Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines
From three previously identified antiplasmodial hit compounds (<b>A</b>–<b>C</b>) and inactive series (<b>D</b>), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline r...
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MDPI AG
2020-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/17/3929 |
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| author | Dyhia Amrane Armand Gellis Sébastien Hutter Marion Prieri Pierre Verhaeghe Nadine Azas Patrice Vanelle Nicolas Primas |
| author_facet | Dyhia Amrane Armand Gellis Sébastien Hutter Marion Prieri Pierre Verhaeghe Nadine Azas Patrice Vanelle Nicolas Primas |
| author_sort | Dyhia Amrane |
| collection | DOAJ |
| description | From three previously identified antiplasmodial hit compounds (<b>A</b>–<b>C</b>) and inactive series (<b>D</b>), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 <i>P. falciparum</i> strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC<sub>50</sub> K1 <i>P. falciparum</i> ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (<b>2</b>, <b>9</b>, <b>16,</b> and <b>24</b>) and two among 4-alkoxy derivatives (<b>41</b> and <b>44</b>). Regarding the two most potent molecules (<b>16</b> and <b>41</b>), five derivatives without a 2-CCl<sub>3</sub> group were prepared, evaluated, and appeared totally inactive (EC<sub>50</sub> > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity. |
| first_indexed | 2024-03-10T16:45:35Z |
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| id | doaj.art-25ad1ed1698e4a08be8d62176353a8ff |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T16:45:35Z |
| publishDate | 2020-08-01 |
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| series | Molecules |
| spelling | doaj.art-25ad1ed1698e4a08be8d62176353a8ff2023-11-20T11:39:42ZengMDPI AGMolecules1420-30492020-08-012517392910.3390/molecules25173929Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl QuinazolinesDyhia Amrane0Armand Gellis1Sébastien Hutter2Marion Prieri3Pierre Verhaeghe4Nadine Azas5Patrice Vanelle6Nicolas Primas7Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille CEDEX 05, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille CEDEX 05, FranceIHU Méditerranée Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, Aix Marseille Univ, 13005 Marseille CEDEX 05, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille CEDEX 05, FranceLCC-CNRS Université de Toulouse, CNRS, UPS, 31400 Toulouse, FranceIHU Méditerranée Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, Aix Marseille Univ, 13005 Marseille CEDEX 05, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille CEDEX 05, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille CEDEX 05, FranceFrom three previously identified antiplasmodial hit compounds (<b>A</b>–<b>C</b>) and inactive series (<b>D</b>), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 <i>P. falciparum</i> strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC<sub>50</sub> K1 <i>P. falciparum</i> ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (<b>2</b>, <b>9</b>, <b>16,</b> and <b>24</b>) and two among 4-alkoxy derivatives (<b>41</b> and <b>44</b>). Regarding the two most potent molecules (<b>16</b> and <b>41</b>), five derivatives without a 2-CCl<sub>3</sub> group were prepared, evaluated, and appeared totally inactive (EC<sub>50</sub> > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.https://www.mdpi.com/1420-3049/25/17/39292-trichloromethylquinazoline<i>Plasmodium falciparum</i>in vitro HepG2 cytotoxicitystructure-activity relationships |
| spellingShingle | Dyhia Amrane Armand Gellis Sébastien Hutter Marion Prieri Pierre Verhaeghe Nadine Azas Patrice Vanelle Nicolas Primas Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines Molecules 2-trichloromethylquinazoline <i>Plasmodium falciparum</i> in vitro HepG2 cytotoxicity structure-activity relationships |
| title | Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines |
| title_full | Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines |
| title_fullStr | Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines |
| title_full_unstemmed | Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines |
| title_short | Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines |
| title_sort | synthesis and antiplasmodial evaluation of 4 carboxamido and 4 alkoxy 2 trichloromethyl quinazolines |
| topic | 2-trichloromethylquinazoline <i>Plasmodium falciparum</i> in vitro HepG2 cytotoxicity structure-activity relationships |
| url | https://www.mdpi.com/1420-3049/25/17/3929 |
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