title: Synthesis and biological evaluation of biguanide and dihydrotriazine derivatives as potential inhibitors of dihydrofolate reductase of opportunistic microorganisms.
abstract: Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms: Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat liver (rl). The most potent compound in the series was B2-07 with 12 nM activity against tgDHFR. The most striking observation was that B2-07 showed similar potency to trimetrexate, approximately 233-fold improved potency over trimethoprim and approximately 7-fold increased selectivity as compared to trimetrexate against tgDHFR. Molecular docking studies in the developed homology model of tgDHFR rationalized the observed potency of B2-07. This molecule can act as a good lead for further design of molecules with better selectivity and improved potency.
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Bag
authors.forename: Nilesh R
authors.initials: NR
authors.lastname: Tawari
authors.forename: Sherry F
authors.initials: SF
authors.lastname: Queener
authors.forename: Mariam S
authors.initials: MS
authors.lastname: Degani
mesh_terms: D000818:Animals; D001645:Biguanides / Q000138:chemical synthesis* / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D008099:Liver / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects / Q000201:enzymology; D009894:Opportunistic Infections / Q000188:drug therapy* / Q000382:microbiology; D045363:Pneumocystis carinii / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects*; D014122:Toxoplasma / Q000187:drug effects / Q000201:enzymology; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology; D014295:Trimethoprim / Q000494:pharmacology; D016597:Trimetrexate / Q000494:pharmacology
chemical_list: D001645:Biguanides; D005493:Folic Acid Antagonists; D014227:Triazines; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase; D016597:Trimetrexate