Medicinal Chemistry - Volume 20, Issue 1, 2024

Long-term exposure to pesticides is associated with the incidence of cancer. With the exponential increase in the number of new pesticides being synthesized, it becomes more and more important to evaluate the toxicity of pesticides by means of simulated calculations. Based on existing data, machine learning methods can train and model the predictions of the effects of novel pesticides, which have limited available data. Combined with other technologies, this can aid the synthesis of new pesticides with specific active structures, detect pesticide residues, and identify their tolerable exposure levels. This article mainly discusses support vector machines, linear discriminant analysis, decision trees, partial least squares, and algorithms based on feedforward neural networks in machine learning. It is envisaged that this article will provide scientists and users with a better understanding of machine learning and its application prospects in pesticide toxicity assessment.

Despite extensive research in the field of drug discovery and development, still there is a need to develop novel molecular entities. Literature reveals a substantial heterocyclic nucleus named, piperazine, which shows an immense therapeutic voyage. For several decades, molecules having the piperazine nucleus have entered the market as a drug exhibiting biological potential. It was known to possess antipsychotic, antihistamine, antianginal, antidepressant, anticancer, antiviral, cardioprotective, and anti-inflammatory activity with a specific basis for structural activity relationship. Thus, it is regarded as a key structural feature in most of the already available therapeutic drugs in the market. Reports also suggest that the extensive utilization of these currently available drugs having a piperazine nucleus shows increasing tolerance significantly day by day. In addition to this, various other factors like solubility, low bioavailability, cost-effectiveness, and imbalance between pharmacokinetics and pharmacodynamics profile limit their utilization. Focusing on that issues, various structural modification studies were performed on the piperazine moiety to develop new derivatives/analogs to overcome the problems associated with available marketed drugs. Thus, this review article aims to gain insight into the number of structural modifications at the N-1 and N-4 positions of the piperazine scaffold. This SAR approach may prove to be the best way to overcome the above-discussed drawbacks and lead to the design of drug molecules with better efficacy and affinity. Hence, there is an urgent need to focus on the structural features of this scaffold which paves further work for deeper exploration and may help medicinal chemists as well as pharmaceutical industries.

Background: Tuberculosis has been the main cause of mortality of infectious diseases worldwide, with strongly limited therapeutic options. With increasing resistance and missing suitable drugs in those cases, there is a strong need for novel antituberculostatic drugs. We developed novel N-aryl 1,4-dihydropyridines with various substitution patterns to evaluate them as antituberculostatic agents.Methods: 1,4-Dihydropyridine derivatives were synthesized and purified by column chromatography or recrystallization. The mycobacterial growth inhibition was determined in a fluorescent mycobacterial growth assay.Results: The compounds were prepared in a simple one-pot reaction under acidic conditions with structurally varied components. The substituent effects on the determined mycobacterial growth inhibitory properties are discussed.Conclusion: Lipophilic diester substituted derivatives show promising activities that were additionally affected by the aromatic substituent functions. Thus, we identified compounds with activities almost reaching that of the used antimycobacterial drug as control.

Background: Drug-resistant infections kill hundreds of thousands of people globally every year. In previous work, we found that tri-methoxy- and pyridine-substituted imidazoles show strong antibacterial activities.Objective: The aim of this work was to investigate the antibacterial activities and bacterial resistances of imidazoles bearing an aromatic heterocyclic, alkoxy, or polycyclic moiety on the central ring.Methods: Three series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4- yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles (13a-e, 14a-d, and 15a-f) were synthesized and their antibacterial activity was evaluated. The structures were confirmed by their ¹H NMR, ¹³C NMR, and HRMS spectra. All the synthesized compounds were screened against Gram-positive, Gramnegative, and multidrug-resistant bacterial strains.Results: More than half of the compounds showed moderate or strong antibacterial activity. Among them, compound 13e (MICs = 1-4 μg/mL) showed the strongest activity against Gram-positive and drug-resistant bacteria as well as high selectivity against Gram-negative bacteria. Furthermore, it showed no cytotoxicity against HepG2 cells, even at 100 μM, and no hemolysis at 20 μM.Conclusion: These results indicate that compound 13e is excellent candicate for further study as a potential antibacterial agent.

Background: Hepatitis C is an inflammatory condition of the liver caused by the hepatitis C virus, exhibiting acute and chronic manifestations with severity ranging from mild to severe and lifelong illnesses leading to liver cirrhosis and cancer. According to the World Health Organization’s global estimates, a population of about 58 million have chronic hepatitis C virus infection, with around 1.5 million new infections occurring every year.Objective: The present study aimed to identify novel molecules targeting the Hepatitis C viral RNA Dependent RNA polymerases, which play a crucial role in genome replication, mRNA synthesis, etc.Methods: Structure-based virtual screening of chemical libraries of small molecules was done using AutoDock/Vina. The top-ranking pose for every ligand was complexed with the protein and used for further protein-ligand interaction analysis using the Protein-ligand interaction Profiler. Molecules from virtual screening were further assessed using the pkCSM web server. The proteinligand interactions were further subjected to molecular dynamics simulation studies to establish dynamic stability.Results: Molecular docking-based virtual screening of the database of small molecules, followed by screening based on pharmacokinetic and toxicity parameters, yielded eight probable RNA Dependent RNA polymerase inhibitors. The docking scores for the proposed candidates ranged from - 8.04 to -9.10 kcal/mol. The potential stability of the ligands bound to the target protein was demonstrated by molecular dynamics simulation studies.Conclusion: Data from exhaustive computational studies proposed eight molecules as potential anti-viral candidates, targeting Hepatitis C viral RNA Dependent RNA polymerases, which can be further evaluated for their biological potential.

Background: Since CDKs have been demonstrated to be overexpressed in a wide spectrum of human malignancies, their inhibition has been cited as an effective technique for anticancer drug development.Methods: In this context, new bis-oxindole/spiro-triazole-oxindole anti-breast cancer drugs with potential CDK4 inhibitory effects were produced in this work. The novel series of bis-oxindole/spirotriazole- oxindole were synthesized from the reaction of bis-oxindole with the aniline derivatives then followed by 1,3-dipolar cycloaddition of hydrazonoyl chloride.Results: The structure of these bis-oxindole/spiro-triazole-oxindole series was proven based on their spectral analyses. Most bis-oxindole and bis-spiro-triazole-oxindole compounds effectively inhibited the growth of MCF-7 (IC50 = 2.81-17.61 μM) and MDA-MB-231 (IC50 = 3.23-7.98 μM) breast cancer cell lines with low inhibitory activity against normal WI-38 cells. While the reference doxorubicin showed IC50 values of 7.43 μM against MCF-7 and 5.71 μM against the MDA-MB-231 cell line. Additionally, compounds 3b, 3c, 6b, and 6d revealed significant anti-CDK4 activity (IC50 = 0.157- 0.618 μM) compared to palbociclib (IC50 = 0.071 μM). Subsequent mechanistic investigations demonstrated that 3c was able to trigger tumor cell death through the induction of apoptosis. Moreover, it stimulated cancer cell cycle arrest in the G1 phase. Furthermore, western blotting disclosed that the 3c-induced cell cycle arrest may be mediated through p21 upregulation.Conclusion: According to all of the findings, bis-oxindole 3c shows promise as a cancer treatment targeting CDK4.

Introduction: Inflammation can be defined as a complex biological response that is produced by body tissues to harmful agents like pathogens, irritants, and damaged cells and thereby acts as a protective response incorporating immune cells, blood vessels, and molecular mediators. Histamine, serotonin, bradykinin, leukotrienes (LTB4), prostaglandins (PGE2), prostacyclins, reactive oxygen species, proinflammatory cytokines like IL-1, IL-11, TNF- anti-inflammatory cytokines like IL-4, IL-10, IL-11, IL-6 and IL-13, etc. all have different effects on both pro and anti-inflammatory mediators. Incorporation of combinatorial chemistry and computational studies have helped the researchers to design xanthones moieties with high selectivity that can serve as a lead compound and help develop potential compounds that can act as effective COX-2 inhibitors. The study aims to design and develop different series of substituted hydroxyxanthone derivatives with anti-inflammatory potential.Methods: The partially purified synthetic xanthone derivatives were orally administered to the carrageenan induced paw oedemic rat models at the dose of 100 mg/kg, and their effect in controlling the degree of inflammation was measured at the time interval of 30 min, 1, 2, 3, 4 and 6 hrs. respectively. Further, these compounds were also subjected to modern analytical studies like UV, IR, NMR and mass spectrometry or their characterization.Results: The results drawn out of the in silico, in vitro, in vivo and analytical studies concluded that the hydroxyxanthone derivatives can obstruct the enzyme COX-2 and produce anti-inflammatory action potentially.Conclusion: With the aim to evaluate the compounds for their anti-inflammatory activity, it was observed that the newly designed xanthonic compounds also possess a safe toxicity margin and hence can be utilized by the researchers to develop hybrid xanthonic moieties that can specifically target the enzyme COX-2.

Background: Epilepsy continues to be a significant global health problem and the search for new drugs for its treatment remains an urgent task. 5-HT2 and GABAA-receptors are among promising biotargets for the search for new anticonvulsants.Methods: New potential 5-HT2 and GABAA ligands in the series of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime were designed using pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out from 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and substituted cinnamoyl chlorides. The anticonvulsant activity of new substances has been established using the maximal electroshock seizure test.Results: Several synthesized substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo [b,d]furan-1-(2H)-one oxime significantly reduced the severity of convulsive manifestations and completely prevented the death of animals after MES. The structure-activity relationship was investigated. The most effective compound was found to be GIZH-348 (1g) (3,4,6,7,8,9-hexahydrodibenzo[ b,d]furan-1(2Ц#157;)-one Ц#158;-(4-chlorophenyl)acryloyl)oxime) at the doses of 10-20 mg/kg.Conclusion: Molecular and pharmacophore modelling methods allowed us to create a new group of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime with anticonvulsant activity.