Design, synthesis, in vitro and in silico studies of 1,2,3-triazole incorporated tetrazoles as potent antitubercular agents

• Design and multi-step synthesis of benzo[d]oxazole-linked triazolyltetrazole hybrids. • In vitro and in vivo studies of synthesized compounds. • Significant antimicrobial and antitubercular activities . • Strong performance against both gram-negative and gram-positive bacteria. • Favourable ADME properties of synthesized compounds indicating their desirable pharmacokinetic properties and bioavailability. The search for effective antimycobacterial agents is a critical focus in medicinal chemistry. To this end, a novel series of benzo[d]oxazole-linked triazolyltetrazole hybrids was designed, synthesized, and characterized using 1 H/ 13 C NMR, FT-IR, and mass spectral data. Compounds 6a to 6k were tested in vitro against Gram-negative bacteria, Gram-positive bacteria, and Mycobacterium tuberculosis ( MTB ). Compounds 6d, 6e , and 6 h exhibited broad-spectrum antimicrobial activities, with compound 6e showing high potency against Gram-negative and Gram-positive bacteria due to low MIC values. Compound 6 h displayed significant antitubercular (anti-TB) activity with an MIC of 3.0 µg/mL, outperforming streptomycin. In silico docking studies with the CYP51 protein as the receptor revealed that both ligands, 6e and 6 h , engage in various hydrophobic interactions, including hydrogen bonds, π-cation, π-alkyl, π-π, and Van der Waals interactions. Based on the binding energy, both 6e and 6 h have shown strong affinity towards CYP51. The high negative binding energy of ligand 6e (-9.27 kcal/mol) indicates stronger and more stable interaction than ligand 6 h (-8.26 kcal/mol), suggesting that ligand 6e has higher binding efficacy to the MTB protein target. The chosen compounds adhere to important drug regulations, such as Lipinski's and Veber's rules, and possess good ADME qualities. Therefore, these bioactive molecules have favorable pharmacokinetic properties and bioavailability.