: The overall goal of this continuation project is the discovery of new drugs against Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (My), and Cryptosporidium parvum (Cp), four opportunistic pathogens known to cause morbidity and mortality in AIDS patients. More specifically, the project will focus on the design and synthesis of several classes of mono- and dicyclic diamino-pyrimidine derivatives that we hope will combine the high potency of trimetrexate (TMQ) and piritrexim (PTX) with the species selectivity of trimethoprim (TMP) and pyrimethamine (PM) against Pc, Tg, or Cp dihydrofolate reductase (DHFR) versus rodent or human DHFR. The lack of binding selectivity of TMQ and PTX requires that they be used with leucovorin (LV) to prevent hematologic toxicity, whereas the relatively low efficacy of TMP and PM as single agents requires them to be used with sulfonamides and other drugs that often cause intolerable side effects. Thus, new DHFR inhibitors that are both potent and selective would be highly desirable. Compounds to be studied include several diaminopyrimidine ring systems with a short CH2 bridge to the aryl side chain. The rationale for a short bridge is that, if the active site is sterically less accommodating in Pc or other non-mammalian DFHR than in mammalian DHFR, optimal hydrophobic contact should occur when the part of the inhibitor entering the active site is relatively compact (i.e., more like TMP than TMQ). We will also test the hypothesis that an effective way to achieve selectivity is with 2,4-diamino-5-[(2-methoxy- and 3,4-dimethoxy-5-(C3-9)alkoxy)-benzyl] pyrimidines containing an acidic carboxyl or tetrazole group at the end of the O-alkyl side chain. A very promising example of this class is 2,4-diamino-5-[2-methoxy-5-(4-carboxybutyl)benzyl]pyrimidine (PY657), which was recently discovered by us to have excellent potency and selectivity against both Pc and Ma DHFR. Also proposed are second-generation analogs of another lead compound we discovered in this project, N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepine (PT653). PT653 is selectively potent against Tg and Ma DHFR, but its bioavailability is limited by low aqueous solubility. Analogs of PT653 with a COOH, NH2, or OH group on the tricyclic moiety, and prodrugs thereof, will be made with the goal of improving aqueous solubility without sacrificing potency or selectivity.
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