Design, microwave-assisted synthesis and HIV-RT inhibitory activity of 2-(2,6-dihalophenyl)-3-(4,6-dimethyl-5-(un)substituted-pyrimidin-2-yl)thiazolidin-4-ones.
A series of novel thiazolidin-4-ones bearing a hydrophobic substituent at 5-position on the 4,6-dimethyl-pyrimidine ring at N-3 (5c-i and 6c-i) were designed on the prediction of QSAR studies, synthesized in good yields of 60.1-85.3% by microwave-assisted one-pot protocol with the combination of using dicyclohexylcarbonimide (DCC) as the promotor, and evaluated as HIV-1 reverse transcriptases inhibitors. The results of in vitro HIV-1 RT kit assay showed that some of the new compounds, such as 5c, 6c, 5d, 6d, 5g, 5h and 6i, could effectively inhibit RT activity. Among them, compounds 5c and 6c where ethyl group existed at 5-position on N-3 pyrimidine ring were the best ones with the IC(50) value of 0.26 microM and 0.23 microM, respectively. Structure-activity relationship analysis of these analogues suggested that the overall hydrophobicity and steric factor were important to the anti-HIV RT activity. The mechanism of the intramolecular cycloamidation promoted by DCC was also investigated with the key uncyclized intermediate 13.
Key Laboratory of Chemical Biology of Hebei Province, Ministry of Education, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China. hua-todd@hbu.cn
Hua
H
Chen
Jie
J
Bai
Lingling
L
Jiao
Zaihong
Z
Guo
Qingmei
Q
Yin
Xiaoliu
X
Li
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008872:Microwaves; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D019380:Anti-HIV Agents; D011743:Pyrimidines; D013844:Thiazoles; D053778:Thiazolidines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase