A plethora of non‐steroidal anti‐inflammatory drugs are available in the market with adverse side effects like gastrointestinal irritation, bleeding, and ulceration. Currently, the focus of researcher on the development of better, synergistic molecules by the hybridization of two or more active biomolecule or ligands to develop newer derivative possessing good anti‐inflammatory activity with minimum side effects. In line with this, the present study was designed to synthesize a series of merged pharmacophore contaning1,2,4‐triazoles and substituted benzyl groups via thio linkage. Purity of the derivatives was confirmed by thin‐layer chromatography, combustion analysis, and melting point. Structure of these derivatives was set up by determining infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectroscopy. All the synthesized derivatives were evaluated for their analgesic and anti‐inflammatory activities in mice and rats, respectively. In animal studies, the derivative 3‐(5‐(4‐nitrobenzylthio)‐4H‐1,2,4‐triazol‐3‐yl) pyridine showed more potent analgesic activity, and the derivative 3‐(5‐(2,4‐dimethylbenzylthio)‐4H‐1,2,4‐triazol‐3‐yl) pyridine showed more potent anti‐inflammatory activity as compared with other derivatives. The results of the present study indicate that reaction of pyridine linked 1,2,4‐triazole‐3‐thiol with different substituted benzyl halides to produce merged pharmacophore contaning1,2,4‐triazoles and substituted benzyl groups with potent analgesic and anti‐inflammatory activities. Docking studies were performed by using Argus lab, and all the derivatives exhibited good docking scores between −10 and −12 kcal/mol and were better as compared with standard drugs aspirin and indomethacin against cyclooxygenase‐2. Among all compounds, 3j has shown the maximum docking score and found in agreement to in pharmacological activities.

A novel 1,2,4‐triazole‐pyridine hybrid derivatives were synthesized by the reaction of nicotinohydrazide with carbon disulfide to yield potassium‐3‐pyridyl‐dithiocarbazate (I). This was further cyclized with ammonia solution to yield 5‐mercapto‐substituted 1,2,4‐triazole‐pyridine hybrid (II). This was finally reacted with different substituted benzyl derivatives to produce 1,2,4‐triazole‐pyridine hybrid derivatives (III). The purity of the derivatives was confirmed by thin‐layer chromatography and melting point. Structure of these derivatives was set up by determining its infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectroscopy. Further, the synthesized derivatives were evaluated for their in vitro antimicrobial activity against the three Gram‐negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Acinetbacter baumannii), three Gram‐positive bacteria (Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis), and two fungus (Aspergillus clavatus and Candida albicans). Minimal inhibitory concentration was also determined against same microorganism. Out of all synthesized derivatives, two derivatives, that is, 3‐(5‐(2‐bromobenzylthio)‐4H‐1,2,4‐triazol‐3‐yl)pyridine and 3‐(5‐(2,4‐dibromobenzylthio)‐4H‐1,2,4‐triazol‐3‐yl)pyridine showing more potent antibacterial activity. Docking studies were performed by using Argus lab, and all the derivatives exhibited good docking scores between −10.5369 and −11.8477 kcal/mol and were better as compared with standard drug methotrexate against a dihydrofolate reductase protein fragment from E. coli and Lactobacillus (4DFR). Among all compounds, 4h has shown the maximum docking score and found in agreement to in vitro antimicrobial studies.