Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors |
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| Affiliation: | 1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Egypt;2. Organic & Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia, 32958, Egypt;3. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azahar University, Cairo 11884, Egypt;4. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University, Cairo 11431, Egypt;5. Department of Pharmacology, Faculty of Medicine, Al-Azher University, 71524 Assiut, Egypt;6. Biochemistry Department, Faculty of Pharmacy, Al-Azher University, 71524 Assiut, Egypt;7. Biochemistry Department, Faculty of Pharmacy, Nahda University, Benisuif, Egypt;1. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea;2. Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea;3. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea;4. Western Seoul Center, Korea Basic Science Institute, Seoul 03760, South Korea;1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China;2. School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, 518060, China;3. Institute of Traditional Chinese Medicine & Natural Products, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China;1. School of Science, China Pharmaceutical University, Nanjing, PR China;2. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China;1. Departamento de Sintese de Farmacos, Instituto de Tecnologia em Farmacos, Farmanguinhos – FIOCRUZ, Fundação Oswaldo Cruz, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil;2. Programa de Pos-graduacao em Quimica, PGQu Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil;3. Departamento de Medicina Veterinaria, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de Sao Paulo, Pirassununga, SP, Brazil;4. Programa de Pos-graduacao em Biociencia Animal, Faculdade de Zootecnia e Engenahria de alimentos, Universidade de São Paulo, Pirassununga, SP, Brazil;5. Laboratorio de Biologia Celular, Instituto Oswaldo Cruz, IOC – FIOCRUZ, Fundacao Oswaldo Cruz, Avenida Brasil 4365, Rio de Janeiro, RJ, Brazil;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt;3. Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt;1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India;2. Biochemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India;3. Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India;4. Academy of Scientific and Innovative Research, Ghaziabad 201002, U.P., India |
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| Abstract: | A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC50 values ranging from 8.31 to 5.16 µM. Pyrazolo[3,4-d]pyrimidin-7-one scaffolds have been rationally designed via consecutive molecular modelling studies prior to their synthesis and biological evaluation. In addition, the results of the pharmacophore-based virtual screening revealed that 1v0p_PVB might have promising activity as a PDE-5 inhibitor. |
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| Keywords: | Phosphodiesterase 5 (PDE5) Sildenafil Cavernosum tissue Molecular modelling PDE-5 inhibitors |
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