Reader, JOpperman, DFLVan der Watt, METheron, AnjoLeshabane, MDa Rocha, STurner, JGarrabrant, KPiña, IMills, C2022-11-282022-11-282022-09Reader, J., Opperman, D., Van der Watt, M., Theron, A., Leshabane, M., Da Rocha, S., Turner, J. & Garrabrant, K. et al. 2022. New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic acid derivatives. <i>ChemBioChem.</i> http://hdl.handle.net/10204/125391439-42271439-7633https://doi.org/10.1002/cbic.202200427http://hdl.handle.net/10204/12539Malaria elimination requires multipronged approaches, including the application of antimalarial drugs able to block human-to-mosquito transmission of malaria parasites. The transmissible gametocytes of Plasmodium falciparum seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post-translational marks. Here, we report exploration of compounds from a chemical library generated during hit-to-lead optimization of inhibitors of the human histone lysine demethylase, KDM4B. Derivatives of 2-([1,1'-biphenyl]-4-carboxamido) benzoic acid, around either the amide or a sulfonamide linker backbone (2-(arylcarboxamido)benzoic acid, 2-carboxamide (arylsulfonamido)benzoic acid and N-(2-(1H-tetrazol-5-yl)phenyl)-arylcarboxamide), showed potent activity towards late-stage gametocytes (stage IV/V) of P. falciparum, with the most potent compound reaching single digit nanomolar activity. Structure-activity relationship trends were evident and frontrunner compounds also displayed microsomal stability and favourable solubility profiles. Simplified synthetic routes support further derivatization of these compounds for further development of these series as malaria transmission-blocking agents.FulltextenAcid DerivativesMalariaNovel derivativesPlasmodium falciparumArticleReader, J., Opperman, D., Van der Watt, M., Theron, A., Leshabane, M., Da Rocha, S., ... Mills, C. (2022). New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic acid derivatives. <i>ChemBioChem</i>, http://hdl.handle.net/10204/12539Reader, J, DFL Opperman, ME Van der Watt, Anjo Theron, M Leshabane, S Da Rocha, J Turner, K Garrabrant, I Piña, and C Mills "New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic acid derivatives." <i>ChemBioChem</i> (2022) http://hdl.handle.net/10204/12539Reader J, Opperman D, Van der Watt M, Theron A, Leshabane M, Da Rocha S, et al. New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic acid derivatives. ChemBioChem. 2022; http://hdl.handle.net/10204/12539.TY - Article AU - Reader, J AU - Opperman, DFL AU - Van der Watt, ME AU - Theron, Anjo AU - Leshabane, M AU - Da Rocha, S AU - Turner, J AU - Garrabrant, K AU - Piña, I AU - Mills, C AB - Malaria elimination requires multipronged approaches, including the application of antimalarial drugs able to block human-to-mosquito transmission of malaria parasites. The transmissible gametocytes of Plasmodium falciparum seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post-translational marks. Here, we report exploration of compounds from a chemical library generated during hit-to-lead optimization of inhibitors of the human histone lysine demethylase, KDM4B. Derivatives of 2-([1,1'-biphenyl]-4-carboxamido) benzoic acid, around either the amide or a sulfonamide linker backbone (2-(arylcarboxamido)benzoic acid, 2-carboxamide (arylsulfonamido)benzoic acid and N-(2-(1H-tetrazol-5-yl)phenyl)-arylcarboxamide), showed potent activity towards late-stage gametocytes (stage IV/V) of P. falciparum, with the most potent compound reaching single digit nanomolar activity. Structure-activity relationship trends were evident and frontrunner compounds also displayed microsomal stability and favourable solubility profiles. Simplified synthetic routes support further derivatization of these compounds for further development of these series as malaria transmission-blocking agents. DA - 2022-09 DB - ResearchSpace DP - CSIR J1 - ChemBioChem KW - Acid Derivatives KW - Malaria KW - Novel derivatives KW - Plasmodium falciparum LK - https://researchspace.csir.co.za PY - 2022 SM - 1439-4227 SM - 1439-7633 T1 - New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic acid derivatives TI - New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic acid derivatives UR - http://hdl.handle.net/10204/12539 ER -