Exploration of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives as DNA intercalative topo II inhibitors: Cytotoxicity and apoptosis induction

• Published in: Bioorganic & medicinal chemistry letters Vol. 65; p. 128697
• Main Authors: Shaikh, Arbaz Sujat, Kiranmai, Gaddam, Parimala Devi, G., Makhal, Priyanka N., Sigalapalli, Dilep Kumar, Tokala, Ramya, Kaki, Venkata Rao, Shankaraiah, Nagula, Nagesh, Narayana, Babu, Bathini Nagendra, Tangellamudi, Neelima D.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.06.2022; Elsevier
• Subjects: 1,3,4-Oxadiazole; ADME/T; Antineoplastic Agents - chemistry; Apoptosis; Cell Proliferation; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cytotoxicity; DNA - pharmacology; DNA Topoisomerases, Type II - metabolism; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Structure; Oxadiazoles; Pharmacology & Pharmacy; Physical Sciences; Pyrimidine; Pyrimidines; Science & Technology; Structure-Activity Relationship; Topoisomerase II; Topoisomerase II Inhibitors; Cytotoxicity; 1,3,4-Oxadiazole; ADME/T; Topoisomerase II; Pyrimidine; Apoptosis; DESIGN; TOPOISOMERASE-II; DOCKING; COMPLEXES; BIOLOGICAL EVALUATION; BINDING
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.128697

[Display omitted] •New Mercaptoacetamide-linked Pyrimidine-1,3,4-Oxadiazole were designed and synthesized.•Compound 9p showed excellent cytotoxic activity against A549 cell line with IC50 value of 3.8 ± 0.02 μM.•Compound 9p induced apoptosis in A549 cell lines.•Compound 9p manifested topoisomerase II inhibition via intercalative mode of binding.•In silico ADME/T properties of compound 9p are in acceptable range. The design and synthesis of a new series of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole hybrids was accomplished. The in vitro cytotoxic potential of these new compounds was evaluated against lung cancer (A549), prostate cancer (PC-3, DU-145) and human embryonic kidney (HEK) cell lines. Compound 9p showed the highest potency on A549 cells with an IC50 value of 3.8 ± 0.02 μM. Moreover, 9p was found to be 25-fold more selective towards cancer cell lines than the non-cancerous (HEK) cell line. The target-based assay revealed the inhibition of the topoisomerase II enzyme by compound 9p. UV–visible spectroscopy, fluorescence, circular dichroism (CD), and viscosity studies inferred the intercalative property and effective binding of compound 9p with CT-DNA. Apoptosis induced by the compound 9p was observed by various morphological staining assays, i.e, DAPI, EtBr/AO. Further, the molecular modeling studies revealed the binding of compound 9p at the active site of the DNA-topoisomerase II complex while the physicochemical properties were in the recommended range. Finally, mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives can be considered as a promising scaffold for development as effective anticancer agents and topoisomerase II inhibitors.