Anticancer Activities of Tetrasubstituted Imidazole‐Pyrimidine‐Sulfonamide Hybrids as Inhibitors of EGFR Mutants

Abstract

A new series of tetrasubstituted imidazole derivatives carrying pyrimidine sulfonamide pharmacophores has been synthesized and evaluated for their anticancer activities. In‐vitro screening of these hybrids against a full 60‐cell‐line panel at a single dose of 10 μM showed significant growth inhibition of up to 95 %. The most active compound showed in‐vitro anticancer activities against (i) abnormal HER2 and (ii) two mutants for EGFR. Apoptotic gene expression revealed that lead compounds induced MCF‐7 cell line apoptosis together with considerable change in the Bax/Bcl‐2 expression ratio. One lead compound led to a significant cell‐cycle S‐phase arrest, while another blocked the cell cycle at G1/S‐phase causing the accumulation of cells. Docking analysis of these two hybrids adopted the orientation and binding interactions with a higher liability to enter the active side pocket of HER2, L858R, and T790 M, preferable to that of co‐crystallized ligands. Modelling simulation was consistent with the acquired biological evaluation.

Recent Advances in Pyrimidine-Based Drugs

“…Research by El Hamd et al sought to develop imidazole–pyrimidine–sulfonamide hybrids as inhibitors for the EGFR in mutant cancer cells [ 39 ]. Currently, there are many research groups across the world interested in developing inhibitors for EGFR, which plays a crucial role in many human cancers.…”

Discovery of Anti‐Breast Cancer Thiophene Sulfonamide Derivatives: Design, Synthesis, Molecular Docking against EGFR, MM‐PBSA, MD Simulations, ADME/Tox, and in vitro Studies

“…The newly produced substances were tested for their cytotoxic activity [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] using the cancer cell line (MCF-7) where Tamoxifen and Brigatinib are used as a cytotoxic reference drug. For this study cancer cells were exposed to the substances for 72 hours.…”

Design, Synthesis, and Anti-Breast Cancer Potential of Imidazole–Pyridine Hybrid Molecules In Vitro and Ehrlich Ascites Carcinoma Growth Inhibitory Activity Assessment In Vivo

“…Imidazole and its derivatives are the most prevalent versatile units of heterocyclic chemistry, and they possess outstanding pharmaceutical activities to control cancer. − Clinical trials have evaluated the efficacy of various imidazole-containing drugs, including dacarbazine, temozolomide, etanidazole, azathioprine, zoledronic acid, pimonidazole, misonidazole, mercaptopurine, nilotinib, fadrozole, and tipifarnib, in the treatment of various types of cancer, with the current availability for clinical use. , Recently, our research efforts have focused on conducting comprehensive studies aimed at developing highly potent anticancer agents. There are numerous scientific studies available which employ innovative and novel synthetic methods to synthesize 2,4,5 tri- and 1,2,4,5 tetra-substituted imidazole heterocyclic compounds. − New hybrid molecules with potent biological activities are produced by the molecular hybridization approach, involving two or more biologically active pharmacophores. − The combination of these two significant moieties could lead to possible imidazole–pyridine hybrid molecules with enhanced biological activities. − The introduction of the hetero unit on position 2 of the imidazole scaffold exhibits potential anticancer activity . In addition, the phenyl rings present at positions 4 and 5 are increasingly crucial for the cytotoxicity of the imidazole moiety when compared to aliphatic substitution on these positions .…”