Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment

Abstract

A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 μM) as compared to gefitinib (IC50 > 20 μM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported.

Design and synthesis of new bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazines) and bis((quinoxalin-2-yl)phenoxy)alkanes as anti-breast cancer agents through dual PARP-1 and EGFR targets inhibition

“…These results of dual PARP-1 and EGFR inhibition agreed with the previously reported results for 1,2,4-triazole, 1,3,4-thiadiazine and quinoxaline derivatives. [28][29][30] Fig. 6 Effect of derivatization of the synthesized bis-triazolothiadiazines 8a-l on their cytotoxicity against MDA-MB-231 cells.…”

29th Annual GP2A Medicinal Chemistry Conference

“…Manvendra Kumar 1 , Raj Kumar 1 1 Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, India; pharma.manvendra003@gmail.com A series of non-covalent imidazo[1,2-a]quinoxaline-based epidermal growth factor receptor (EGFR) inhibitors were designed and synthesized [129,130]. EGFR inhibitory assessment (against wild type) data of compounds has showed compounds 6b (IC50 = 211.22 nM), 7h (IC50 = 222.21 nM), 7j (IC50 = 193.18 nM), 9a (IC50 = 223.32 nM), and 9c (IC50 = 221.53 nM) as potent EGFRWT inhibitors, which were comparable to erlotinib (221.03 nM), a positive control.…”

In vitro Anticancer and Insilico Studies of Quinoxaline‐sulfonyl‐1,2,4‐triazole Hybrids

“…On the other aspect, the quinoxaline derivatives are recognized as a novel group of cancer chemotherapeutic targets with noteworthy therapeutic efficiency in opposition of solid tumors [19–21] . As well, few quinoxaline derivatives showed anticancer activity via EGFR‐TK inhibition [22] . Remarkably, the [1,2,4] triazolo[4,3‐ a ] quinoxaline analogues have shown potent anticancer activity through the inhibition of both EGFR kinase and tubulin polymerization [23] …”