title: In vitro biological evaluation of biguanides and dihydrotriazines against Brugia malayi and folate reversal studies.
abstract: Dihydrofolate reductase (DHFR) is a well-known target for antibacterial and anticancer therapy. DHFR inhibitors are useful for protozoan parasites, but are yet to be explored against metazoan species; hence the present work was designed to evaluate the efficacy of DHFR inhibitors against filariasis, one of the major neglected tropical diseases. Molecules from our in-house library of synthetic antifolate agents (biguanide and dihydrotriazine derivatives) were evaluated along with the antimalarial drug pyrimethamine and the antibacterial drug trimethoprim in an in vitro model against Brugia malayi microfilariae (Mf). Three biguanides and two dihydrotriazines were more potent than trimethoprim and pyrimethamine against B. malayi Mf. Trimethoprim, pyrimethamine and four of the five compounds active against Mf were also active against adult worms. To probe the mechanism of action of the compounds, reversal of activity of active compounds by folic acid and folinic acid was studied. In conclusion, DHFR inhibitors could be used as leads for new antifilarial drugs.
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Bag
authors.forename: Nilesh R
authors.initials: NR
authors.lastname: Tawari
authors.forename: Richa
authors.initials: R
authors.lastname: Sharma
authors.forename: Kalyan
authors.initials: K
authors.lastname: Goswami
authors.forename: M V R
authors.initials: MV
authors.lastname: Reddy
authors.forename: Mariam S
authors.initials: MS
authors.lastname: Degani
mesh_terms: D000818:Animals; D001645:Biguanides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017178:Brugia malayi / Q000187:drug effects* / Q000201:enzymology; D005368:Filariasis / Q000188:drug therapy; D005369:Filaricides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011739:Pyrimethamine / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014295:Trimethoprim / Q000494:pharmacology
chemical_list: D001645:Biguanides; D005369:Filaricides; D005493:Folic Acid Antagonists; D014227:Triazines; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine