neuronal apoptosis as per the Western blot analysis against caspase and cleaved caspase. Upon treatment with pyridone 99, there was no change in the functioning of platelets as indicated by the thrombin and collagen dependent biochemical processes. More importantly, we compared the outcome by using cilostazol standard drug (Scheme [12]), which indicates the superiority of the pyridine 99, over cilostazol.[80] [81]

Pyridone 99, indeed, reduces stroke effect by controlling neurodegradation via biochemical pathways by the reduction in BBB, reduction in inflammation, and reducing neural apoptosis. Pyridone is superior to the marketed drug cilostazol in many aspects. The other possible models, like hypertensive animal model, are to be tried and also the dosage, delivery of 99, continuous treatment, long term effects, and other factors must be evaluated before deciding to take 99 forward to trials.


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# 8

Anticancer Activity

8.1

Anticancer Activity of MBH-Derived Tetrazoles

Molecules having affinity to bind with DNA can display anticancer activity.[82] [83] These DNA binding molecules will be highly cytotoxic. Tetrazole compounds with interesting properties, have several applications and one of them is to reduce the toxic nature of the drug by attaching a tetrazole moiety,[84] furthermore tetrazole has complexing ability with metal ions. The tetrazole moiety is part of the marketed hypertension drugs, valsartan, losartan, and irbesartan. Many believe that these tetrazoles can act as to reduce hypertension and may not be good for evaluating other bioactivities. We have explored the synthesis of new tetrazole molecules to test them for anticancer activity and also cDNA binding nature.

MBH adducts 30 were prepared and converted into the corresponding acetates 31. The acetates 31 were treated with NaN3 to produce MBH allyl azides 100 that were treated with Zn/NH4Cl to give amines 101 which were reacted with HC(OEt)3 and NaN3 to give tetrazoles 102 (Scheme [14]).[85] The MBH adduct prepared using acrylonitrile provides a different stereoisomer of tetrazole 105 compared to the tetrazole generated using acrylate ester 102. Crystal structures for two tetrazoles synthesized were also recorded.[85] All the 16 tetrazole compounds were subjected to in vitro cytotoxicity using cell lines such as Hep-G2 liver carcinoma, A-549 lung adenocarcinoma, MDA-MB-231 breast cancer cells, DU-145 prostate carcinoma, and SK-N-SH neuroblastoma. Nocodazole and podophyllotoxin were the standards used in evaluating IC50 values for all 16 tetrazole compounds. A few tetrazole compounds exhibited decent activity and the structures are given in Figure [8] along with IC50 values. There are six molecules found to be active towards various cancer cell lines. We have taken tetrazole 109 and studied its binding nature with calf thymus DNA using UV-visible and fluorescence techniques. Tetrazole 109 at fixed concentrations was incubated with cDNA at various concentrations in a given buffer media. The changes in its UV-vis absorption and fluorescence recorded upon mixing of tetrazole 109 and cDNA inform tetrazole 109 association or binding with cDNA, the binding constant determined by applying UV-vis spectral changes is k b = 0.75 × 10–5 M.

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Scheme 14 Synthesis of tetrazoles as anticancer agents via MBH chemistry
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Figure 8 Tetrazoles as anticancer agents with IC50 values

From the structure activity relationship (SAR), it is noticed that substituents like p-trifluoromethyl, p-chloro, and p-nitro on the phenyl ring, as well as those with a 1,5-disubstituted tetrazole structure, exhibited higher anticancer activity in comparison to other compounds. All the compounds demonstrated varying degrees of anticancer activity, ranging from moderate (15.0–70.0 μM) to good (7.0–15.0 μM), against both breast and neuronal cell lines.


# 8.2

Anticancer Activity of Azetidinones

β-Lactams are a special structural feature in the medicinal chemistry research domain.[86] Azetidin-2-one compounds exhibit several bioactivities, including anticancer activity.[87] [88] [89] Tripodi et al. [90] and Valtorta et al. [91] examined the colorectal anticancer activity of 1,4-diarylazetidin-2-one derivatives mediated by AMP activated protein kinase leading to apoptosis. We synthesized various azetidinones and investigated their anticancer activity towards breast cancer and also probed the signal transduction mechanism leading apoptosis.[92]

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Figure 9 1,4-Diarylazetidin-2-ones

Figure [9] illustrates the structure of 1,4-diarylazetidin-2-ones and the changes that we introduced into the structure. MBH chemistry was applied to make various analogues of 1,4-diarylazetidin-2-ones (Scheme [15]).

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Scheme 15 Synthesis of trisubstituted azetidin-2-ones as antibreast cancer agents

MBH allyl amines 101 and 104 were prepared by following the established protocol.[85] Allylamines 101 and 104 were treated with a substituted benzaldehyde and then with methoxyacetyl chloride/triethylamine reagent. First the allylamine part formed a Schiff’s base and then it reacted with the in situ generated ketene; a [2+2] cycloaddition provided 25 azetidinones 112 and 113 in high diastereomeric ratio (Scheme [15]). The stereochemistry of the azetidinone product was confirmed by 1H NMR coupling constants and also by crystal structure for compound azetidinone 114 (Figure [10]).

The 25 azetidinones (analogues of β-lactam) were examined for their bioactivity using breast cancer cell lines, such as MCF-7 and MDA-MB-231, with mammary epithelial cells used as control (MEpiC). Colchicine was used as standard in these studies to determine IC50 values. Among the 25 compounds tested, only three compounds 114, 115, and 116 were found to be active with antibreast cancer activity. The structures of the azetidinones showing breast anticancer activity are shown in Figure [10] along with IC50 values. Among the three active azetidinones 114, 115, and 116, compound 116 was found to exhibit more pro-apoptotic activity by triggering pro-apoptotic genes and at the same time suppressing the anti-apoptotic genes, compared to standard colchicine. Furthermore, azetidinone 116 was found to affect cell cycle arrest more compared to standard colchicine, as per the enzyme and protein analysis.[92]

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Figure 10 Azetidinones as antibreast cancer agents

From the SAR study perspective, a fluorine atom in the para position of 3-methoxy-4-phenylazetidin-2-one 114 was relatively more active against both cancer cell lines than other halogen atoms at the same position of phenylacrylonitrile derivatives. Additionally, a methyl group in the para position of phenylacrylonitrile derivative 115 gave it a strong antiproliferative effect. The inclusion of a bromine atom at the ortho position in ethyl phenylacrylate derivatives of 3-methoxy-4-phenylazetidin-2-one 116 demonstrated significant antiproliferative and pro-apoptotic effects on both luminal and basal types of breast cancer cell lines.


# 8.3

Anticancer Activity of 4H-Pyran Compounds

The 4H-pyran scaffold is an important structure having widespread applications,[93] like fluorescence, OLEDs, agrochemicals, cosmetics, and also pharmaceutical purposes, particularly anticancer activities.[94] [95] We have synthesized various 4H-pyran compounds[96] via MBH chemistry to investigate their anticancer properties. MBH adduct 44 was converted into cyanoaldehyde 45 and the resulting cyanoaldehyde was treated with malononitrile to obtain 4H-pyran compounds 118 (Scheme [16]). 4H-Pyran compounds were synthesized and submitted for anticancer activity.

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Scheme 16 Synthesis of tetrasubstituted 4H-pyran compounds via MBH chemistry as anticancer agents

We have used four types of cancer cell lines to measure the bioactivity, A549 (lung cancer), MCF7 (breast cancer), DU145 (prostate cancer), and HeLa (cervical cancer), and doxorubicin as standard to measure the IC50 values. Out of 23 compounds, there are only four compounds 119, 120, 121, and 122 that effectively exhibited anticancer activity. The structures of the four compounds 119122 along with IC50 values are provided in Figure [11].

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Figure 11 Anticancer activity of 4H-pyrans

From a structure-activity relationship (SAR) viewpoint, it can be observed that the phenyl group with an o-fluoro, m-bromo, and o-bromo group and with 2-furyl motif demonstrated greater activity than the other synthesized compounds.


# 8.4

Role of an Aldose Reductase Inhibitor in Anticancer Activity

We have reported a series of aldose reductase inhibitors[51] as antidiabetic compounds and identified a few lead compounds. We have used the lead molecule 52 (Figure [12]) from the earlier work,[51] in the series of aldose reductase inhibitors in biorelated cancer experiments. Aldo-keto reductase family 1, member B (AKR1B1) is expressed/produced during inflammatory process and also in various cancers. The AKR1B1 is found to be inhibited by compound 52 (Figure [12]) which provides an opportunity to use compound 52 as an adjuvant along with anticancer medicine to improve efficiency of cancer medicine. In vivo and in vitro experiments conducted to understand colitis-associated colorectal cancer (CS-CRC) using compound 52 informs that AKR1B1 was inhibited and it the 52 can be a potential inhibitor of AKR1B1.[97]

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Figure 12 Aldose reductase lead molecules

In vivo experiments conducted using anticancer agent doxorubicin and together with compound 52 acting as AKR1B1 inhibitor[98] improved the efficacy of doxorubicin and also arrested the doxorubicinol (doxol) formation thereby reduced the risk of cardiotoxicity. In vitro model experiments conducted found that inhibition of AKR1B1 by compound 52 triggered the formation of reactive oxygen species (ROS).[99]

Aldose reductase lead molecules are employed in cancer studies as an adjuvant drug which in turn initiates apoptosis in colon cancer cells. Indeed, the compound 52 was found to be tenfold more effective than the marketed drug epalrestat as an aldose reductase inhibitor. Liver cancer cells contain high expression of AKR1B1 and its inhibition by 52 improves glucose metabolism leading to the prevention of hepatic pre-cancer.[100] Recent investigations conducted[97] [98] [99] [100] by us indicate that compound 52 is a promising AKR1B1 inhibitor and also can act as an adjuvant.


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# 9

Asymmetric Morita–Baylis–Hillman Reactions

The Morita–Baylis–Hillman reaction can lead to the formation of a new chiral center, allowing for potential asymmetric induction. Traditionally, this reaction involves three components: an electrophile, an electron-deficient alkene, and a nucleophilic catalyst/trigger, all of which can influence the stereochemistry at the newly formed stereogenic carbon. Recent advancements have significantly enhanced the utility of the reaction in synthesizing carbon–carbon bonds in organic chemistry. Asymmetry in the MBH reaction can be achieved through the use of homochiral electrophiles, homochiral Michael acceptors, homochiral catalysts, or by the combined effect of any of these components. Recent developments in the asymmetric version of MBH reaction and their prospects are widely reported in the literature.[101] [102] [103] [104] The true value of a method is evident in its effective implementation. The asymmetric MBH reaction was successfully employed in the synthesis of important bicyclic lactones, diverse range of stereochemical entities, in total synthesis for synthesizing target molecules, etc.

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Scheme 17 Synthesis of chiral sulfones with 3-hydroxy-oxindoles using an organocatalyst

To illustrate this, Chen and co-workers described[105] the production of biologically active chiral sulfones that contain 3-hydroxy-oxindoles 124 (Scheme [17]) through an organocatalytic asymmetric MBH reaction. β-Isocupreidine is used as an effective catalyst for this process. They conducted the initial reaction using an isatin 86 and vinyl methyl sulfone (123, R3 = Me) as model substrates. The optimized conditions involved utilizing β-isocupreidine (10 mol%) as the catalyst in 1,4-dioxane at 40 °C under an argon atmosphere; the desired products 124 were obtained successfully with a high level of enantioselectivity.

Pan and co-workers[106] demonstrated an interesting application of nitrostyrenes in the Rauhut–Currier reaction. When pyrazolone 125 interacts with β-nitrostyrene (126) in the presence of DMAP catalyst, tetrahydropyranopyrazoles were obtained in an effective manner (Scheme [18]). These compounds have an important role in pharmaceutical development.

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Scheme 18 Synthesis of tetrahydropyranopyrazoles from pyrazolones

Huang and co-workers described a novel method for the synthesis of trisubstituted cyclopentenes 130 via the Rauhut–Currier/Wittig domino reaction as shown in Scheme [19].[107] The ideal conditions involved using PBu3 (100 mol%) as the catalyst with 2 equiv. of AcOH in dioxane at a temperature of 100 °C. Aryl vinyl ketones 128 featuring both electron-donating and electron-withdrawing substituents showed favorable results in this reaction on treatment with chalcones 129. This methodology effectively accommodated a broad spectrum of functional groups, including bromo, chloro, fluoro, methyl, and trifluoromethyl, on the phenyl ring of the chalcone.

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Scheme 19 Synthesis of trisubstituted cyclopentenes using cross the Rauhut–Currier reaction
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Scheme 20 Synthesis of syributins using asymmetric MBH reaction as key step

Another fascinating and valuable use of the asymmetric Baylis–Hillman reaction is in the total synthesis of syributins (Scheme [20]). This synthesis was achieved by Radha Krishna and co-workers[108] in seven steps, beginning with the Baylis–Hillman adduct 132 derived from 2,3-O-isopropylidene-(R)-glyceraldehyde (131) and ethyl acrylate, with ring-closing metathesis (RCM) serving as the crucial step.


# 10

Conclusion

Our work on the application of Morita–Baylis–Hillman chemistry in the synthesis of bioactive molecules is narrated in this review. A brief introduction to Morita–Baylis–Hillman chemistry is provided by highlighting a few aspects. The synthesis of variety of new chemical entities or heterocycles involving Morita–Baylis–Hillman chemistry is explained in this review. Crystal structures solved for a few molecules are also indicated. We have considered the work related in making heterocycles via MBH chemistry and evaluating their bioactivity. Various MBH adducts originating from 2-chloronicotinaldehyde and 2-chloroquinoline-3-carbaldehydes were analyzed for their antimalarial activity and identified several hit molecules. Interestingly, the synthesized molecules showed antimalarial activity towards chloroquine resistant species also. MBH bromides were coupled with various heterocycles via C–S bond formation to find out their specificity towards COX-2 inhibition activity. Several lead molecules were identified as COX-2 inhibitors. Epalrestat analogues synthesized were tested towards aldose reductase inhibition activity and 5 compounds were identified as lead molecules to be taken to the next level of analysis as antidiabetic compounds. Quinolines, tetrazolones, and benzothiazolopyrimidines resulting from MBH chemistry were synthesized and tested for their antibiotic and antifungal activities. Several molecular entities identified as hit molecules having comparable activity with respect to standards used. N-Cinnamyl-isatin compounds were prepared and their antitubercular activity was examined but one hit compound was identified.

Phosphodiesterase inhibitors are found to improve the concentration of cAMP or cGMP at a given site upon binding with inhibitors. cAMP or cGMP are intracellular secondary messengers involved in cell signaling pathways like vision, cell division, hormonal secretion, and several other functions. Several pyridine moieties synthesized were found to be PDE3 inhibitors and help in cardiac problems. Many lead molecules working as PDE3 inhibitors were identified. Animal model studies conducted on these PDE3 inhibitors informed us that one of the PDE3 inhibitors has 5 times better activity compared to marketed medicine cilostazol. Further, these animal model studies indicate that the lead molecules identified needs to be tested with other animal model studies before submitting them for trials. Various heterocycles like, tetrazoles, azetidinones, and 4H-pyrans synthesized via Morita–Baylis–Hillman chemistry were tested for anticancer activity. Quite a few lead molecules identified from tetrazoles and azetidinones as anticancer agents. Biological studies conducted on azetidinones informs that these are act better than standards and also have potential to take forward. The recent investigations conducted by us indicates that compound 52 is a promising AKR1B1 inhibitor and also can act as an adjuvant.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

CHNSSP thank VFSTR and VDC. VJR thank AcSIR-Ghaziabad for Honorary Professorship and CSIR-New Delhi for Emeritus Scientist Honor.


Corresponding Author

V. Jayathirtha Rao
Organic Synthesis and Process Chemistry Department, AcSIR-Ghaziabad, CSIR-Indian Institute of Chemical Technology
Uppal Road Tarnaka, Hyderabad – 500007, Telangana
India   

Publication History

Received: 11 December 2024

Accepted after revision: 07 February 2025

Accepted Manuscript online:
07 February 2025

Article published online:
07 April 2025

© 2025. Thieme. All rights reserved

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


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Scheme 1 A simplified mechanism of the Morita–Baylis–Hillman reaction
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Scheme 2 Synthesis of substituted 2-chloronicotinaldehydes
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Scheme 3 Synthesis of MBH adducts derived from substituted 2-chloronicotinaldehydes and their IC50 values towards antimalarial activity
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Scheme 4 Synthesis of substituted 2-chloroquinoline-3-carbaldehydes and their corresponding MBH adducts with IC50 values towards antimalarial activity
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Figure 1 Specific inhibitors for COX-2
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Scheme 5 Synthesis of MBH bromide and heterocycle-thiol coupled products as anti-inflammatory compounds
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Figure 2 Selected heterocycles synthesized with IC50 numbers for COX-2 inhibitory activity indicating lead molecules
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Scheme 6 Synthesis of aldose reductase inhibitors
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Figure 3 Aldose reductase inhibitor lead molecules and their IC50 values
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Scheme 7 Synthesis of quinoline derivatives via MBH acetates
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Figure 4 Quinoline derivatives exhibiting antibacterial activity comparable to standards penicillin or streptomycin
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Scheme 8 Synthesis of tetrazolones via MBH bromides
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Figure 5 Antimicrobial activities of tetrazolones: identified hits
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Scheme 9 Synthesis of benzothiazolopyrimidinones from MBH acetates
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Scheme 10 Synthesis of N-cinnamyl-isatin derivatives and their anti-TB activity
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Scheme 11 Biochemical route of ATP to cAMP to AMP
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Scheme 12 Synthesis of substituted 2-pyridones and 2-aminopyridines via MBH chemistry
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Scheme 13 Mechanism of formation of 2-pyridones synthesized via MBH chemistry
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Figure 6 Milrinone scaffold based structure activity relationships (SAR)
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Figure 7 Selected pyridines showing PDE3 inhibition activity; IC50 values are given
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Scheme 14 Synthesis of tetrazoles as anticancer agents via MBH chemistry
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Figure 8 Tetrazoles as anticancer agents with IC50 values
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Figure 9 1,4-Diarylazetidin-2-ones
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Scheme 15 Synthesis of trisubstituted azetidin-2-ones as antibreast cancer agents
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Figure 10 Azetidinones as antibreast cancer agents
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Scheme 16 Synthesis of tetrasubstituted 4H-pyran compounds via MBH chemistry as anticancer agents
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Figure 11 Anticancer activity of 4H-pyrans
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Figure 12 Aldose reductase lead molecules
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Scheme 17 Synthesis of chiral sulfones with 3-hydroxy-oxindoles using an organocatalyst
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Scheme 18 Synthesis of tetrahydropyranopyrazoles from pyrazolones
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Scheme 19 Synthesis of trisubstituted cyclopentenes using cross the Rauhut–Currier reaction
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Scheme 20 Synthesis of syributins using asymmetric MBH reaction as key step