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Eur J Med Chem. 2013 Aug;66:135-45. doi: 10.1016/j.ejmech.2013.05.039. Epub 2013 Jun 4.

Nonclassical antifolates, part 4. 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: synthesis, biological evaluation and molecular modeling study.

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Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.


A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC₅₀ 0.03 μM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors.


DHFR inhibitors; Molecular modeling study; Substituted thiazoles; Synthesis

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