Evaluation of the antitrypanosoma activity and SAR study of novel LINS03 derivatives |
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| Institution: | 1. Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, 09913-030 Diadema, SP, Brazil;2. Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Av. dos Estados 5001, 09210-580 Santo André, SP, Brazil;3. Centre for Parasitology and Mycology, Instituto Adolfo Lutz, Av. Dr. Arnaldo 351, 01246-000 São Paulo, SP, Brazil;1. B. Verkin Institute for Low Temperature Physics and Engineering of NASU, Nauky 47, Kharkov 61103, Ukraine;2. Institute of Physics, Faculty of Sciences, P. J. Safarik University, Park Angelinum 9, 041 54 Ko?ice, Slovakia;3. ISIS Facility, Rutherford Appleton Laboratory, Chilton, Didcot, Oxfordshire OX11 0QX, United Kingdom;4. Department of Materials and Ceramic Engineering/CICECO, University of Aveiro, Aveiro 3810-193, Portugal;5. Department of Physics, Faculty of Electrical Engineering and Informatics, Technical University of Ko?ice, Park Komenského 2, 042 00 Ko?ice, Slovakia;6. V. N. Karazin Kharkiv National University, 4 Svobody sq., Kharkiv 61000, Ukraine;7. Scientific-Practical Materials Research Centre of NASB, P. Brovka 19, Minsk 220072, Belarus;8. Faculty of Chemistry, Vilnius University, Naugarduko 24, Vilnius LT-03225, Lithuania;1. The George Washington University, Department of Chemistry, 725 21st St., NW Washington, DC 20052, USA;2. Los Alamos National Laboratory, Los Alamos, NM 87545, USA;1. Institute of Magnetism, National Academy of Sciences of Ukraine and Ministry of Education and Science of Ukraine, Vernadsky Blvd. 36b, 03142, Kyiv, Ukraine;2. National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, Peremohy Ave. 37, 03056, Kyiv, Ukraine;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;2. Department of Chemistry, Faculty of Science and Technology, Al-Neelain University, Khartoum, Sudan;3. Department of Biochemistry, College of Science, King Saud University, PO Box 22452, Riyadh 11451, Saudi Arabia;1. Institute of Functional Materials and Agricultural Applied Chemistry, College of Science, Jiangxi Agricultural University, Nanchang 330045, PR China;2. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;3. Department of Hematology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;4. Institute of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Avenue, Qixia District, Nanjing 210023, PR China;5. Nanchang Jiangteng Pharmaceutical Co., Ltd., Nanchang 330045, PR China |
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| Abstract: | Chagas’ disease is a parasitic infection caused by Trypanosoma cruzi that is still treated by old and toxic drugs. In the search for novel alternatives, natural sources are an important source for new drug prototypes against T. cruzi to further structural exploitation. A set of natural-based compounds (LINS03) was designed, showing promising antitrypanosoma activity and low cytotoxicity to host cells. In this paper, nine novel LINS03 derivatives were evaluated against T. cruzi trypomastigotes and amastigotes. The selectivity was assessed through cytotoxicity assays using NCTC mammalian cells and calculating the CC50/IC50 ratio. The results showed that compounds 2d and 4c are noteworthy, due their high activity against amastigotes (IC50 13.9 and 5.8 µM) and low cytotoxicity (CC50 107.7 µM and >200 µM, respectively). These compounds did not showed alteration on plasma membrane permeability in a Sytox green model. SAR analysis suggested an ideal balance between hydrosolubility and lipophilicity is necessary to improve the activity, and that insertion of a meta-substituent is detrimental to the activity of the amine derivatives but not to the neutral derivatives, suggesting different mechanisms of actions. The results presented herein are valuable for designing novel compounds with improved activity and selectivity to be applied in future studies. |
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| Keywords: | Antiparasitic compounds Hydrophilic lipophilic balance Natural product analogues SAR analysis |
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