Introduction:
Progress in the development of triazolyl-oxadiazoles is a bisphosphonate-700 inhibitor is still continuing with an outcome of the good scaffold as oxadiazole as well as triazoles individually for antibacterial activity. Hence, we proposed a suitable approach for the synthesis of dual heterocyclic analogues consisting of the therapeutically used non steroidal anti-inflammatory drugs in a combined form and evaluated for their antibacterial, antifungal activities, docking studies.
Methods:
The chemical structures were confirmed by various spectroscopic methods like IR, 1H NMR, 13C NMR, mass, and elemental analysis. The antibacterial, antifungal activity of these compounds was screened against Gram-positive, Gram-negative bacteria and fungal stains by agar well diffusion method. The crystal structure of S. aureus complexed with active site of bisphosphonate BPH-700 (2ZCS) was obtained from the Protein Database (PDB, http://www.rcsb.org). Molecular properties, drug likeness score, lipophilicity and solubility parameters by Molinspiration and Molsoft software.
7f (2-NO2, 5-Ome), 7g (3-Cl, 4-Cl), 7a (2-NO2)
Results:
Among the synthesised NSAID-triazolyl-oxadiazole containing 2-nitro-5-methoxy (7f), 3,4-dichloro (7g) derivatives were found to be high active antibacterial agents against S. aureus, E. coli with MICs 16, 19 μg/mL respectively. 2-nitro-5-methoxy (7f), 4-bromo (7h) and 2-nitro (7a) derivatives displayed superior antifungal activity against A. niger and MICs 56, 76, 130 μg/mL respectively. From molecular docking NSAID linked to 3,4-dichloro analogue (7g) revealed stronger binding interaction (ΔG =7.90 Kcal/Mol) with amino acids Asp49 (1.19 A˚), Arg45 (2.17 A˚), Lys17, Lys46 in the active site of S. aureus complexed with bisphosphonate Bph-700 (2ZCS). The compounds followed the Lipinski ‘Rule of five’ were synthesized for antimicrobial screening as oral bioavailable drugs/leads. Maximum drug likeness model score 0.49, 0.41 was found for compounds 7h, 7b.
Conclusion: The present work, through simple synthetic approaches, led to the development of novel hybrids of triazole-oxadiazole pharmacophores that exhibited remarkable biological activities against different microorganisms. The compounds showed suitable drug like properties and are expected to present good bioavailability profile.
Discussion:
An efficient combination of molecular modeling and biological activity provided an insight into QSAR guide lines that could aid in further development of these derivatives.
Design, Synthesis, and Antifungal Activity of New α-Aminophosphonates
