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

• Synthesis of 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols.
• Compound 22, antibacterial comparable to Gentamicin and Ciprofloxacin.
• Compound 29, schistosomicidal comparable to Praziquantel.
• Compound 34, DHFR inhibitor, IC50 0.03 μM, 2.7 fold more active than MTX.
• Compound 36, antitumor comparable to Doxorubicin.

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.

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