Design,synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors |
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| Institution: | 1. Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, DE 72076 Tübingen, Germany;2. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland;3. Laboratory of Molecular Biology applied to Diagnosis (LBMAD), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil;4. Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Faculty of Pharmaceutical Sciences, University of São Paulo, Prof. Lineu Prestes Avenue, 580, Bl.13, São Paulo, SP, Brazil;5. Laboratory of Design and Synthesis of Chemotherapeutics Potentially Active in Neglected Diseases (LAPEN), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil;6. Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil;7. Department of Biological Sciences, School of Pharmaceutical Sciences, São Paulo State University, Araraquara (UNESP Araraquara), São Paulo, Brazil;8. Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, Prof. Lineu Prestes Avenue, 580, Bl.13, São Paulo, SP, Brazil;9. Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK;1. Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1–3, Moscow 119991, Russian Federation;2. EDASA Scientific, Via Stingi 37, San Salvo 66050, Italy;3. Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan;4. Dulbecco Telethon Laboratory of Prions & Amyloids, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, Trento 38123, Italy;5. A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov St. 28, Moscow, Russian Federation;1. School of Pharmacy, Jinan University, Guangzhou 510632, China;2. YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China;3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China;4. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;5. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States;2. Center for Pulmonary Vascular Disease, Duke University Medical Center, Durham, NC 27710, United States;1. Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;2. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;3. Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;4. Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;5. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149, Germany;1. Department of Pesticide Chemistry, College of Science, China Agricultural University, Beijing, China;2. State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection and Shenzhen Agricultural Genome Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China;1. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China;2. State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau, China;3. The Center for Disease Control and Prevention of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830002, China;4. Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA;5. Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Road, Headington, Oxford OX3 7LE, United Kingdom;6. Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China |
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| Abstract: | The enzyme dihydrofolate reductase from M. tuberculosis (MtDHFR) has a high unexploited potential to be a target for new drugs against tuberculosis (TB), due to its importance for pathogen survival. Preliminary studies have obtained fragment-like molecules with low affinity to MtDHFR which can potentially become lead compounds. Taking this into account, the fragment MB872 was used as a prototype for analogue development by bioisosterism/retro-bioisosterism, which resulted in 20 new substituted 3-benzoic acid derivatives. Compounds were active against MtDHFR, with IC50 values ranging from 7 to 40 μM, where compound 4e not only had the best inhibitory activity (IC50 = 7 μM), but also was 71-fold more active than the original fragment MB872. The 4e inhibition kinetics indicated an uncompetitive mechanism, which was supported by molecular modeling which suggested that the compounds can access an independent backpocket from the substrate and competitive inhibitors. Thus, based on these results, substituted 3-benzoic acid derivatives have strong potential to be developed as novel MtDHFR inhibitors and also anti-TB agents. |
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| Keywords: | Bioisosterism Fragment optimization and drug design Tuberculosis |
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