Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major
Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasiti...
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MDPI AG
2018-07-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/7/1626 |
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| author | Felipe Rodriguez Eva Iniguez Guadalupe Pena Contreras Haidar Ahmed Thadeu E. M. M. Costa Rachid Skouta Rosa A. Maldonado |
| author_facet | Felipe Rodriguez Eva Iniguez Guadalupe Pena Contreras Haidar Ahmed Thadeu E. M. M. Costa Rachid Skouta Rosa A. Maldonado |
| author_sort | Felipe Rodriguez |
| collection | DOAJ |
| description | Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure–activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells. |
| first_indexed | 2024-12-21T17:33:04Z |
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| id | doaj.art-3ec05a57fbb54f7385794a820fa6138c |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-21T17:33:04Z |
| publishDate | 2018-07-01 |
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| spelling | doaj.art-3ec05a57fbb54f7385794a820fa6138c2022-12-21T18:55:52ZengMDPI AGMolecules1420-30492018-07-01237162610.3390/molecules23071626molecules23071626Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania majorFelipe Rodriguez0Eva Iniguez1Guadalupe Pena Contreras2Haidar Ahmed3Thadeu E. M. M. Costa4Rachid Skouta5Rosa A. Maldonado6Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USADepartment of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USADepartment of Chemistry, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USADepartment of Chemistry, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USACentro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040-361, BrazilDepartment of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USADepartment of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USALeishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure–activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells.http://www.mdpi.com/1420-3049/23/7/1626thiophene compoundsLeishmania majorcutaneous leishmaniasisdrug screeningchemotherapystructure–activity relationship (SAR)in silico dockingreactive oxygen species |
| spellingShingle | Felipe Rodriguez Eva Iniguez Guadalupe Pena Contreras Haidar Ahmed Thadeu E. M. M. Costa Rachid Skouta Rosa A. Maldonado Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major Molecules thiophene compounds Leishmania major cutaneous leishmaniasis drug screening chemotherapy structure–activity relationship (SAR) in silico docking reactive oxygen species |
| title | Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major |
| title_full | Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major |
| title_fullStr | Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major |
| title_full_unstemmed | Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major |
| title_short | Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major |
| title_sort | development of thiophene compounds as potent chemotherapies for the treatment of cutaneous leishmaniasis caused by leishmania major |
| topic | thiophene compounds Leishmania major cutaneous leishmaniasis drug screening chemotherapy structure–activity relationship (SAR) in silico docking reactive oxygen species |
| url | http://www.mdpi.com/1420-3049/23/7/1626 |
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