Design, Synthesis, Anti-Cancer Activity, and in silico Studies of Novel Imidazo[1,2- a ]pyridine Derivatives
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esign, Synthesis, Anti-Cancer Activity, and in silico Studies of Novel Imidazo[1,2-a]pyridine Derivatives S. Endooria, K. C. Gulipallia, S. Bodigea, J. N. Narendra Sharath Chandrab, and N. Seelama,* a Department
of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502 India of Pharmaceutical Chemistry, Gurukrupa Institute of Pharmacy, Maharashtra, 431129 India *e-mail: [email protected]
b Department
Received July 27, 2020; revised August 18, 2020; accepted September 9, 2020
Abstract—A novel series of imidazo [1,2-a]pyridine derivatives has been designed, synthesized and tested for the anti-proliferative activity against three different human cancer cell lines. Most of the synthesized compounds exhibit anti-proliferative activity with IC50 values ranging from 5.35–59.8 μM. Six compounds demonstrate efficient inhibition of growth of all cell lines with IC50 values close to that of standard drug, and the compound 16h is more potent than the standard drug cisplatin for the HeLa cell line. Keywords: synthesis, imidazo[1,2-a]pyridine, anticancer activity, molecular docking
DOI: 10.1134/S1070363220090212 INTRODUCTION Imidazopyridine derivatives possess a vast variety of biological activities [1] including antifungal, antiinflammatory, antitumor, and many more [2–5]. Various drugs containing imidazo[1,2-a]pyridine scaffold are currently available on the market [6–9]. Urea derivatives have attracted close attention as building blocks in the molecules of anticancer agents due to their significant inhibitory activity against protein tyrosine kinases (PTKs), DNA topoisomerase, Raf kinase, and NADH oxidase, that play a vital role in the cell proliferation [10]. Sorafenib, a diaryl urea derivative has been reported to inhibit several kinases, such as VEGFR (vascular endotheliael growth factor receptor), Raf and platelet derived growth factor receptor [11]. Shuch important chemotherapeutic activities of both pharmacophores (imidazo[1,2-a]pyridine and urea moieties) gave an impulse to our design and synthesys of anticancer agents with enhanced potency and/or reduced toxicity. RESULTS AND DISCUSSION Synthesis of target molecules was achieved in seven steps, starting with treatment of 2-amino pyridine (1) by 1,3-dichloroacetone (2) and formation of 2-(chloromethyl)imidazo[1,2-a]pyridine (3), which upon nitration followed by coupling with potasium pthalimide (5) gave 2-[(3-nitroimidazo[1,2-a]pyridin-2-yl)methyl]-
isoindoline-1,3-dione (6). Reduction of the intermediate 6 in presence of Na2S2O4 led to the crucial intermediate 7 which was used in reductive amination with compounds 8 and 13 followed by pathalimide deprotection with hydrazine hydrate which gave intermediates 9 and 15, respectively. Finally, the latter compounds 9 and 15 reacted with aryl isocyanates 11a–11j in presence of TEA with formation of the corresponding target compounds 12a–12j (Scheme 1) and 16a–16j (Scheme 2). Anticancer activity. In vitro anti-proliferative activity of all synthesized compounds 12a–12j and 16a
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