. The object of this study is the synthesis of some 130 deazapteridine analogs of trimetrexate and piritrexim, most of which are distinguished by the absence of 5-methyl group. These studies were prompted by significant potency and/or selectivity or 4,5- desmethyl-8-aza analogs of trimetrexate as inhibitors of dihydrofolate reductases from human P. carinii, T. gondii and M. avium. Seven series of compounds will be developed to explore a variety of considerations regarding selectivity and binding to these various DHFRs. The syntheses will be carried out in Dr. Gangjee's laboratory; biological evaluations will be carried out by Dr. Roy Kisliuk in isolated enzyme systems and by Dr. Sherry Queener in tissue culture and animal studies. Dr. Vivian Cody will attempt to co-crystallize the best inhibitors into appropriate DHFRs and carry out crystallographic studies on them. The investigators anticipate this combined effort will lead to potent and selective inhibitors of pathogen DHFRs which may lead to clinically useful agents to interfere with opportunistic infections in AIDS patients.
