Synthesis and biological evaluation of novel imidazo[1,2-a]pyridine-oxadiazole hybrids as anti-proliferative agents: Study of microtubule polymerization inhibition and DNA binding

Dilep Kumar Sigalapalli; Gaddam Kiranmai; G Parimala Devi; Ramya Tokala; Sravani Sana; Chaturvedula Tripura; Govinda Shivaji Jadhav; Manasa Kadagathur; Nagula Shankaraiah; Narayana Nagesh; Bathini Nagendra Babu; Neelima D Tangellamudi

doi:10.1016/j.bmc.2021.116277

Synthesis and biological evaluation of novel imidazo[1,2-a]pyridine-oxadiazole hybrids as anti-proliferative agents: Study of microtubule polymerization inhibition and DNA binding

Bioorg Med Chem. 2021 Aug 1:43:116277. doi: 10.1016/j.bmc.2021.116277. Epub 2021 Jun 16.

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. Electronic address: shankar@niperhyd.ac.in.
⁵ CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEXE II, Uppal Road, Hyderabad 500007, India. Electronic address: nagesh@ccmb.res.in.
⁶ Department of Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: bathini@iict.res.in.
⁷ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Electronic address: tdneelima@gmail.com.

PMID: 34175586
DOI: 10.1016/j.bmc.2021.116277

Abstract

Efforts towards the development of potential anticancer agents, a new series of imidazo[1,2-a]pyridine-oxadiazole hybrids were synthesized and evaluated for their in vitro anticancer activity against lung cancer (A549) and prostate cancer (PC-3, DU-145) cell lines. Amongst the compounds tested, 6d showed the highest potency on A549 cells with an IC₅₀ value of 2.8 ± 0.02 μM. Flow cytometric analysis of compound 6d treated A549 cells showed apoptosis induction by annexin-v/PI dual staining assay and the effect of 6d on different phases of cell cycle was also analyzed. Target based studies demonstrated the inhibition of tubulin polymerization by 6d at an IC₅₀ value of 3.45 ± 0.51 μM and its effective binding with CT-DNA. Further, the molecular modelling studies revealed that 6d has a prominent binding affinity towards α/β-tubulin receptor with admirable physico-chemical properties.

Keywords: 1,3,4-oxadiazole; ADME/T; Apoptosis; Cytotoxicity; Imidazo[1,2-a]pyridine; Molecular docking; Tubulin polymerization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Binding Sites
Cell Line
Cell Proliferation / drug effects
DNA / chemistry*
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Microtubules / drug effects*
Microtubules / metabolism
Molecular Structure
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Polymerization / drug effects
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Oxadiazoles
Pyridines
DNA
calf thymus DNA
imidazo(1,2-a)pyridine