Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity

The 2-phenoxybenzamide <b>1</b> from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of <i>P. falciparum</i>. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new d...

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Autores principales:	Theresa Hermann, Patrick Hochegger, Johanna Dolensky, Werner Seebacher, Eva-Maria Pferschy-Wenzig, Robert Saf, Marcel Kaiser, Pascal Mäser, Robert Weis
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	antimalarial CYP3A4 inhibition PAMPA 2-phenoxybenzamides <i>Plasmodium falciparum</i> Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/176a80a80aa24a23946632a02a7cfb4b
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spelling	oai:doaj.org-article:176a80a80aa24a23946632a02a7cfb4b2021-11-25T18:39:24ZSynthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity10.3390/ph141111091424-8247https://doaj.org/article/176a80a80aa24a23946632a02a7cfb4b2021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1109https://doaj.org/toc/1424-8247The 2-phenoxybenzamide <b>1</b> from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of <i>P. falciparum</i>. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of <i>P. falciparum</i>. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D<sub>7</sub>.<sub>4</sub> and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The <i>tert</i>-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against <i>P. falciparum</i> NF54 (<i>Pf</i>NF54 IC<sub>50</sub> = 0.2690 µM) and very low cytotoxicity (L-6 cells IC<sub>50</sub> = 124.0 µM) resulting in an excellent selectivity index of 460. Compared to the lead structure <b>1</b> the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.Theresa HermannPatrick HocheggerJohanna DolenskyWerner SeebacherEva-Maria Pferschy-WenzigRobert SafMarcel KaiserPascal MäserRobert WeisMDPI AGarticleantimalarialCYP3A4 inhibitionPAMPA2-phenoxybenzamides<i>Plasmodium falciparum</i>MedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1109, p 1109 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimalarial CYP3A4 inhibition PAMPA 2-phenoxybenzamides <i>Plasmodium falciparum</i> Medicine R Pharmacy and materia medica RS1-441
spellingShingle	antimalarial CYP3A4 inhibition PAMPA 2-phenoxybenzamides <i>Plasmodium falciparum</i> Medicine R Pharmacy and materia medica RS1-441 Theresa Hermann Patrick Hochegger Johanna Dolensky Werner Seebacher Eva-Maria Pferschy-Wenzig Robert Saf Marcel Kaiser Pascal Mäser Robert Weis Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity
description	The 2-phenoxybenzamide <b>1</b> from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of <i>P. falciparum</i>. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of <i>P. falciparum</i>. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D<sub>7</sub>.<sub>4</sub> and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The <i>tert</i>-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against <i>P. falciparum</i> NF54 (<i>Pf</i>NF54 IC<sub>50</sub> = 0.2690 µM) and very low cytotoxicity (L-6 cells IC<sub>50</sub> = 124.0 µM) resulting in an excellent selectivity index of 460. Compared to the lead structure <b>1</b> the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.
format	article
author	Theresa Hermann Patrick Hochegger Johanna Dolensky Werner Seebacher Eva-Maria Pferschy-Wenzig Robert Saf Marcel Kaiser Pascal Mäser Robert Weis
author_facet	Theresa Hermann Patrick Hochegger Johanna Dolensky Werner Seebacher Eva-Maria Pferschy-Wenzig Robert Saf Marcel Kaiser Pascal Mäser Robert Weis
author_sort	Theresa Hermann
title	Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity
title_short	Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity
title_full	Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity
title_fullStr	Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity
title_full_unstemmed	Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity
title_sort	synthesis and structure-activity relationships of new 2-phenoxybenzamides with antiplasmodial activity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/176a80a80aa24a23946632a02a7cfb4b
work_keys_str_mv	AT theresahermann synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity AT patrickhochegger synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity AT johannadolensky synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity AT wernerseebacher synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity AT evamariapferschywenzig synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity AT robertsaf synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity AT marcelkaiser synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity AT pascalmaser synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity AT robertweis synthesisandstructureactivityrelationshipsofnew2phenoxybenzamideswithantiplasmodialactivity
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Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity

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