Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt.
Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt.
Arch Pharm (Weinheim). 2021 Nov;354(11):e2100202. doi: 10.1002/ardp.202100202. Epub 2021 Jul 27.
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 IC values of 68.48, 82.39, and 48.48 nM, respectively, compared with IDO5L at IC 67.40 nM. Benzo[d]imidazo[2,1-b]thiazoles 17, 20, and 22 showed promising IDO1 inhibition at IC 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.
新型咪唑并[2,1-b]噻唑类化合物被设计、合成并作为吲哚胺 2,3-双加氧酶（IDO1）抑制剂进行了生物评估。与 IDO5L 的 IC67.40nM 相比，咪唑并[2,1-b]噻唑 6、7 和 8 对 IDO1 的抑制谱分别在 IC 值为 68.48、82.39 和 48.48nM 时表现出抑制作用。苯并[d]咪唑并[2,1-b]噻唑 17、20 和 22 对 IDO1 的抑制作用分别在 IC 值为 53.58、53.16 和 57.95nM 时表现出良好的抑制作用。化合物 7 对 MCF7 乳腺癌细胞系的 GI 为 39.33%，显示出生长抑制谱，而 8 对 ACHN 肾癌细胞具有致死作用。用化合物 17 和 22 处理的细胞表现出典型的 DNA 片段凋亡模式，反映了细胞周期的 G0/G1、S 和 G2/M 期，以及与凋亡细胞相对应的 G1 期之前，这表明细胞生长停滞发生在 S 期。分子模拟模拟验证了苯并[d]咪唑并[2,1-b]噻唑类似物螯合 IDO1 结合口袋内铁（III）的潜力，因此通过疏水-疏水相互作用具有更好的结合亲和力。
