Design, Synthesis, Antimicrobial, and Antimalarial Evaluation of Quinoline Hydrazone Derivatives: Insight through Density Functional Theory Analysis, Molecular Docking, and Absorption, Distribution, Metabolism, Excretion, and Toxicity Predictions.

Abstract

Antimicrobial and antimalarial resistance are the major global health threats and indicating to develop novel targeted molecules to overcome the resistance problem. In this concern, in the present study, some quinoline hydrazone derivatives (6a-6o) have been synthesized and evaluated as antimicrobial and antimalarial agents. Compound 6o is observed to be the most active and presented equipotent antibacterial activity (MIC = 6.25 μg mL^-1) as the standard drug ofloxacin against Escherichia coli and Pseudomonas aeruginosa. Antimalarial activity showed that compound 6g exhibits maximum inhibitory action (IC₅₀ = 0.56 μg mL^-1) and is significant in contrast to standard drugs chloroquine (IC₅₀ = 0.020 μg mL^-1) and quinine (IC₅₀ = 0.268 μg mL^-1) against Plasmodium falciparum. Density functional theory analysis evaluates the chemical reactivity of molecular orbitals of the most active compounds 6g and 6o. Furthermore, molecular docking study showed that most active antimalarial (6g) and antimicrobial (6o) compounds exhibit potent interactions with targeted enzymes (lactate dehydrogenase and dihydrofolate reductase (DHFR), respectively). In silico drug-likeness parameters and absorption, distribution, metabolism, excretion, and toxicity study indicate that all the synthesized derivatives followed the acceptance criteria. The present study emphasizes that compounds 6g (antimalarial) and 6o (antimicrobial) can be developed as novel inhibitors against lactate dehydrogenase and DHFR enzyme, respectively, on the completion of drug discovery approaches.