Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities
For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 N-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing gro...
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Elsevier
2024-12-01
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| Series: | Results in Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211715624005861 |
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| author | Ameera Mohammed Dawoodjee John Sichinga Harrison Banda Steve Mbaya Evelyn Funjika Godfrey Mayoka Christabel Hikaambo Karol R. Francisco Yujie Uli Sun Lawrence J. Liu Conor R. Caffrey Peter Mubanga Cheuka |
| author_facet | Ameera Mohammed Dawoodjee John Sichinga Harrison Banda Steve Mbaya Evelyn Funjika Godfrey Mayoka Christabel Hikaambo Karol R. Francisco Yujie Uli Sun Lawrence J. Liu Conor R. Caffrey Peter Mubanga Cheuka |
| author_sort | Ameera Mohammed Dawoodjee |
| collection | DOAJ |
| description | For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 N-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing groups that benefited potency. This study sought to enhance the potency of this chemotype by incorporating other electron-withdrawing functionalities not studied previously and to overcome the potential pharmacokinetic liabilities associated with the high lipophilicity of frontrunner compounds. Compared to the most potent compound, 9 (EC50 = 80 nM), from our previous work, the most potent compounds in the current study (32 (EC50 = 1.17 µM), 34 (EC50 = 1.64 µM) and 38 (EC50 = 1.16 µM)) were less active although they retained single digit micromolar potency. Furthermore, compound 38 generated a CC50 value of > 20 µM in counter toxicity screens using HEK 293 cells, translating to a wide selectivity index of > 17. |
| format | Article |
| id | doaj-art-79d0dd0602cc48f4b4d7c306a5f0ed47 |
| institution | DOAJ |
| issn | 2211-7156 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Results in Chemistry |
| spelling | doaj-art-79d0dd0602cc48f4b4d7c306a5f0ed472025-08-20T02:50:08ZengElsevierResults in Chemistry2211-71562024-12-011210189010.1016/j.rechem.2024.101890Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalitiesAmeera Mohammed Dawoodjee0John Sichinga1Harrison Banda2Steve Mbaya3Evelyn Funjika4Godfrey Mayoka5Christabel Hikaambo6Karol R. Francisco7Yujie Uli Sun8Lawrence J. Liu9Conor R. Caffrey10Peter Mubanga Cheuka11Department of Chemistry, School of Natural Sciences, University of Zambia, P.O. Box 32379, Lusaka, ZambiaDepartment of Chemistry, School of Natural Sciences, University of Zambia, P.O. Box 32379, Lusaka, ZambiaDepartment of Chemistry, School of Natural Sciences, University of Zambia, P.O. Box 32379, Lusaka, ZambiaDepartment of Chemistry, School of Natural Sciences, University of Zambia, P.O. Box 32379, Lusaka, ZambiaDepartment of Chemistry, School of Natural Sciences, University of Zambia, P.O. Box 32379, Lusaka, ZambiaSchool of Pharmacy, Jomo Kenyatta University of Agriculture and Technology, P.O. Box 62 000 – 00200, Nairobi, KenyaDepartment of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South AfricaCenter for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA; Corresponding authors.Department of Chemistry, School of Natural Sciences, University of Zambia, P.O. Box 32379, Lusaka, Zambia; Corresponding authors.For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 N-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing groups that benefited potency. This study sought to enhance the potency of this chemotype by incorporating other electron-withdrawing functionalities not studied previously and to overcome the potential pharmacokinetic liabilities associated with the high lipophilicity of frontrunner compounds. Compared to the most potent compound, 9 (EC50 = 80 nM), from our previous work, the most potent compounds in the current study (32 (EC50 = 1.17 µM), 34 (EC50 = 1.64 µM) and 38 (EC50 = 1.16 µM)) were less active although they retained single digit micromolar potency. Furthermore, compound 38 generated a CC50 value of > 20 µM in counter toxicity screens using HEK 293 cells, translating to a wide selectivity index of > 17.http://www.sciencedirect.com/science/article/pii/S2211715624005861N-phenylbenzamide analogsN-pyridazinylbenzamide analogsSchistosoma mansoni |
| spellingShingle | Ameera Mohammed Dawoodjee John Sichinga Harrison Banda Steve Mbaya Evelyn Funjika Godfrey Mayoka Christabel Hikaambo Karol R. Francisco Yujie Uli Sun Lawrence J. Liu Conor R. Caffrey Peter Mubanga Cheuka Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities Results in Chemistry N-phenylbenzamide analogs N-pyridazinylbenzamide analogs Schistosoma mansoni |
| title | Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities |
| title_full | Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities |
| title_fullStr | Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities |
| title_full_unstemmed | Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities |
| title_short | Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities |
| title_sort | structure activity relationships of antischistosomal n phenylbenzamides by incorporation of electron withdrawing functionalities |
| topic | N-phenylbenzamide analogs N-pyridazinylbenzamide analogs Schistosoma mansoni |
| url | http://www.sciencedirect.com/science/article/pii/S2211715624005861 |
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