The object of this proposal is to extend our previous studies via the synthesis of a series of novel bicyclic and tricyclic antifolates and their biological evaluations as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystic carinii (PC) and Toxoplasmosis gondii (TG) and as potential inhibitors of these organisms which cause fatal infections in patients with acquired immunodeficiency syndrome (AIDS). Further, the synergistic effects, if any, with sulfa drugs are also proposed. The target compounds are 2,4-diaminopyrido[2,3-d]pyrimidine derivatives which are designed based on trimetrexate (TMQ) 1 and a 5,10-dimethylpyrido[2,3- d]pyrimidine analog 4 of TMQ, which we have recently identified to be a more potent and selective inhibitor of PC DHFR than TMQ and a significantly more potent (12x) and selective (31x) inhibitor of TG DHFR than TMQ. We intend to carry out a structure activity/selectivity study of compound 4 to identify the most potent and/or selective candidates for animal and perhaps clinical trials. This proposal specifically addresses the importance of the phenyl ring substituents (compounds 6-25), the N10-substituents (compounds 26-31), the importance of the N10-nitrogen (compounds 32-33), the N8-nitrogen (compound 53) and the conformational restrictions of the 6- anilinomethy side chain (compounds 34-52) of 4 as it pertains to inhibition and selectivity against PC and TG. The rigid analogs (34-52) incorporate the flexible 3,4,5-trimethoxyanilinomethyl side chain of 1 and 4 as parts of ring systems to provide specific restricted rotations in an attempt to define the optimum side chain conformation for potency and/or selectivity. The synthesis of the target compounds are proposed via suitable modifications of methods developed in our laboratory and by modifications of established literature procedures. The biological studies will be performed on a collaborative basis with Dr. Sherry F. Queener, University of Indiana, School of Medicine and Dr. David S. Roos, University of Pennsylvania, School of Medicine. In the absence of any structural information of PC DHFR and TG DHFR and the urgent need for better, less toxic agents, this study will provide a better understanding of the structural and stereochemical requirements for inhibition of and/or selectivity for DHFR from PC and TG and the infections of these organisms. Further, this study may provide selective, less toxic, clinically useful agents and lead to the rational design of selective antifolates to be used alone or in combination therapy against PC and TG infections in AIDS patients.
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