The overall goal of this continuation project is the discovery of new drugs against Pneumocystis carinii and Toxoplasma gondii, two of the opportunistic pathogens known to cause significant morbidity and mortality in patients with the acquired immune deficiency syndrome (AIDS). More specifically, the project will focus on the design and synthesis of several classes of previously uninvestigated mono- and dicyclic diaminopyrimid-ine derivatives that we hope will combine the high potency of trimetrexate (TMQ) and piritrexim (PTX) with the binding selectivity of trimethoprim (TMP) and pyrimethamine (PM) against P. carinii (Pc) and T. gondii (Tg) dihydrofolate reductase (DHFR) versus mammalian DHFR.
The lack of selectivity of TMQ and PTX requires that they be used with leucovorin (LV) to prevent hematotoxicity, 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 intoler-able side effects. Thus new DHFR inhibitors that are both potent and selective would be highly desirable. Proposed synthetic targets include 4 general types, with emphasis on molecules with a CH2 bridge or no bridge (i.e., a zero-carbon bridge ) between the diaminopyrimidine and substituted Phe moiety. Substituents on the phenyl ring will include two MeO groups as in PTX, three MeO groups as in TMQ, or a Cl atom as in PM. The 2,4-diamino compounds to be studied include: (a) pyridol[2,3-d]pyrimidines with H or Me at C5 and a small alkyl group or substituted Phe ring at C6; (b) pyrrolo[2,3-d]pyrimidines with a substituted Phe ring joined to C5 without a bridge or via a CH2 bridge; (c) pyrimidines with a 3,4-(MeO)2-5-(C4-8-alkoxy)Phe or 2-MeO-5-(c4-8- alkoxy)Phe ring joined to C5 via a CH2 bridge; and (d) pyridol[2,3- d]pyrimidines with a 3,4-(MeO)2-5-(C4-8 alkoxy)Phe or 2-MeO-5-(c4-8- alkoxy)Phe ring joined to C6 via a CH2 bridge. The rationale for a short bridge rests on published indications that the P. carinii DHFR active site is more compact than that of mammalian DHFR. Because of this topology difference, a greater difference in hydrophobic binding is thought to be possible between the P. carinii and mammalian enzyme when the portion of the inhibitor that fits into the tight inner region of the active site is likewise compact (i.e., more like TMP and PM than like TMQ or PTX). The rationale for placing midlength (up to C8) hydrophobic alkoxy groups distally in the Phe ring is that this may increases potency while preserving the active-site binding selectivity of TMQ and PM.