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

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

  • Bioorg Med Chem Lett. 2022 Jun 1:65:128697. doi: 10.1016/j.bmcl.2022.128697.
Arbaz Sujat Shaikh 1,  Gaddam Kiranmai 2,  G Parimala Devi 3,  Priyanka N Makhal 1,  Dilep Kumar Sigalapalli 4,  Ramya Tokala 1,  Venkata Rao Kaki 1,  Nagula Shankaraiah 5,  Narayana Nagesh 6,  Bathini Nagendra Babu 7,  Neelima D Tangellamudi 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
  • 2 CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEXE II, Uppal Road, Hyderabad 500007, India.
  • 3 Department of Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
  • 4 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India; Department of Pharmaceutical Chemistry, Vignan Pharmacy College, Jawaharlal Nehru Technological University, Vadlamudi 522213, Andhra Pradesh, India.
  • 5 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Electronic address: shankar@niperhyd.ac.in.
  • 6 CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEXE II, Uppal Road, Hyderabad 500007, India. Electronic address: nagesh@ccmb.res.in.
  • 7 Department of Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: bathini@iict.res.in.
  • 8 Swarnandhra Institute of Engineering and Technology, Narsapur, West Godavari district, Andhra Pradesh, India. Electronic address: tdneelima@gmail.com.
PMID: 35339645 DOI: 10.1016/j.bmcl.2022.128697
Abstract

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.

Keywords

1,3,4-Oxadiazole; ADME/T; Apoptosis; Cytotoxicity; Pyrimidine; Topoisomerase II.

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