TY - JOUR
T1 - Nanomolar potency of imidazo[2,1-b]thiazole analogs as indoleamine 2,3-dioxygenase inhibitors
AU - Ewida, Menna A.
AU - Ewida, Heba A.
AU - Ahmed, Mahmoud S.
AU - Allam, Heba Abdelrasheed
AU - ElBagary, Ramzia I.
AU - George, Riham F.
AU - Georgey, Hanan H.
AU - El-Subbagh, Hussein I.
N1 - Publisher Copyright:
© 2021 Deutsche Pharmazeutische Gesellschaft
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - IDO1 inhibitors
KW - antitumor testing
KW - cell cycle analysis
KW - imidazo[2,1-b]thiazole
KW - molecular modeling simulations
KW - synthesis
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U2 - 10.1002/ardp.202100202
DO - 10.1002/ardp.202100202
M3 - Article
C2 - 34313342
AN - SCOPUS:85111133656
SN - 0365-6233
VL - 354
JO - Archiv der Pharmazie
JF - Archiv der Pharmazie
IS - 11
M1 - 2100202
ER -