Targeting species specific amino acid residues: Design,synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents |
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Authors: | Khushbu Shah Xin Lin Sherry F. Queener Vivian Cody Jim Pace Aleem Gangjee |
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Affiliation: | 1. Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States;2. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States;3. Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, United States |
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Abstract: | To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC50) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold. |
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Keywords: | Pj PCP Pneumocystis pneumonia ART antiretroviral therapy TMP trimethoprim SMX sulfamethoxazole DHFR dihydrofolate reductase DHPS dihydropteroate synthase PTX piritrexim TMQ trimetrexate PC DHFR inhibitors hDHFR Pneumocystis pneumonia Opportunistic infections Corresponding author. |
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