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In this study, new series of N'-(2-(substitutedphenoxy)acetyl)-4-(1H-pyrrol-1-yl)benzohydrazides (3a-j) 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N'-(2-(substitutedphenoxy)acetyl)benzohydrazides (5a-j) were synthesized, characterized and assessed as inhibitors of enoyl ACP reductase and DHFR. Most of the compounds exhibited dual inhibition against the enzymes enoyl ACP reductase and DHFR. Several synthesized substances also demonstrated significant antibacterial and antitubercular properties. A molecular docking analysis was conducted in order to determine the potential mechanism of action of the synthesized compounds. The results indicated that there were binding interactions seen with the active sites of dihydrofolate reductase and enoyl ACP reductase. Additionally, important structural details were identified that play a critical role in sustaining the dual inhibitory activity. These findings were useful for the development of future dual inhibitors. Therefore, this study provided strong evidence that several synthesized molecules could exert their antitubercular properties at the cellular level through multi-target inhibition. By shedding light on the mechanisms through which these compounds exert their inhibitory effects, this research opens up promising avenues for the future development of dual inhibitors with enhanced antibacterial and antitubercular properties. The study's findings underscore the importance of multi-target approaches in drug design, providing a strong foundation for the design and optimization of novel compounds that can effectively target bacterial infections at the cellular level.

In this study, a new series of 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N’-(2-(substituted)acetyl) benzohydrazides (5a–n) were prepared and new heterocycles underwent thorough characterization and evaluation for antibacterial activity; some of them underwent further testing for in vitro inhibition of enoyl ACP reductase and DHFR enzymes. The majority of the synthesized molecules exhibited appreciable action against DHFR and enoyl ACP reductase enzymes. Some of the synthesized compounds also showed strong antibacterial and antitubercular properties. In order to determine the potential mode of action of the synthesized compounds, a molecular docking investigation was conducted. The results revealed binding interactions with both the dihydrofolate reductase and enoyl ACP reductase active sites. These molecules represent excellent future therapeutic possibilities with potential uses in the biological and medical sciences due to the compounds’ pronounced docking properties and biological activity.

In search of potent anti-mycobacterial agents, enoyl-ACP reductase enzyme found to be most probable due to its imperative role in type II fatty acid synthesis (FAS), while mycolic acid production in Mycobacterium tuberculosis (M. tuberculosis), which is the appropriate entity for the discovery of antimycobacterial agents due to its primary role in the metabolism. Hence, blocking of enoyl ACP reductase would be important to develop novel antitubercular drugs development. Pyrrole, which is one of the five membered heterocyclic moieties habitually institute in few of naturally occurring and organic products of various classes, plays a significant part in medicinal drug discovery. In this work, docking and 3D-QSAR (CoMFA and CoMSIA) studies were performed on a set of pyrrolyl phenoxy acetohydrazides. As per docking study, TYR158 and co-factor NAD+ are important amino acid residue at active site of enzyme for binding with the ligand. Among all the tested molecules, Compounds 4 and 28 have shown good docking scores of 7.08 and 8.85 respectively, steric and electrostatic field in CoMFA model displayed q2 = 0.511, r 2 = 0.822 while that of CoMSIA model displayed q2 = 0.625, r2 = 0.764 with the SEE values of of 0.314 and 0.607. Docking study revealed complete structurally imperative binding topographies between the pyrrole scaffolds and enoyl ACP reductase enzyme. Our studies offered useful information and evidence for designing of molecules with enhanced InhA inhibition. [ABSTRACT FROM AUTHOR]