Investigation of potential anti-malarial lead candidate 2-(4-fluorobenzylthio)-5-(5-bromothiophen-2-yl)-1,3,4-oxadiazole: Insights from crystal structure, DFT, QTAIM and hybrid QM/MM binding energy analysis

• Published in: Journal of molecular structure 2019-01, Vol.1175, p.230-240
• Main Authors: Al-Wahaibi, Lamya H., Santhosh Kumar, Nandakumar, El-Emam, Ali A., Venkataramanan, Natarajan S., Ghabbour, Hazem A., Al-Tamimi, Abdul-Malek S., Percino, Judith, Thamotharan, Subbiah
• Format: Article
• Language: English
• Subjects: Anti-malarial; DHFR; Hetero-halogen contact; Hybrid QM/MM; Oxadiazole; Thiophene
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2018.07.102

A combined study involving single crystal X-ray diffraction and various theoretical approaches has been used to characterize the 2-(4-fluorobenzylthio)-5-(5-bromothiophen-2-yl)-1,3,4-oxadiazole compound. The crystal structure is primarily stabilized by intermolecular CH···π, CH⋯N and CH⋯F. A short and very rare halogen-halogen contact (Br⋯F) which adopts type I trans geometry along with the S⋯S, N⋯S contacts, which play an important role in the stabilization of the crystal packing. The importance of these contacts is established through various theoretical approaches such as QTAIM and NBO analysis. A detailed CSD analysis of Br⋯F contacts is performed to understand the geometrical preference. A detailed in silico analysis is performed to explore the binding potential of the title compound against the Plasmodium falciparum dihydrofolate reductase (PfDHFR). The results clearly suggest that the title compound may be a promising anti-malarial lead candidate by inhibiting the DHFR target and halogenated fragments of the molecule are important for the stabilization of the protein-ligand complex formation. [Display omitted] •Type I hereto halogen-halogen (Br⋯F) contact is observed.•Experimental structure is compared with optimized models in gas and solvent phases.•Relative contributions of various intermolecular contacts are quantified using Hirshfeld surface analysis.•Interaction energies of dimers are quantified using PIXEL and QTAIM analysis.•Anti-malarial potential is explored using molecular docking and QM/MM methods.