Design and Synthesis of Non-Covalent Imidazo[1,2-<i>a</i>]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment
Manvendra Kumar,
Gaurav Joshi,
Sahil Arora,
Tashvinder Singh,
Sajal Biswas,
Nisha Sharma,
Zahid Rafiq Bhat,
Kulbhushan Tikoo,
Sandeep Singh,
Raj Kumar
Affiliations
Manvendra Kumar
Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
Gaurav Joshi
Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
Sahil Arora
Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
Tashvinder Singh
Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, Punjab, India
Sajal Biswas
Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
Nisha Sharma
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar 160062, Punjab, India
Zahid Rafiq Bhat
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar 160062, Punjab, India
Kulbhushan Tikoo
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar 160062, Punjab, India
Sandeep Singh
Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, Punjab, India
Raj Kumar
Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
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.
