Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives
A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalaria...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/12/1709 |
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| author | Joyce E. Gutiérrez Hegira Ramírez Esteban Fernandez-Moreira María E. Acosta Michael R. Mijares Juan Bautista De Sanctis Soňa Gurská Petr Džubák Marián Hajdúch Liesangerli Labrador-Fagúndez Bruno G. Stella Luis José Díaz-Pérez Gustavo Benaim Jaime E. Charris |
| author_facet | Joyce E. Gutiérrez Hegira Ramírez Esteban Fernandez-Moreira María E. Acosta Michael R. Mijares Juan Bautista De Sanctis Soňa Gurská Petr Džubák Marián Hajdúch Liesangerli Labrador-Fagúndez Bruno G. Stella Luis José Díaz-Pérez Gustavo Benaim Jaime E. Charris |
| author_sort | Joyce E. Gutiérrez |
| collection | DOAJ |
| description | A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of <i>Plasmodium berghei</i> ANKA in this study. The compounds significantly reduced haeme crystallization, with IC<sub>50</sub> values < 10 µM. The values were comparable to chloroquine’s, with an IC<sub>50</sub> of 1.50 ± 0.01 µM. The compounds <b>4c</b> and <b>4e</b> prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds <b>4b</b>, <b>4c,</b> and <b>4e</b> on another important human parasite, <i>Leishmania mexicana</i>, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC<sub>50</sub> < 10 µM. Concerning the possible mechanism of action of these compounds on <i>Lesihmania mexicana</i>, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber’s rules, and except for <b>2</b> and <b>4i</b>, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo. |
| first_indexed | 2024-03-08T20:27:21Z |
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| id | doaj.art-c3ae8e752e514bfdab501d036bed6509 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-08T20:27:21Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-c3ae8e752e514bfdab501d036bed65092023-12-22T14:31:38ZengMDPI AGPharmaceuticals1424-82472023-12-011612170910.3390/ph16121709Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate DerivativesJoyce E. Gutiérrez0Hegira Ramírez1Esteban Fernandez-Moreira2María E. Acosta3Michael R. Mijares4Juan Bautista De Sanctis5Soňa Gurská6Petr Džubák7Marián Hajdúch8Liesangerli Labrador-Fagúndez9Bruno G. Stella10Luis José Díaz-Pérez11Gustavo Benaim12Jaime E. Charris13Organic Synthesis Laboratory, Faculty of Pharmacy, Central University of Venezuela, Los Chaguaramos 1041-A, Caracas 1040, VenezuelaFacultad de Ciencias de la Salud y Desarrollo Humano, Univesidad Ecotec, Km. 13.5 Samborondón, Guayas, Guayaquil 092302, EcuadorEscuela de Medicina, Universidad Espíritu Santo, Samborondón, Guayas, Guayaquil 092301, EcuadorUnidad de Bioquímica, Facultad de Farmacia, Central University of Venezuela, Los Chaguaramos 1041-A, Caracas 1040, VenezuelaBiotechnology Unit, Faculty of Pharmacy, Central University of Venezuela, Los Chaguaramos 1041-A, Caracas 1040, VenezuelaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 1333/5, 779 00 Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 1333/5, 779 00 Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 1333/5, 779 00 Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 1333/5, 779 00 Olomouc, Czech RepublicUnidad de Bioquímica de Parásitos y Señalización Celular, Instituto de Estudios Avanzados (IDEA), Caracas 1080, VenezuelaUnidad de Bioquímica de Parásitos y Señalización Celular, Instituto de Estudios Avanzados (IDEA), Caracas 1080, VenezuelaUnidad de Bioquímica de Parásitos y Señalización Celular, Instituto de Estudios Avanzados (IDEA), Caracas 1080, VenezuelaUnidad de Bioquímica de Parásitos y Señalización Celular, Instituto de Estudios Avanzados (IDEA), Caracas 1080, VenezuelaOrganic Synthesis Laboratory, Faculty of Pharmacy, Central University of Venezuela, Los Chaguaramos 1041-A, Caracas 1040, VenezuelaA series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of <i>Plasmodium berghei</i> ANKA in this study. The compounds significantly reduced haeme crystallization, with IC<sub>50</sub> values < 10 µM. The values were comparable to chloroquine’s, with an IC<sub>50</sub> of 1.50 ± 0.01 µM. The compounds <b>4c</b> and <b>4e</b> prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds <b>4b</b>, <b>4c,</b> and <b>4e</b> on another important human parasite, <i>Leishmania mexicana</i>, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC<sub>50</sub> < 10 µM. Concerning the possible mechanism of action of these compounds on <i>Lesihmania mexicana</i>, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber’s rules, and except for <b>2</b> and <b>4i</b>, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.https://www.mdpi.com/1424-8247/16/12/1709malarialeishmaniasiscytotoxicityADMETchloroquineaminoalkylbenzoates |
| spellingShingle | Joyce E. Gutiérrez Hegira Ramírez Esteban Fernandez-Moreira María E. Acosta Michael R. Mijares Juan Bautista De Sanctis Soňa Gurská Petr Džubák Marián Hajdúch Liesangerli Labrador-Fagúndez Bruno G. Stella Luis José Díaz-Pérez Gustavo Benaim Jaime E. Charris Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives Pharmaceuticals malaria leishmaniasis cytotoxicity ADMET chloroquine aminoalkylbenzoates |
| title | Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives |
| title_full | Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives |
| title_fullStr | Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives |
| title_full_unstemmed | Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives |
| title_short | Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives |
| title_sort | synthesis antimalarial antileishmanial and cytotoxicity activities and preliminary in silico admet studies of 2 7 chloroquinolin 4 ylamino ethyl benzoate derivatives |
| topic | malaria leishmaniasis cytotoxicity ADMET chloroquine aminoalkylbenzoates |
| url | https://www.mdpi.com/1424-8247/16/12/1709 |
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