Nanomolar potency of imidazo[2,1-b]thiazole analogs as indoleamine 2,3-dioxygenase inhibitors

Menna A. Ewida, Heba A. Ewida, Mahmoud S. Ahmed, Heba Abdelrasheed Allam, Ramzia I. ElBagary, Riham F. George, Hanan H. Georgey, Hussein I. El-Subbagh

Research output: Contribution to journalArticlepeer-review

Abstract

Novel series of imidazo[2,1-b]thiazole analogs were designed, synthesized, and biologically evaluated as indoleamine 2,3-dioxygenase (IDO1) inhibitors. Imidazo[2,1-b]thiazoles 6, 7, and 8 showed inhibitory profiles against IDO1 at IC50 values of 68.48, 82.39, and 48.48 nM, respectively, compared with IDO5L at IC50 67.40 nM. Benzo[d]imidazo[2,1-b]thiazoles 17, 20, and 22 showed promising IDO1 inhibition at IC50 values of 53.58, 53.16, and 57.95 nM, respectively. Compound 7 showed a growth-inhibitory profile at GI of 39.33% against the MCF7 breast cancer cell line, while 8 proved lethal to ACHN renal cancer cells. Cells treated with compounds 17 and 22 showed a typical apoptosis pattern of DNA fragments that reflected the G0/G1, S, and G2/M phases of the cell cycle, together with a pre-G1 phase corresponding to apoptotic cells, which indicates that cell growth arrest occurred at the S phase. Molecular modeling simulations validated the potential of benzo[d]imidazo[2,1-b]thiazole analogs to chelate iron(III) within the IDO1 binding pocket and, hence, to have a better binding affinity via hydrophobic–hydrophobic interactions.

Original languageEnglish (US)
Article number2100202
JournalArchiv der Pharmazie
Volume354
Issue number11
DOIs
StatePublished - Nov 2021

Keywords

  • IDO1 inhibitors
  • antitumor testing
  • cell cycle analysis
  • imidazo[2,1-b]thiazole
  • molecular modeling simulations
  • synthesis

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery

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