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Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3-d]pyrimidine antifolates

✍ Scribed by Aleem Gangjee; Farahnaz Mavandadi; Sherry F. Queener

Publisher
Journal of Heterocyclic Chemistry
Year
2001
Tongue
English
Weight
79 KB
Volume
38
Category
Article
ISSN
0022-152X

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✦ Synopsis

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.

📜 SIMILAR VOLUMES

ChemInform Abstract: Conformationally Re
ChemInform Abstract: Conformationally Restricted Tricyclic Analogues of Lipophilic Pyrido[2,3-d]pyrimidine Antifolates.
✍ Aleem Gangjee; Farahnaz Mavandadi; Sherry F. Queener 📂 Article 📅 2010 🏛 John Wiley and Sons ⚖ 32 KB 👁 1 views

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Pyrrolo[2,3-d]pyrimidines and pyrido[2,3
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✍ Lee F Kuyper; Janice M Garvey; David P Baccanari; John N Champness; David K Stam 📂 Article 📅 1996 🏛 Elsevier Science 🌐 English ⚖ 876 KB

Conformationally restricted analogues of the antibacterial agent trimethoprim (TMP) were designed to mimic the conformation of drug observed in its complex with bacterial dihydrofolate reductase (DHFR). This conformation of TMP was achieved by linking the 4-amino function to the methylene group by o