Pneumocystis jirovecii, Toxoplasma gondii, Mycobacterium avium and M. intracellular are some of the most common organisms that cause life-threatening opportunistic infections in AIDS and other immunocompromised patients. Selective dihydrofolate reductase (DHFR) inhibitors in combination, represent a viable therapeutic approach for the treatment of these infectious diseases as well as in cancer chemotherapy. First line treatment of Pneumocystis pneumonia (PCP) requires a combination of trimethoprim (TMP)-sulfamethoxazole (SMX), due to weak inhibitory activity of TMP. The second line treatment involves potent, but non-selective DHFR inhibitors such as trimetrexate (TMQ) and piritrexim (PTX) which cause myelosuppression and require co-administration of leucovorin increasing the cost of therapy. Thus there is a significant unmet clinical need for agents that combine the potency of PTX and selectivity of TMP in single agents.  We synthesized a series of 6-substituted pyrrolo[2,3-d]pyrimidines that are selective and potent inhibitors of DHFR derived from Pneumocystis jirovecii. The synthesis and biological evaluation of the further analogs designed in an attempt to optimize selectivity and potency for pjDHFR over hDHFR will be presented.

6-Substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic agents

248th National Meeting (2014)

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