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Introduction: In malaria management, insecticides play a crucial role in targeting disease vectors. Benzothiazole derivatives have also been reported to possess insecticidal properties, among several other properties they exhibit. The female Anopheles mosquito is responsible for transmitting the malaria parasite when infected. Anopheles gambiae (Ag) and Anopheles funestus (Af) are two of the most notable Anopheles species known to spread malaria in Nigeria. Trehalase is an enzyme that breaks down trehalose. Recent research has proposed it as a viable target for inhibition since it aids in flight and stress adaptation. Methods: This study aimed to investigate benzothiazole derivatives as potential inhibitors of trehalase of Anopheles funestus (AfTre) and Anopheles gambiae (AgTre) using toxicity profiling, molecular docking, and dynamic simulation for future insecticidal intervention. A total of 4,214 benzothiazole-based compounds were obtained from the PubChem database and subjected to screening against the 3D modelled structure of AfTre and AgTre. Compounds with some toxicity levels were optimised, and the obtained lead compounds were further investigated through molecular docking studies. Furthermore, the best hit was subjected to parameters such as RMSD, RMSF, SASA, Rg, and hydrogen bond to confirm its stability when in a complex with AfTre, and these parameters were compared to that of validamycin A (control ligand). Results and discussion: The post-screening analysis showed binding affinities of -8.7 and -8.2 kcal/mol (compound 1), -8.2 and -7.4 kcal/mol (compound 2), compared to -6.3 and -5.1 kcal/mol (Validamycin A, a known inhibitor) against AfTre and AgTre, respectively. The molecular dynamics simulation showed that compound 1 (the best hit) had good stability when in complex with AfTre. These findings suggest that these best hits can serve as potential inhibitors for the development of novel insecticides in the control of malaria vectors.
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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.
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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.
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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.
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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.