title: Synthesis of solution-phase combinatorial library of 4,6-diamino-1,2-dihydro-1,3,5-triazine and identification of new leads against A16V+S108T mutant dihydrofolate reductase of Plasmodium falciparum.
abstract: An efficient method to synthesize solution-phase combinatorial library of 1-aryl-4,6-diamino-1,2-dihydro-1,3,5-triazine was developed. The strategy involved an acid-catalyzed cyclocondensation between arylbiguanide hydrochlorides and carbonyl compounds in the presence of triethyl orthoacetate as water scavenger. A 96-membered combinatorial library was constructed from 6 aryl biguanides and 16 carbonyl compounds. Screening of the library by iterative deconvolution method revealed two candidate leads which are equally active against wild-type Plasmodium falciparum dihydrofolate reductase, but are about 100-fold more effective against the A16V+S108T mutant enzyme as compared to cycloguanil.
authors.affiliation: Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand. vtirayut@chula.ac.th
authors.forename: Tirayut
authors.initials: T
authors.lastname: Vilaivan
authors.forename: Neungruthai
authors.initials: N
authors.lastname: Saesaengseerung
authors.forename: Deanpen
authors.initials: D
authors.lastname: Jarprung
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
authors.forename: Worachart
authors.initials: W
authors.lastname: Sirawaraporn
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001645:Biguanides / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003500:Cyclization; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D002727:Proguanil; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D001645:Biguanides; D005493:Folic Acid Antagonists; D014227:Triazines; C026009:cycloguanil; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil