title: 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.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Hassan
authors.forename: Shahenda M
authors.initials: SM
authors.lastname: El-Messery
authors.forename: Fatmah A M
authors.initials: FA
authors.lastname: Al-Omary
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Al-Rashood
authors.forename: Marwa I
authors.initials: MI
authors.lastname: Shabayek
authors.forename: Yasmin S
authors.initials: YS
authors.lastname: Abulfadl
authors.forename: El-Sayed E
authors.initials: el-SE
authors.lastname: Habib
authors.forename: Salwa M
authors.initials: SM
authors.lastname: El-Hallouty
authors.forename: Walid
authors.initials: W
authors.lastname: Fayad
authors.forename: Khaled M
authors.initials: KM
authors.lastname: Mohamed
authors.forename: Bassem S
authors.initials: BS
authors.lastname: El-Menshawi
authors.forename: Hussein I
authors.initials: HI
authors.lastname: El-Subbagh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008727:Methotrexate / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D012550:Schistosoma mansoni / Q000187:drug effects; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000977:Antiparasitic Agents; D005493:Folic Acid Antagonists; D014230:Triazoles; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate
keywords: DHFR inhibitors; Molecular modeling study; Substituted thiazoles; Synthesis