Synthesis, ADME Profiling, Antibacterial Screening and Molecular Docking of Some New Tetrazole-Heterocycle Hybrids

Over the past 20 years, there has been a notable rise in the incidence of invasive bacterial infections. This increase has been mostly linked to the growth of drug-resistant bacteria. Tetrazoles have been considered as promising antibacterial agents and their effectiveness may be enhanced by hybridization with other antibacterial pharmacophores. In this work, a series of tetrazole hybrids (1-6) containing oxazepane and pyrazole rings as well as Mannich bases (7,8) were synthesized via the Schiff and Mannich reactions, respectively. The compositions were proven spectroscopically using infrared spectra, proton (1H) and carbon-13 (13C) nuclear magnetic resonance spectra and elemental analyses. Moreover, the pharmacokinetic properties viz Absorption, Distribution, Metabolism and Excretion (ADME) were predicted in silico using SwissADME server. Compounds 1,2 and 4-6 attaining the best drug-likeness properties were screened for their antibacterial activities against Staphylococcus epidermidis and Streptococcus mutans at different concentrations in comparison with tetracycline and amikacin, respectively. Afterwards, a molecular docking study was performed to explore the potential binding patterns of the new antibacterial compounds. Collectively, the tetrazole hybrids 4 and 5 have been found to have higher inhibitory potencies compared to tetracycline, serving them as potential antibacterial candidates which can be further optimized in the future. This work aims at discovering novel antibacterial agents through hybridization of the tetrazole functionality with some heterocyclic moieties such as oxazepanes and pyrazoles. The new hybrids were tested for their antibacterial activity after achieving good physicochemical properties using SwissADME. Then, the new compounds were docked into the binding site of Staphylococcus epidermis TcaR to rationalize the obtained activity. image