dc.contributor.author |
Reader, J
|
|
dc.contributor.author |
Opperman, DFL
|
|
dc.contributor.author |
Van der Watt, ME
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|
dc.contributor.author |
Theron, Anjo
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|
dc.contributor.author |
Leshabane, M
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|
dc.contributor.author |
Da Rocha, S
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|
dc.contributor.author |
Turner, J
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|
dc.contributor.author |
Garrabrant, K
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|
dc.contributor.author |
Piña, I
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|
dc.contributor.author |
Mills, C
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|
dc.date.accessioned |
2022-11-28T06:17:56Z |
|
dc.date.available |
2022-11-28T06:17:56Z |
|
dc.date.issued |
2022-09 |
|
dc.identifier.citation |
Reader, 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/10204/12539 |
en_ZA |
dc.identifier.issn |
1439-4227 |
|
dc.identifier.issn |
1439-7633 |
|
dc.identifier.uri |
https://doi.org/10.1002/cbic.202200427
|
|
dc.identifier.uri |
http://hdl.handle.net/10204/12539
|
|
dc.description.abstract |
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. |
en_US |
dc.format |
Fulltext |
en_US |
dc.language.iso |
en |
en_US |
dc.relation.uri |
https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202200427 |
en_US |
dc.source |
ChemBioChem |
en_US |
dc.subject |
Acid Derivatives |
en_US |
dc.subject |
Malaria |
en_US |
dc.subject |
Novel derivatives |
en_US |
dc.subject |
Plasmodium falciparum |
en_US |
dc.title |
New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic acid derivatives |
en_US |
dc.type |
Article |
en_US |
dc.description.pages |
9 |
en_US |
dc.description.note |
© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH. |
en_US |
dc.description.cluster |
Next Generation Health |
en_US |
dc.description.impactarea |
Array Print Compan Diagnostics |
en_US |
dc.identifier.apacitation |
Reader, 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/10204/12539 |
en_ZA |
dc.identifier.chicagocitation |
Reader, 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/10204/12539 |
en_ZA |
dc.identifier.vancouvercitation |
Reader 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. |
en_ZA |
dc.identifier.ris |
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 -
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en_ZA |