Hybrids of 4-aminosalicylic acid with dual anti-mycobacterial and anti-inflammatory activities: Synthesis, biological evaluation, in silico investigation and structure-activity relationships exploration

Studies point toward a beneficial effect of NSAIDs as an adjunctive tuberculosis treatment. To discover new antitubercular compounds with anti-inflammatory activity and favorable safety profiles, three new series of non-carboxylic 4-aminosalicylic acid hybrids bearing various hydrazides (3 and 5), heterocyclic scaffolds (6-15), hydrazones (16a-d) and carboxylic analogues bearing 1,2,3-triazoles (19 and 20), were synthesized. The synthesized hybrids were evaluated for their antimycobacterial activity against H37Rv using MABA assay. Among them, compounds 8, 16a-c, 19 and 20 exhibited MIC values (9.90 - 37.62 µM) with good selectivity index. 16b and 20 were the most potent with MIC 9.90 and 11.40 µM, respectively. Based on an in silico docking study at COX-2 active site, 11 compounds 13a, 13b, 14a-g, 16a and 16b were selected for testing their COX-2 inhibition. The most active compounds, 13a, 16a and 16b were further tested for COX-1 and 5-LOX inhibition. Also, their COX-2 selectivity indices (SI) were determined. 16a and 16b showed the highest potency and selectivity against COX-2 IC50 = 0.31, 1.26 µg/mL, respectively, and 5-LOX with IC50 = 5.49, 25.44 µg/mL, respectively. Computational docking simulations and in Silico ADME/pharmacokinetic studies for the most active hybrids were performed and discussed. Thus structure-activity relationships were explored. In conclusion, compounds 16a and 16b represent a good starting point for the development of new potential drugs of dual antitubercular and anti-inflammatory activities.