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The transmissible gametocytes of <jats:italic>Plasmodium falciparum<\/jats:italic> seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post\u2010translational marks. Here, we report exploration of compounds from a chemical library generated during hit\u2010to\u2010lead optimization of inhibitors of the human histone lysine demethylase, KDM4B. Derivatives of 2\u2010([1,1\u2032\u2010biphenyl]\u20104\u2010carboxamido) benzoic acid, around either the amide or a sulfonamide linker backbone (2\u2010(arylcarboxamido)benzoic acid, 2\u2010carboxamide (arylsulfonamido)benzoic acid and <jats:italic>N<\/jats:italic>\u2010(2\u2010(1<jats:italic>H<\/jats:italic>\u2010tetrazol\u20105\u2010yl)phenyl)\u2010arylcarboxamide), showed potent activity towards late\u2010stage gametocytes (stage IV\/V) of <jats:italic>P. falciparum<\/jats:italic>, with the most potent compound reaching single digit nanomolar activity. Structure\u2010activity 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\u2010blocking agents.<\/jats:p>","DOI":"10.1002\/cbic.202200427","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T03:35:04Z","timestamp":1663212904000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["New Transmission\u2010Selective Antimalarial Agents through Hit\u2010to\u2010Lead Optimization of 2\u2010([1,1\u2032\u2010Biphenyl]\u20104\u2010carboxamido)benzoic Acid Derivatives"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9026-0583","authenticated-orcid":false,"given":"Janette","family":"Reader","sequence":"first","affiliation":[{"name":"Department of Biochemistry Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria  Lynnwood Road Pretoria 0028 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0346-1403","authenticated-orcid":false,"given":"Daniel F. L.","family":"Opperman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria  Lynnwood Road Pretoria 0028 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9933-8647","authenticated-orcid":false,"given":"Mari\u00ebtte E.","family":"van der Watt","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria  Lynnwood Road Pretoria 0028 South Africa"},{"name":"School of Health Systems and Public Health University of Pretoria, Hatfield  Pretoria 0028 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0497-4473","authenticated-orcid":false,"given":"Anjo","family":"Theron","sequence":"additional","affiliation":[{"name":"Next Generation Health Council for Scientific and Industrial Research  Pretoria 0001 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6885-1483","authenticated-orcid":false,"given":"Meta","family":"Leshabane","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria  Lynnwood Road Pretoria 0028 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2623-0114","authenticated-orcid":false,"given":"Shant\u00e9","family":"da Rocha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria  Lynnwood Road Pretoria 0028 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6162-3063","authenticated-orcid":false,"given":"Jonathan","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences Medical University of South Carolina  Charleston SC 29425 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5225-8212","authenticated-orcid":false,"given":"Kathleen","family":"Garrabrant","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences Medical University of South Carolina  Charleston SC 29425 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3417-4418","authenticated-orcid":false,"given":"Ivett","family":"Pi\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences Medical University of South Carolina  Charleston SC 29425 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1423-6327","authenticated-orcid":false,"given":"Catherine","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences Medical University of South Carolina  Charleston SC 29425 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-1916","authenticated-orcid":false,"given":"Patrick M.","family":"Woster","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences Medical University of South Carolina  Charleston SC 29425 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5888-2905","authenticated-orcid":false,"given":"Lyn\u2010Mari\u00e9","family":"Birkholtz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria  Lynnwood Road Pretoria 0028 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.bbrc.2014.07.006","volume":"455","author":"Dhanak D.","year":"2014","journal-title":"Biochem. 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