New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors |
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| Institution: | 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. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt;3. Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt;4. Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, 12578 Cairo, Egypt;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. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt;2. Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt;4. Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany;5. School of Chemistry, University of Wollongong, Wollongong, 2522, New South Wales, Australia;6. Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia;7. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt;8. Pharmacy Program, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Kingdom of Bahrain;9. Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt;1. Department of Biotechnology, Chemistry and Pharmacy, “Department of Excellence 2018-2022\", University of Siena, Via Aldo Moro 2, 53100, Siena, Italy;2. Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132, Genoa, Italy;3. Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, I-27100, Pavia, Italy;4. Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), via Vela 6, 6500, Bellinzona, Switzerland;5. Biotechnology College of Science and Technology, Temple University, Biolife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA, 19122, United States;6. Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo, Berardenga, Italy;1. Pharmaceutical Chemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo 12311, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt |
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| Abstract: | Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo3,4-d]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized. All compounds were initially tested at 100 µM concentration against Leishmania amazonensis ARG (LaARG), showing inhibitory activity ranging from 36 to 74%. Two compounds, 1 (R=H) and 6 (R=CF3), showed arginase inhibition >70% and IC50 values of 12 µM and 47 µM, respectively. Thus, the kinetics of LaARG inhibition were analyzed for compounds 1 and 6 and revealed that these compounds inhibit the enzyme by an uncompetitive mechanism, showing Kis values, and dissociation constants for ternary complex enzyme-substrate-inhibitor, of 8.5 ± 0.9 µM and 29 ± 5 µM, respectively. Additionally, the molecular docking studies proposed that these two uncompetitive inhibitors interact with different LaARG binding sites, where compound 1 forms more H-bond interactions with the enzyme than compound 6. These compounds showed low activity against L. amazonensis free amastigotes obtained from mice lesions when assayed with as much as 30 µM. The maximum growth inhibition reached was between 20 and 30% after 48 h of incubation. These results suggest that this system can be promising for the design of potential antileishmanial compounds. |
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| Keywords: | Pyrazolopyrimidine Arginase Trypanothione Polyamines |
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