Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection |
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| Institution: | 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;1. Institute of Technology of Organic Chemistry, Faculty of Material Science and Applied Chemistry, Riga Technical University, P. Valdena 3/7, Riga LV-1048, Latvia;2. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia;1. College of Pharmacy, Jouf University, Aljouf, Sakaka, Saudi Arabia;2. College of Pharmacy, King Khalid University, Abha, Saudi Arabia;3. Glocal School of Pharmacy, Glocal University, Saharanpur, UP, India;4. KIET School of Pharmacy, Ghaziabad, UP, India;1. Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States;2. Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 421 E. Canfield Street, Detroit, MI 48201, United States;3. Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States;4. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, United States;1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China;1. Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States;2. Department of Physiology, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States;3. Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK 73117, United States;4. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China;2. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium |
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| Abstract: | Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido3,2-d]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors. |
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| Keywords: | PCP DHFR |
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