Synthesis, biological evaluation and detailed computational studies of N-sulfonyl indole-based dihydrothiazoles against colorectal carcinoma

  • Sci Rep. 2026 Jun 10;16(1):18334. doi: 10.1038/s41598-026-56442-4.
Zahra Batool  1 ,  Iqra Naseer  1 ,  Şeyma Ateşoğlu  2  3 ,  Furkan Çakır  4  5 ,  Fahri Akbaş  3 ,  Norah A Albekairi  6 ,  Halil Şenol  7 ,  Asif Rasool  8 ,  Zahid Shafiq  9 ,  Abdulrahman Alshammari  6
Affiliations
  • 1. Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan.
  • 2. Department of Medical Biology, Institute of Health Sciences, Bezmialem Vakif University, 34093, Fatih, Istanbul, Turkey.
  • 3. Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, 34093, Fatih, Istanbul, Turkey.
  • 4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093, Fatih, Istanbul, Turkey.
  • 5. Institute of Health Sciences, Department of Pharmaceutical Chemistry, Istanbul University, 34126, Fatih, Istanbul, Turkey.
  • 6. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, 11451, Riyadh, Saudi Arabia.
  • 7. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093, Fatih, Istanbul, Turkey. [email protected].
  • 8. School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China.
  • 9. Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan. [email protected].
PMID: 42270895 DOI: 10.1038/s41598-026-56442-4
Abstract

A novel series of N-sulfonyl indole-based dihydrothiazole hybrids (5a-5u) was synthesized and comprehensively evaluated as potential Anticancer agents against colorectal carcinoma. All compounds were structurally confirmed by NMR and HRMS and screened for cytotoxicity against HCT-116 colorectal Cancer cells, with selectivity evaluated using CCD-1076Sk normal fibroblasts. Several derivatives displayed significantly higher potency than sorafenib, with compound 5d emerging as the lead molecule (IC50 = 4.10 µM, SI = 12.0).To elucidate the molecular basis of activity, induced-fit docking and MM-GBSA calculations were performed against four key colorectal cancer-related targets (TNF-α, PI3K p110α, Akt1, and mTOR). Compound 5d exhibited the most favorable multi-target binding profile, supported by highly stable ligand-protein interactions. Molecular dynamics simulations confirmed the dynamic stability of 5d, particularly with TNF-α and mTOR. In addition, DFT, ESP, and GCR analyses revealed that 5d combines optimal electronic reactivity with stability, while ADME predictions indicated a favorable pharmacokinetic profile. Overall, 5d is identified as a promising multi-target lead for colorectal Cancer therapy.

Keywords
N-sulfonyl-indole; Colorectal carcinoma; Dihydrothiazoles; Molecular docking; Molecular dynamics.
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