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Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐ d ]pyrimidine antifolates
Author(s) -
Gangjee Aleem,
Mavandadi Farahnaz,
Queener Sherry F.
Publication year - 2001
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570380132
Subject(s) - dihydrofolate reductase , chemistry , pneumocystis carinii , stereochemistry , pyrimidine , tricyclic , lactam , antifolate , enzyme inhibitor , reductase , bicyclic molecule , enzyme , biochemistry , antimetabolite , organic chemistry , human immunodeficiency virus (hiv) , toxicity , virology , biology , pneumocystis jirovecii
Abstract The effect of conformational restriction of the C9‐N10 bridge on inhibitory potency and selectivity of trimetrexate against dihydrofolate reductase, was studied. Specifically three nonclassical tricyclic 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐ c ]pyrido[2,3‐ d ]pyrimidin‐6(5 H ,8 H )‐one ( 4 ), 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐9‐hydro‐pyrrolo[3,4‐c]pyrido[2,3‐ d ]pyrimidin‐6‐(8 H )‐one ( 5 ) and 1,3‐diamino‐( 8H )‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐ c ]pyrido[2,3‐ d ]pyrimidine ( 7 ) antifolates were synthesized. The tricyclic analogues 4 and 5 were obtained via the regiospecific cyclo‐condensation of the β‐keto ester 17 with 2,4,6‐triaminopyrimidine. The analogue 7 was obtained via reduction of the lactam 4 with borane in tetrahydrofuran. Compounds 4, 5 and 7 were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii and rat liver. All three compounds were more selective than trimetrexate against Pneumocystis carinii dihydrofolate reductase and significantly more selective than trimetrexate against Toxoplasma gondii dihydrofolate reductase compared with rat liver dihydrofolate reductase.