The object of this proposal is the synthesis of a series of novel antifolates as potential inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii organisms and consequently as possible treatments of fatal pneumonia caused by the organism in patients with acquired immunodeficiency syndrome (AIDS). The target compounds have been designed as conformationally restricted analogs of trimetrexate and BW 301U both of which have shown potent inhibition of the growth of P. carinii. The proposed compounds possess rigid and semirigid orientations of the methylamino side chain in defined geometries and would provide considerable insight into the geometrical requirements of binding and inhibition of DHFR from P. carinii. Six of the analogs contain geometrical (cis and trans) isomers. In appropriate cases these will be separated. Further the (plus/minus)-cis enantiomers of appropriate compounds will also be separated. The synthesis of the compounds are proposed via suitable modifications of established literature procedures. In the absence of any structural information of DHFR from P. carinii the activity of these compounds could lead to a significant understanding of the stereochemistry of binding to and inhibition of DHFR from P. carinii. Further they may provide selective, less toxic, clinically useful agents and lead to the rational design of selective folate antimetabolites to be used alone or in combination therapy against P. carinii infections in AIDS patients.
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