Novel Antitubercular Derivatives of Mannich and Schiff Bases of p-Aminosalicylic Acid – Rational Design

Abstract

Aims: The aim of the current study is to utilize computational drug design resources to develop and identify promising structural analogs of p-aminosalicylic acid (PAS), to improvise antitubercular activity followed by their synthesis, characterization, and in-vitro biological activity determination. Study Design: Design of the structural analogs of PAS by functional group modification at -COOH and -NH2 groups followed by in-silico prediction of biological activity, toxicity, drug-likeness filters, and molecular docking study to select promising analogs. Synthesis of selected analogs, structural characterization, and screening of biological activity of the same. Methodology: Using the Prediction of Activity Spectrum of Substances (PASS Online) database, prediction of biological activity was performed for PAS and 22 designed structural analogs of PAS. All these analogs were screened for their drug-likeness properties using Lipinski’s rule of five. Later all these 22 analogs were predicted for their toxicities using OSIRIS Property Explorer. At this stage, out of 22 analogs, only 6 analogs were selected to go for molecular docking using AutoDock Tools and AutoDock Vina for the determination of their binding energies by comparing with PAS. The selected 6 analogs were synthesized using three-step syntheses. The synthesized analogs were screened for their antitubercular activity using the Microplate Alamar Blue Assay (MABA) method. Results: Overall 22 structural analogs were designed and screened for their estimated activity (all analogs showed antitubercular activity as primary activity), drug-likeness (all analogs passed), and toxicities (only 10 analogs passed) using computational tools. Out of 22 analogs, 6 analogs were selected and performed molecular docking using AutoDock Vina. All 6 analogs showed better binding affinity than PAS. These 6 analogs (7a-f) were synthesized, characterized, and screened for their in-vitro antitubercular activity. Results showed that 5 analogs, 7b-7f, showed excellent antitubercular potency greater than PAS and equipotent activity to that of standard drugs. Analog 7a was found to be less potent than PAS. Conclusion: Hence, the structural analogs of PAS, 7b-7f, were found to have better antitubercular activity than the lead compound, PAS, and equipotent to that of the standards, streptomycin, ciprofloxacin, and pyrazinamide.