Search

A new series of benzenesulfonamide derivatives, namely N-(1-(2-chloropyrimidin-4-yl)-1 H -indazol-5-yl) compounds (4a-i) and N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1 H -indazol-5-yl) derivatives (5a-i), were synthesized. This was achieved by reducing 1-(2-halopyrimidin-4-yl)-5-nitro-1 H -indazole (3) with SnCl2, followed by reacting with various aryl sulphonyl chlorides in pyridine. Structural confirmation was carried out through IR, 1H-NMR, 1 3 C-NMR and mass spectral methods. Anticancer activity evaluation of compounds 4a-i and 5a-i revealed that N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1H-indazol-5-yl)-2-nitrobenzenesulfonamide (5b) displayed exceptional efficacy. Molecular dynamics simulations were employed to rigorously assess the stability of ligand–protein complexes, highlighting a consistent and robust binding of the most potent compound within the binding sites of target proteins. The results unequivocally affirmed the remarkable anticancer activity, supported by comprehensive molecular docking analyses uncovering intricate interactions involving hydrogen bonds, electrostatic forces and hydrophobic contacts. These findings collectively offer invaluable insights into the complex molecular structure and dynamics of receptor target sites, establishing a robust foundation for the development of novel and potent anticancer agents with promising pharmaceutical implications. Research into newer N-benzenesulfonamide derivatives has identified potent anticancer agents, particularly compounds 5b and 5d, which exhibit exceptional efficacy through hydrogen bonding interactions with critical protein residues. The study combines anticancer activity assays, molecular docking, and molecular dynamics simulations to underscore their therapeutic potential. These findings highlight the promise of these compounds in combating cancer. [ABSTRACT FROM AUTHOR]

The essential oils (OEs) of the leaves, stems, and spikes of P. marginatum were obtained by hydrodistillation, steam distillation, and simultaneous extraction. The chemical constituents were identified and quantified by GC/MS and GC-FID. The preliminary biological activity was determined by assessing the toxicity of the samples to Artemia salina Leach larvae and calculating the mortality rate and lethal concentration (LC50). The antioxidant activity of the EOs was determined by the DPPH radical scavenging method. Molecular modeling was performed using molecular docking and molecular dynamics, with acetylcholinesterase being the molecular target. The OES yields ranged from 1.49% to 1.83%. The EOs and aromatic constituents of P. marginatum are characterized by the high contents of (E)-isoosmorhizole (19.4–32.9%), 2-methoxy-4,5-methylenedioxypropiophenone (9.0–19.9%), isoosmorhizole (1.6–24.5%), and 2-methoxy-4,5-methylenedioxypropiophenone isomer (1.6–14.3%). The antioxidant potential was significant in the OE of the leaves and stems of P. marginatum extracted by SD in November (84.9 ± 4.0 mg TE·mL−1) and the OEs of the leaves extracted by HD in March (126.8 ± 12.3 mg TE·mL−1). Regarding the preliminary toxicity, the OEs of Pm-SD-L-St-Nov and Pm-HD-L-St-Nov had mortality higher than 80% in concentrations of 25 µg·mL−1. This in silico study on essential oils elucidated the potential mechanism of interaction of the main compounds, which may serve as a basis for advances in this line of research. [ABSTRACT FROM AUTHOR]

Hydrazones typically have an azomethine '–NHN=CH group' which is crucial for varieties of pharmacological activities. In this study, we have synthesized a set of 15 new hydrazones (5A–5O) of 2-((2,3-dihydro-1H-inden-4-yl)oxy)acetohydrazide, which were characterized with various spectroscopic methods. It was found that the compound 5H had significant bioactivities (Antioxidant: DPPH assay: 80.3% inhibition; at 100 μ g/mL concentration; Antibacterial: Minimum inhibitory concentration (MIC) of 6.25 μ g/mL against E. coli; Antimycobacterial, H37Rv Vaccine strain: MIC of 3.12 μ g/mL; Anticancer: Trypan Blue assay, MCF-7; IC 5 0 values of 84.3 mM). To understand the probable underlying antibacterial mechanisms, we examined all hydrazones against a common bacterial target (2,2-dialkylglycine decarboxylase, PDB ID: 1d7u) and pantothenate synthase from Mycobacteria (PDB ID: 3ivx) using molecular docking. Our molecular dynamics simulations for 100 ns for both the complexes (5H:1d7u and 5H:3ivx) revealed significant stability of ligand–protein complex. Moreover, to correlate structural features with biological activity, we have developed statistically significant 5-parametric Quantitative Structure–Activity Relationships (QSAR) models. The pharmacophore hypothesis, AADHR_1 (5-point) signifies its importance for biological activities. Finally, we have examined the theoretical and pharmacokinetics and toxicity properties of all synthesized compounds. We have synthesized a set of 15 new hydrazones (5A-5O) of 2-((2,3-dihydro-1H-inden-4-yl)oxy)acetohydrazides. All compounds were characterized with various spectroscopic methods. It was found that the compound 5H had significant bioactivities (Antioxidant: DPPH assay: 80.3 % inhibition; at 100μg/mL concentration; Antibacterial: minimum inhibitory concentration (MIC) of 6.25 μg/mL against E. Coli; Antimycobacterial, H37Rv Vaccine strain: MIC of 3.12 μg/mL; Anticancer: Trypan Blue assay, MCF-7; IC50 values of 84.3 mM). Further, molecular modelling approaches were employed to investigate further for molecular mechanisms. [ABSTRACT FROM AUTHOR]

Human African trypanosomiasis (HAT), a fatal infection caused by Trypanosoma brucei (T. brucei) is considered as a neglected disease in the tropical areas, and newer agents with unique mechanism of action are urgently needed. In this work, 65 Imidazopyridine analogues from known literature were selected for building statistically robust genetic algorithm (GA) based QSAR models. Furthermore, values for the various cross-validation properties supported its statistical robustness (model 1, R tr 2 = 0. 8 5 3 7 , RMSE cv = 0. 3 5 8 6 , MAE cv = 0. 2 6 4 2 , CCC cv = 0. 8 9 5 3 , and Q LMO 2 = 0. 7 8 8 7). Our in silico ADMET analysis revealed that a designed molecule, S10 may act as potent lead (T. brucei, pEC 5 0 (μ M), predicted = 8. 2 0 0) with better pharmacokinetics, no carcinogenicity, class III acute oral toxicity, minimal OCT1 and OCT2 inhibitions and no eye corrosion profiles. Our molecular docking analysis (on 42 drug targets) for a dataset and designed molecules demonstrated higher binding affinity of Imidazopyridine analogues with T. brucei farnesyl diphosphate synthase (TbFPPS) (PDB id: 2I19). This observation was further supported by 100 ns molecular dynamics analysis retaining better stability of complex. Thus, imidazopyridine analogues would provide a promising scaffold for the development of anti-HAT agents. Human African trypanosomiasis (HAT), a fatal infection caused by Trypanosoma brucei, is considered as a neglected disease in the tropical areas, and newer agents with unique mechanism of action are urgently needed. In this present work, 65 Imidazopyridine analogues from known literature were selected for building statistically robust genetic algorithm (GA) based QSAR models. Furthermore, values for the various cross-validation properties supported its statistical robustness. Our in-silico ADMET analysis revealed that a designed molecule, S10 may act as potent lead (T. brucei, pEC 50 (μM), predicted = 8.200) with better pharmacokinetics, no carcinogenicity, class III acute oral toxicity, minimal OCT1 and OCT2 inhibitions, and no eye corrosion profiles. [ABSTRACT FROM AUTHOR]