Pneumocystis pneumonia (PCP) is an opportunistic disease caused by the invasion of the lung by the unicellular fungus Pneumocystis jirovecii (pj). It is a life-threatening pulmonary infection that occurs in immunocompromised individuals and HIV-infected patients. Despite advances of combination antiretroviral therapy (cART), Pneumocystis pneumonia continues to occur in HIV-infected patients with late presentation for cART or virological and immunological failure after receiving cART. PCP has also emerged as a concern in patients with non–HIV-related immune deficiencies. Selective dihydrofolate reductase (DHFR) inhibitors, in combination, represent a viable therapeutic approach for the treatment of these infectious diseases. First line treatment of Pneumocystis pneumonia (PCP) requires a combination of trimethoprim (TMP)-sulfamethoxazole (SMX), due to the 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 have been discontinued. The failure of these two options is due to adverse reactions and resistance to the sulfa drug as well as adverse reactions of second-line agents. Thus there is a substantial unmet clinical need for agents that combine the potency of PTX and selectivity of TMP in single agents. We designed and synthesized a series of 6-substituted pyrido[2,3-d]pyrimidines that are selective and potent inhibitors of DHFR derived from Pneumocystis jirovecii. Copper-catalyzed Ullmann type chemistry of substituted thiophenols with pivaloyl protected 2-amino-5-iodonicotinonitrile was successfully explored to synthesize these analogs. The synthesis, molecular modeling, and biological evaluation of the new analogs designed to improve selectivity and potency for pjDHFR over hDHFR will be presented.

Design, synthesis, and molecular modeling of novel 6-substituted pyrido[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic agents

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.