A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell Lines
Cancer and parasitic diseases, such as leishmaniasis and Chagas disease, share similarities that allow the co-development of new antiproliferative agents as a strategy to quickly track the discovery of new drugs. This strategy is especially interesting regarding tropical neglected diseases, for whic...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Tropical Medicine and Infectious Disease |
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| Online Access: | https://www.mdpi.com/2414-6366/7/12/403 |
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| author | Paulo Pitasse-Santos Eduardo Salustiano Raynná Bittencourt Pena Otávio Augusto Chaves Leonardo Marques da Fonseca Kelli Monteiro da Costa Carlos Antônio do Nascimento Santos Jhenifer Santos Dos Reis Marcos André Rodrigues da Costa Santos Jose Osvaldo Previato Lucia Mendonça Previato Leonardo Freire-de-Lima Nelilma Correia Romeiro Lúcia Helena Pinto-da-Silva Célio G. Freire-de-Lima Débora Decotè-Ricardo Marco Edilson Freire-de-Lima |
| author_facet | Paulo Pitasse-Santos Eduardo Salustiano Raynná Bittencourt Pena Otávio Augusto Chaves Leonardo Marques da Fonseca Kelli Monteiro da Costa Carlos Antônio do Nascimento Santos Jhenifer Santos Dos Reis Marcos André Rodrigues da Costa Santos Jose Osvaldo Previato Lucia Mendonça Previato Leonardo Freire-de-Lima Nelilma Correia Romeiro Lúcia Helena Pinto-da-Silva Célio G. Freire-de-Lima Débora Decotè-Ricardo Marco Edilson Freire-de-Lima |
| author_sort | Paulo Pitasse-Santos |
| collection | DOAJ |
| description | Cancer and parasitic diseases, such as leishmaniasis and Chagas disease, share similarities that allow the co-development of new antiproliferative agents as a strategy to quickly track the discovery of new drugs. This strategy is especially interesting regarding tropical neglected diseases, for which chemotherapeutic alternatives are extremely outdated. We designed a series of (<i>E</i>)-3-aryl-5-(2-aryl-vinyl)-1,2,4-oxadiazoles based on the reported antiparasitic and anticancer activities of structurally related compounds. The synthesis of such compounds led to the development of a new, fast, and efficient strategy for the construction of a 1,2,4-oxadiazole ring on a silica-supported system under microwave irradiation. One hit compound (<b>23</b>) was identified during the in vitro evaluation against drug-sensitive and drug-resistant chronic myeloid leukemia cell lines (EC<sub>50</sub> values ranging from 5.5 to 13.2 µM), <i>Trypanosoma cruzi</i> amastigotes (EC<sub>50</sub> = 2.9 µM) and <i>Leishmania amazonensis</i> promastigotes (EC<sub>50</sub> = 12.2 µM) and amastigotes (EC<sub>50</sub> = 13.5 µM). In silico studies indicate a correlation between the in vitro activity and the interaction with tubulin at the colchicine binding site. Furthermore, ADMET in silico predictions indicate that the compounds possess a high druggability potential due to their physicochemical, pharmacokinetic, and toxicity profiles, and for hit 23, it was identified by multiple spectroscopic approaches that this compound binds with human serum albumin (HSA) via a spontaneous ground-state association with a moderate affinity driven by entropically and enthalpically energies into subdomain IIA (site I) without significantly perturbing the secondary content of the protein. |
| first_indexed | 2024-03-09T15:46:37Z |
| format | Article |
| id | doaj.art-4cb9d0829caf4b10b3b7a55a9b082f65 |
| institution | Directory Open Access Journal |
| issn | 2414-6366 |
| language | English |
| last_indexed | 2024-03-09T15:46:37Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Tropical Medicine and Infectious Disease |
| spelling | doaj.art-4cb9d0829caf4b10b3b7a55a9b082f652023-11-24T18:27:58ZengMDPI AGTropical Medicine and Infectious Disease2414-63662022-11-0171240310.3390/tropicalmed7120403A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell LinesPaulo Pitasse-Santos0Eduardo Salustiano1Raynná Bittencourt Pena2Otávio Augusto Chaves3Leonardo Marques da Fonseca4Kelli Monteiro da Costa5Carlos Antônio do Nascimento Santos6Jhenifer Santos Dos Reis7Marcos André Rodrigues da Costa Santos8Jose Osvaldo Previato9Lucia Mendonça Previato10Leonardo Freire-de-Lima11Nelilma Correia Romeiro12Lúcia Helena Pinto-da-Silva13Célio G. Freire-de-Lima14Débora Decotè-Ricardo15Marco Edilson Freire-de-Lima16Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica 23890-000, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilLaboratório Integrado de Computação Científica (LICC), Universidade Federal do Rio de Janeiro—Centro Multidisciplinar UFRJ Macaé, Macaé 27930-560, Rio de Janeiro, BrazilLaboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-900, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilLaboratório Integrado de Computação Científica (LICC), Universidade Federal do Rio de Janeiro—Centro Multidisciplinar UFRJ Macaé, Macaé 27930-560, Rio de Janeiro, BrazilInstituto de Veterinária, Universidade Federal Rural do Rio de Janeiro, Seropédica 23890-000, Rio de Janeiro, BrazilInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21491-170, Rio de Janeiro, BrazilInstituto de Veterinária, Universidade Federal Rural do Rio de Janeiro, Seropédica 23890-000, Rio de Janeiro, BrazilInstituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica 23890-000, Rio de Janeiro, BrazilCancer and parasitic diseases, such as leishmaniasis and Chagas disease, share similarities that allow the co-development of new antiproliferative agents as a strategy to quickly track the discovery of new drugs. This strategy is especially interesting regarding tropical neglected diseases, for which chemotherapeutic alternatives are extremely outdated. We designed a series of (<i>E</i>)-3-aryl-5-(2-aryl-vinyl)-1,2,4-oxadiazoles based on the reported antiparasitic and anticancer activities of structurally related compounds. The synthesis of such compounds led to the development of a new, fast, and efficient strategy for the construction of a 1,2,4-oxadiazole ring on a silica-supported system under microwave irradiation. One hit compound (<b>23</b>) was identified during the in vitro evaluation against drug-sensitive and drug-resistant chronic myeloid leukemia cell lines (EC<sub>50</sub> values ranging from 5.5 to 13.2 µM), <i>Trypanosoma cruzi</i> amastigotes (EC<sub>50</sub> = 2.9 µM) and <i>Leishmania amazonensis</i> promastigotes (EC<sub>50</sub> = 12.2 µM) and amastigotes (EC<sub>50</sub> = 13.5 µM). In silico studies indicate a correlation between the in vitro activity and the interaction with tubulin at the colchicine binding site. Furthermore, ADMET in silico predictions indicate that the compounds possess a high druggability potential due to their physicochemical, pharmacokinetic, and toxicity profiles, and for hit 23, it was identified by multiple spectroscopic approaches that this compound binds with human serum albumin (HSA) via a spontaneous ground-state association with a moderate affinity driven by entropically and enthalpically energies into subdomain IIA (site I) without significantly perturbing the secondary content of the protein.https://www.mdpi.com/2414-6366/7/12/403chagas disease<i>Trypanosoma cruzi</i><i>Leishmania amazonensis</i>anticancerchronic myeloid leukemiamolecular docking |
| spellingShingle | Paulo Pitasse-Santos Eduardo Salustiano Raynná Bittencourt Pena Otávio Augusto Chaves Leonardo Marques da Fonseca Kelli Monteiro da Costa Carlos Antônio do Nascimento Santos Jhenifer Santos Dos Reis Marcos André Rodrigues da Costa Santos Jose Osvaldo Previato Lucia Mendonça Previato Leonardo Freire-de-Lima Nelilma Correia Romeiro Lúcia Helena Pinto-da-Silva Célio G. Freire-de-Lima Débora Decotè-Ricardo Marco Edilson Freire-de-Lima A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell Lines Tropical Medicine and Infectious Disease chagas disease <i>Trypanosoma cruzi</i> <i>Leishmania amazonensis</i> anticancer chronic myeloid leukemia molecular docking |
| title | A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell Lines |
| title_full | A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell Lines |
| title_fullStr | A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell Lines |
| title_full_unstemmed | A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell Lines |
| title_short | A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia Cell Lines |
| title_sort | novel protocol for the synthesis of 1 2 4 oxadiazoles active against trypanosomatids and drug resistant leukemia cell lines |
| topic | chagas disease <i>Trypanosoma cruzi</i> <i>Leishmania amazonensis</i> anticancer chronic myeloid leukemia molecular docking |
| url | https://www.mdpi.com/2414-6366/7/12/403 |
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