Synthesis of Pyrazoline Carbothioamide Derivatives, Analysis of their Antimicrobial Potential by in-silico Molecular Docking, DFT and ADMET Studies and in-vitro Phenotypic Evaluation of their Antibacterial and Antioxidant Activities

Abstract

Pyrazoline is a five-membered heterocyclic compound that contains two adjacent nitrogen atoms; one is pyrrole-like nitrogen which is non-basic nitrogen with a lone pair involved in the aromaticity while the other is pyridine-like nitrogen with a lone pair which is basic and nucleophilic. Pyrazolines are dihydropyrazoles, with only one double bond (imine bond), existing in three possible tautomeric forms, namely 1-, 2- and 3-pyrazolines. Pyrazoline containing heterocyclic compounds constitute an interesting class due to their synthetic versatility and effective therapeutic activities against several diseases. Currently, synthetic modifications of pyrazoline carbothioamide derivatives turn out to be an exciting approach to enhance their biological properties in line with their application. As a result, pyrazoline carbothioamide derivatives become good candidates and potential classes of organic compounds to play an important role in medicinal chemistry. In present study, five novel pyrazoline carbothioamide derivatives were synthesized with yield range of 56-78 %. The synthesized compounds were characterized using spectroscopic techniques (1H-NMR and 13C-NMR). Furthermore, the synthesized compounds were evaluated for their in-vitro antibacterial activity against two Gram-positive bacterial strains (S. aureus and S. pyogenes) and two Gram-negative bacterial strains (P. aeruginosa and E. coli) by minimum inhibitory concentration method. The synthesized compounds showed good inhibitory activity against S. pyogenes and P. aeruginosa when compared to standard drug amoxicillin. The radical scavenging activities of these compounds were evaluated using DPPH radical assay and among the synthesized compounds, compound 102c and 102d showed the strongest activity with IC50 values of 1.92 and 1.90 µg/mL, respectively. The synthesized compounds were evaluated for their in silico molecular docking analysis using S. aureus Gyrase and found to have minimum binding energy ranging from -9.0 to -9.6 kcal/mol. Compound 102b scored better docking efficiency with binding affinity of -9.6 kcal/mol. The drug likenesses of the synthesized compounds were performed and satisfy the Lipinski’s rule of five with zero violations. Hence, all the synthesized compounds might be candidates for further in-vivo antibacterial studies.