A novel sulfamoylphenyl-dihydro-thiadiazole derivative as a dual EGFR and carbonic anhydrase inhibitor for cancer therapy

A novel sulfamoylphenyl-dihydro-thiadiazole derivative (compound 14) has been designed and synthesized as a dual inhibitor targeting EGFR and human carbonic anhydrases (hCAIX and hCAXII). Computational studies, including density functional theory (DFT), molecular docking, and molecular dynamics simulations, confirmed its stability, favorable binding interactions, and reactivity profiles. Compound 14 showed potent inhibition of EGFR (IC₅₀ = 10. 12 ± 0. 29 nM), hCAIX and hCAXII (IC₅₀ = 79 ± 1. 2 nM and 58 ± 0. 9 nM, respectively). Cytotoxicity assays demonstrated selective activity against cancer cells, with IC₅₀ values of 16. 13 µM in MDA-MB-231 and 22. 57 µM in MCF-7 cells, compared to 148. 32 µM in non-cancerous Vero cells. Compared to acetazolamide, compound 14 exhibited improved selectivity for cancer cells. Apoptosis studies revealed significant cell death in MDA-MB-231 cells, with early and late apoptosis rates of 22. 50% and 58. 27%, respectively, alongside a marked G1-phase cell cycle arrest (49. 10% in treated cells vs. 44. 98% in controls). In silico toxicological evaluations indicated a favorable safety profile, with low irritancy and acceptable rat oral LD₅₀ (15. 81 mg/kg) and carcinogenic potency (TD₅₀ = 36. 95). Compound 14 ’s potent dual inhibition and selective cytotoxicity make it a promising candidate for further optimization and in vivo studies.