1,3,4-oxadiazole derivatives: synthesis, characterization, antifungal activity, DNA binding investigations, TD-DFT calculations, and molecular modelling

Abstract

1,3,4-Oxadiazole-based heterocyclic analogs (3a–3m) were synthesized via cyclization of Schiff bases with substituted aldehydes in the presence of bromine and acetic acid. The structural clarification of synthesized molecules was carried out with various spectroscopic techniques such as FT-IR,¹H and ¹³C-NMR, UV–visible spectroscopy, and mass spectrometry. In-vitro antifungal activity was performed against C. albicans, C. glabrata and C. tropicalis and analogs 3g, 3i, and 3m showed potent MIC at 200 µg/ml and excellent ZOI measurements of 17–21 nm. The cell viability on Huh7 for lead molecules 3g, 3i, and 3m was found to be 99.5%, 92.3%, and 86.9% at 20, 10, and 20 μM, respectively. The antioxidant activity of molecules 3 g, 3i, and 3 m was estimated and exhibited great IC₅₀ values of 0.104 ± 0.021, 0.145 ± 0.05, and 0.165 ± 0.018 μg/mL with DPPH and 0.107 ± 0.04, 0.191 ± 0.12, and 0.106 ± 0.08 with H₂O₂, respectively. The binding interaction mode for the lead molecules was also carried out with Ct-DNA using the absorption, emission, CV, CD, and Time resolve fluorescence techniques. The results showed good binding constant (K_b) values of 9.1 × 10⁵, 9.94 × 10⁵, and 9.32 × 10⁵ M⁻¹ for 3g, 3i, and 3m, respectively. TD-DFT study of compounds 3g, 3i, and 3m was done to find out HOMO/LUMO energy levels, surface study of the molecular electrostatic potential, Mulliken population analysis, and natural bond orbitals showing the linkages between the donors and acceptors.Molecular docking of three lead analogs with PDB ID: 1BNA and molecular modelling of compounds 3g, 3i, and 3m with C. albicans CYP51 protein (PDB ID: 5FSA) were carried out.

Communicated by Ramaswamy H. Sarma

Keywords:

• 1
• 3
• 4-Oxadiazole derivatives
• antifungal
• antioxidant
• Ct-DNA binding
• MD simulations
• TD-DFT calculations

Acknowledgments

Authors are very thankful to the In-charge, Centre Instrumentation Facilities, JMI, New Delhi. R. Mehandi (BMI/11(64)/2022) also acknowledges to the ICMR, New Delhi, for ICMR-SRF.

Data availability statement

The datasets generated and/or analyzed during the current study are available in the manuscript file.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author’s contribution

Rabiya Mehandi: Experimental work, investigation, data analysis, writing the original draft. Charmy Twala: MD simulation studies. Saiema Ahmedi: Antifungal studies. Aysha Fatima: DFT calculations and data analysis. Khursheed Ul Islam: MTT assay analysis. Manish Rana: Data analysis. Razia Sultana: Data analysis. Nikhat Manzoor: Antifungal studies, data analysis. Saleem Javed: DFT calculations and data analysis. Mohammad Mahfuzul Haque: Thermal analysis. Jawed Iqbal: MTT assay analysis. Rahisuddin- Data analysis, Methodology, Editing the manuscript, Supervision. Nahid Nishat: Data analysis, Editing the manuscript, Supervision.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.