In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance.

The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of -9.1, -8.9, and -8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (-9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants.

Structure-based design, and development of amidinyl, amidoximyl and hydroxamic acid based organic molecules as novel antimalarial drug candidates.

Malaria remains a significant global health concern causing numerous fatalities and the emergence of antimalarial drug resistance highlights the urgent need for novel therapeutic options with innovative mechanisms of action and targets. This study aimed to design potential inhibitors of Plasmodium falciparum 6-pyruvoyltetrahydropterin synthase (PfPTPS), synthesize them, and experimentally validate their efficacy as antimalarial agents. A structure-based approach was employed to design a series of novel derivatives, including amidinyl, amidoximyl and hydroxamic acid analogs (1c, 1d, 2b, and 3b), with a focus on their ability to bind to the Zn2+ present in the active site of PfPTPS. The syntheses of these compounds were accomplished through various multi-step synthetic pathways and their structural identities were confirmed using 1H and 13C NMR spectra, mass spectra, and elemental analysis. The compounds were screened for their antiplasmodial activity against the NF54 strain of P. falciparum and in vitro cytotoxicity testing was performed using L-6 cells. The in vivo acute toxicity of the compounds was evaluated in mice. Docking studies of the compounds with the 3D structure of PfPTPS revealed their strong binding affinities, with compound 3b exhibiting notable metal-acceptor interaction with the Zn2+ in the protein binding pocket thereby positioning it as a lead compound for PfPTPS inhibition. The in vitro antiplasmodial studies revealed moderate efficacies against the Pf NF54 strain, particularly compounds 1d and 3b which displayed IC50 < 0.2 µM. No significant cytotoxicity was noted on the L-6 rat cell line. Moreover, in vivo studies suggested that compound 3b exhibited both safety and efficacy in treating rodent malaria. The identified lead compound in this study represents a possible candidate for antimalarial drug development and can be further explored in the search for alternative antifolate drugs to combat the malaria menace.

Synthesis, in silico and in vitro antimicrobial efficacy of substituted arylidene-based quinazolin-4(3H)-one motifs.

Introduction: Quinazolin-4(3H)-one derivatives have attracted considerable attention in the pharmacological profiling of therapeutic drug targets. The present article reveals the development of arylidene-based quinazolin-4(3H)-one motifs as potential antimicrobial drug candidates. Methods: The synthetic pathway was initiated through thermal cyclization of acetic anhydride on anthranilic acid to produce 2-methyl-4H-3,1-benzoxazan-4-one 1, which (upon condensation with hydrazine hydrate) gave 3-amino-2-methylquinazolin-4(3H)-one 2. The reaction of intermediate 2 at its amino side arm with various benzaldehyde derivatives furnished the final products, in the form of substituted benzylidene-based quinazolin-4(3H)-one motifs 3a-l, and with thiophene-2-carbaldehyde to afford 3 m. The purified targeted products 3a-m were effectively characterized for structural authentication using physicochemical parameters, microanalytical data, and spectroscopic methods, including IR, UV, and 1H- and 13C-NMR, as well as mass spectral data. The substituted arylidene-based quinazolin-4(3H)-one motifs 3a-m were screened for both in silico and in vitro antimicrobial properties against selected bacteria and fungi. The in silico studies carried out consisted of predicted ADMET screening, molecular docking, and molecular dynamics (MD) simulation studies. Furthermore, in vitro experimental validation was performed using the agar diffusion method, and the standard antibacterial and antifungal drugs used were gentamicin and ketoconazole, respectively. Results and discussion: Most of the compounds possessed good binding affinities according to the molecular docking studies, while MD simulation revealed their levels of structural stability in the protein-ligand complexes. 2-methyl-3-((thiophen-2-ylmethylene)amino) quinazolin-4(3H)-one 3 m emerged as both the most active antibacterial agent (with an minimum inhibitory concentration (MIC) value of 1.95 µg/mL) against Staphylococcus aureus and the most active antifungal agent (with an MIC value of 3.90 µg/mL) against Candida albicans, Aspergillus niger, and Rhizopus nigricans.

Chemistry and Pharmacological diversity of Benzothiazepine - Excellent pathway to drug discovery.

In this era of sporadic advancement in science and technology, a substantial amount of intervention is being set in motion to reduce health-related diseases. Discoveries from researchers have pinpointed the usefulness of heterocyclic compounds, amongst which benzothiazepine (BTZ) derivatives have been synthesized for their various pharmacological activities. This also contributes to their undeniable application in therapeutic medicine for the development of efficacious drugs. BTZs are compounds with a benzene ring fused with a thiazepine ring. This work contains several methods that have been used to synthesize 1,3-, 1,4-, 1,5-, and 4-1-benzothiazepine derivatives. In addition, up-to-date information about the crucial pharmacological activities of BTZ derivatives has been reviewed in this present study to appreciate their druggable potential in therapeutic medicine for drug development. Drug design and development have further been simplified with the implementation of computer aided approaches to predict biological interactions which can help in the design of several derivatives. Hence, the structural activity relationship (SAR), ADMET and the molecular docking studies of BTZ derivatives were discussed to further establish their interactions and safety in biological systems. This present work aims to expound on the reported chemistry and pharmacological propensity of BTZ moiety in relation to other relevant moieties to validate their potential as excellent pharmacophores in drug design and development.

Recent advances in chemistry and therapeutic potential of functionalized quinoline motifs - a review.

Quinoline, which consists of benzene fused with N-heterocyclic pyridine, has received considerable attention as a core template in drug design because of its broad spectrum of bioactivity. This review aims to present the recent advances in chemistry, medicinal potential and pharmacological applications of quinoline motifs to unveil their substantial efficacies for future drug development. Essential information in all the current and available literature used was accessed and retrieved using different search engines and databases, including Scopus, ISI Web of Knowledge, Google and PUBMED. Numerous derivatives of the bioactive quinolines have been harnessed via expeditious synthetic approaches, as highlighted herein. This review reveals that quinoline is an indisputable pharmacophore due to its tremendous benefits in medicinal chemistry research and other valuable areas of human endeavour. The recent in vivo and in vitro screening reported by scientists is highlighted herein, which may pave the way for novel drug development. Owing to the array of information available and highlighted herein on the medicinal potential of quinoline and its functionalized derivatives, a new window of opportunity may be opened to medicinal chemists to access more biomolecular quinolines for future drug development.

Recent advances in functionalized quinoline scaffolds and hybrids-Exceptional pharmacophore in therapeutic medicine.

Quinoline is one of the most common nitrogen-containing heterocycles owing to its fascinating pharmacological properties and synthetic value in organic and pharmaceutical chemistry. Functionalization of this moiety at different positions has allowed for varying pharmacological activities of its derivative. Several publications over the last few decades have specified various methods of synthesis. This includes classical methods of synthesizing the primary quinoline derivatives and efficient methods that reduce reaction time with increased yield employing procedures that fulfill one of the twelve green chemistry principles, "safer solvent". The metal nanoparticle-catalyzed reaction also serves as a potent and effective technique for the synthesis of quinoline with excellent atom efficiency. The primary focus of this review is to highlight the routes to synthesizing functionalized quinoline derivatives, including hybrids that have moieties with predetermined activities bound to the quinoline moiety which are of interest in synthesizing drug candidates with dual modes of action, overcoming toxicity, and resistance amongst others. This was achieved using updated literature, stating the biological activities and mechanisms through which these compounds administer relief. The ADMET studies and Structure-Activity Relationship (SAR) of novel derivatives were also highlighted to explore the drug-likeness of the quinoline-hybrids and the influence of substituent characteristics and position on the biological activity of the compounds.

Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[d]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium falciparum Adenylosuccinate Lyase Receptor.

Plasmodium falciparum adenylosuccinate lyase (PfADSL) is an important enzyme in purine metabolism. Although several benzimidazole derivatives have been commercially developed into drugs, the template design as inhibitor against PfADSL has not been fully explored. This study aims to model the 3-dimensional (3D) structure of PfADSL, design and predict in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) of 8 substituted benzo[d]imidazol-1-yl)methyl)benzimidamide compounds as well as predict the potential interaction modes and binding affinities of the designed ligands with the modelled PfADSL. PfADSL 3D structure was modelled using SWISS-MODEL, whereas the compounds were designed using ChemDraw Professional. ADMET predictions were done using OSIRIS Property Explorer and Swiss ADME, whereas molecular docking was done with AutoDock Tools. All designed compounds exhibited good in silico ADMET properties, hence can be considered safe for drug development. Binding energies ranged from -6.85 to -8.75 kcal/mol. Thus, they could be further synthesised and developed into active commercial antimalarial drugs.

Chemistry and pharmacological diversity of quinoxaline motifs as anticancer agents.

Surpassing heart diseases, cancer is taking the lead as the deadliest disease because of its fast rate of spreading in all parts of the world. Tireless commitment to searching for novel therapeutic medicines is a worthwhile adventure in synthetic chemistry because of the drug resistance predicament and regular outbreak of new diseases due to abnormal cell growth and proliferation. Medicinal chemistry researchers and pharmacists have unveiled quinoxaline templates as precursors of importance and valuable intermediates in drug discovery because they have been established to possess diverse pharmacological potentials. Hence, this review highlights the current versatile routes to accessing functionalized quinoxaline motifs and harnessing their documented therapeutic potentials for anticancer drug development.

Structure-based design of functionalized 2-substituted and 1,2-disubstituted benzimidazole derivatives and their in vitro antibacterial efficacy.

The aim of this present study was to synthesize 2-substituted and 1,2-disubstituted benzimidazole derivatives to investigate their antibacterial diversity for possible future drug design. The structure-based design of precursors 2-(1H-benzimidazol-2-yl)aniline 1, 2-(3,5-dinitro phenyl)-1H-benzimidazole 3 and 2-benzyl-1H-benzimidazole 5 were achieved by the condensation reaction of o-phenylenediamine with anthranilic acid, 3,5-dinitrophenylbenzoic acid, and phenylacetic acid, respectively. The precursors 1, 3 and 5, upon reaction with six different electrophile-releasing agents, furnished the corresponding 2-substituted benzimidazole, 2a-f and 1,2-disubstituted benzimidazole derivatives 4a-f and 6a-f, respectively. The structural identity of the targeted compounds was authenticated by elemental analytical data and spectral information from FT-IR, UV, 1H, and 13C NMR. The outcome of the findings from the in vitro screening unveiled 2-benzyl-1-(phenylsulfonyl)-1H-benzimidazole 6b as the most active derivative with lowest MIC value of 15.63 µg/mL.

Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine.

Benzimidazole derivatives are crucial structural scaffolds found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal research. They are structural isosteres of naturally occurring nucleotides, which allows them to interact with the biopolymers of living systems. Hence, there is a need to couple the latest information with the earlier documentations to understand the current status of the benzimidazole nucleus in medicinal chemistry research. This present work unveils the benzimidazole core as a multifunctional nucleus that serves as a resourceful tool of information for synthetic modifications of old existing candidates in order to tackle drug resistance bottlenecks in therapeutic medicine. This manuscript deals with the recent advances in the synthesis of benzimidazole derivatives, the widespread biological activities as well as pharmacokinetic reports. These present them as a toolbox for fighting infectious diseases and also make them excellent candidates for future drug design.

Room temperature synthesis and antibacterial activity of new sulfonamides containing n,n-diethyl-substituted amido moieties.

Sulfonamide drugs which have brought about an antibiotic revolution in medicine are associated with a wide range of biological activities. We have synthesized a series of α-tolylsulfonamide, 1-11 and their substituted N,N-diethyl-2-(phenylmethylsulfonamido) alkanamide derivatives, 12-22 in improved and excellent yields in aqueous medium at room temperature through highly economical synthetic routes. The chemical structures of the synthesized compounds 1-22 were confirmed by analytical and spectral data such as IR, (1)H- and (13)C-NMR, and mass spectra. The in vitro antibacterial activity of these compounds along with standard clinical reference, streptomycin, was investigated on two key targeted organisms. It was observed that 1-(benzylsulfonyl)pyrrolidine-2-carboxylic acid, 2 emerged as the most active compound against Staphylococcus aureus at MIC value of 1.8 µg/mL while 4-(3-(diethylamino)-3-oxo-2-(phenylmethylsulfonamido) propyl)phenyl phenylmethanesulfonate, 22 was the most active sulfonamide scaffold on Escherichia coli at MIC value of 12.5 µg/mL.

Microwave assisted synthesis and antimicrobial activity of 2-quinoxalinone-3-hydrazone derivatives.

A simple and efficient method has been developed for the synthesis of various 2-quinoxalinone-3-hydrazone derivatives using microwave irradiation technique. The series of 2-quinoxalinone-3-hydrazone derivatives synthesized, were structurally confirmed by analytical and spectral data and evaluated for their antimicrobial activities. The results showed that this skeletal framework exhibited marked potency as antimicrobial agents. The most active antibacterial agent was 3-{2-[1-(6-chloro-2-oxo-2H-chromen-3-yl)ethylidene]hydrazinyl}quinoxalin-2(1H)-one, 7 while 3-[2-(propan-2-ylidene)hydrazinyl]quinoxalin-2(1H)-one, 2 appeared to be the most active antifungal agent.