Bicyclic Conformationally Restricted Analogs of Nonclassical Pyrido[2,3-d] Pyrevddines as Potential Inhibitors of Dihydrofolate Reductases
Pneumocystis carinii and Toxoplasma gondii remain the major cause of morbidity and mortality in patients with AIDS. We have recently reported the synthesis of a series of 2,4-diamino-5-methyl-6-substituted pyrido[2,3-d]pyrimidines of general structure 1 1,2 and their selective and potent inhibitory activity against dihydrofolate reductases (DHFR) from P. carinii and T. gondii. These compounds, like the clinically used nonclassical antifolates, trimethoprim, pyrimethamine and trimetrexate (TMQ), bypass the folate uptake mechanisms necessary for classical antifolates such as methotrexate and thus are able to penetrate P. carinii and T. gondii organisms which appear to lack the folate uptake systems. Compounds 1 were designed as hybrid molecules of the nonselective DHFR inhibitors TMQ and piritrexim (PTX) to provide more potent and selective inhibitors of P. carinii DHFR and/or T. gondii DHFR. The most potent and selective of the series of compounds 1 was that with R1 = CH3 and R2 = 3’,4’,5’-trimethoxy which was several times as potent and selective as the analog with R1 = H as well as TMQ and PTX against both P. carinii DHFR and T. gondii DHFR. Larger R1 substituents such as Et, i-Pr and propargyl decrease potency (except R1 = i-Pr for P. carinii DHFR) with some loss of selectivity towards both P. carinii DHFR (except R1 = i-Pr) and T. gondii DHFR. In an attempt to study the effect of conformational restrictions of τ3 of 1 to potency and selectivity we have synthesized the methoxy indoline analogs 2–4, the corresponding indole analogs 5–7 and the 6,7-dimethoxytetrahydroisoquinoline analog 8. In a previous report,3 we had shown that restriction of τ3, by means of an indoline, in the 2,4-diaminotetrahydroquinazoline series, does indeed provide increased potency and selectivity for T. gondii DHFR compared to the unrestricted analog.
KeywordsDihydrofolate Reductase Folate Uptake Guanidine Hydrochloride Toxoplasma Gondii Reductive Amination
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