2-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity
<b>Background/Objectives</b>: Leishmaniasis is one of the 20 Neglected Tropical Diseases according to the WHO, affecting approximately 12 million people in four continents, generating serious public health problems. The lack of therapeutic options, associated with toxicity and the emerge...
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MDPI AG
2025-01-01
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| author | Rodrigo Santos Aquino de Araújo Vitória Gaspar Bernardo Robert da Silva Tibúrcio Danilo Cesar Galindo Bedor Michel Leandro de Campos Roberto Pontarolo Julyanne Maria Saraiva de Sousa Klinger Antonio da Franca Rodrigues Marcus Tullius Scotti Anuraj Nayarisseri Pascal Marchand Francisco Jaime Bezerra Mendonça-Junior |
| author_facet | Rodrigo Santos Aquino de Araújo Vitória Gaspar Bernardo Robert da Silva Tibúrcio Danilo Cesar Galindo Bedor Michel Leandro de Campos Roberto Pontarolo Julyanne Maria Saraiva de Sousa Klinger Antonio da Franca Rodrigues Marcus Tullius Scotti Anuraj Nayarisseri Pascal Marchand Francisco Jaime Bezerra Mendonça-Junior |
| author_sort | Rodrigo Santos Aquino de Araújo |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: Leishmaniasis is one of the 20 Neglected Tropical Diseases according to the WHO, affecting approximately 12 million people in four continents, generating serious public health problems. The lack of therapeutic options, associated with toxicity and the emergence of resistance to the few available drugs, makes it urgent to develop new drug options. In this context, the aims of this work are to expand the knowledge about the pharmacophore group responsible for the antileishmanial potential of 2-aminothiophene derivatives. Thus, new compounds were synthesized containing chemical modifications at the C-3, C-4, and C-5 positions of the 2-aminothiophene ring, in addition to the S-Se bioisosterism. <b>Methods</b>: Dozens of 2-AT and 2-aminoselenophen (2-AS) derivatives were sequentially synthesized through applications of the Gewald reaction and were then evaluated in vitro for their activities against <i>L. amazonensis</i> and for cytotoxicity against macrophages. <b>Results</b>: Several series of compounds were synthesized, and it was possible to identify some substitution patterns favorable to the activity generating compounds with IC<sub>50</sub> values below 10 µM, such as the non-essentiality of the presence of a carbonitrile group at C-3; the importance of the presence and size of cycloalkyl/piperidinyl chains at C-4 and C-5 in modulating the activity; and the increase in activity without affecting the safety of the S/Se bioisosteric substitution. <b>Conclusions</b>: Taken together, these findings reaffirm the great potential of 2-aminothiophenes to generate antileishmanial drug candidates and offers contributions to the drug design of compounds with an even more promising profile for the problem of leishmaniasis. |
| format | Article |
| id | doaj-art-c8f09dcce5144444baf987388f27d07c |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj-art-c8f09dcce5144444baf987388f27d07c2025-01-24T13:45:29ZengMDPI AGPharmaceuticals1424-82472025-01-0118112510.3390/ph180101252-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial ActivityRodrigo Santos Aquino de Araújo0Vitória Gaspar Bernardo1Robert da Silva Tibúrcio2Danilo Cesar Galindo Bedor3Michel Leandro de Campos4Roberto Pontarolo5Julyanne Maria Saraiva de Sousa6Klinger Antonio da Franca Rodrigues7Marcus Tullius Scotti8Anuraj Nayarisseri9Pascal Marchand10Francisco Jaime Bezerra Mendonça-Junior11Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraíba, João Pessoa 58071-160, BrazilLaboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraíba, João Pessoa 58071-160, BrazilLaboratory of Planning and Synthesis in Medicinal Chemistry, Pharmaceutical Sciences Department, Federal University of Pernambuco, Recife 50740-520, BrazilPharmaceutical and Cosmetic Development Center (NUDFAC), Department of Pharmaceutical Science, Federal University of Pernambuco, Recife 50740-520, BrazilHealth Sciences Institute, Federal University of Mato Grosso (UFMT), Sinop 78550-000, BrazilDepartamento de Farmácia, Universidade Federal do Paraná, Av. Prefeito Lothário Meissner 632, Curitiba 80210-170, BrazilInfectious Disease Laboratory, Campus Ministro Reis Velloso, Federal University of Parnaíba Delta, Parnaíba 64202-020, BrazilDepartamento de Farmácia, Universidade Federal do Paraná, Av. Prefeito Lothário Meissner 632, Curitiba 80210-170, BrazilPostgraduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, BrazilIn Silico Research Laboratory, Eminent Biosciences, Mahalakshmi Nagar, Indore 452010, IndiaNantes Université, Cibles et médicaments des infections et de l’immunité, IICiMed, UR 1155, F-44000 Nantes, FranceLaboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraíba, João Pessoa 58071-160, Brazil<b>Background/Objectives</b>: Leishmaniasis is one of the 20 Neglected Tropical Diseases according to the WHO, affecting approximately 12 million people in four continents, generating serious public health problems. The lack of therapeutic options, associated with toxicity and the emergence of resistance to the few available drugs, makes it urgent to develop new drug options. In this context, the aims of this work are to expand the knowledge about the pharmacophore group responsible for the antileishmanial potential of 2-aminothiophene derivatives. Thus, new compounds were synthesized containing chemical modifications at the C-3, C-4, and C-5 positions of the 2-aminothiophene ring, in addition to the S-Se bioisosterism. <b>Methods</b>: Dozens of 2-AT and 2-aminoselenophen (2-AS) derivatives were sequentially synthesized through applications of the Gewald reaction and were then evaluated in vitro for their activities against <i>L. amazonensis</i> and for cytotoxicity against macrophages. <b>Results</b>: Several series of compounds were synthesized, and it was possible to identify some substitution patterns favorable to the activity generating compounds with IC<sub>50</sub> values below 10 µM, such as the non-essentiality of the presence of a carbonitrile group at C-3; the importance of the presence and size of cycloalkyl/piperidinyl chains at C-4 and C-5 in modulating the activity; and the increase in activity without affecting the safety of the S/Se bioisosteric substitution. <b>Conclusions</b>: Taken together, these findings reaffirm the great potential of 2-aminothiophenes to generate antileishmanial drug candidates and offers contributions to the drug design of compounds with an even more promising profile for the problem of leishmaniasis.https://www.mdpi.com/1424-8247/18/1/125leishmaniasis2-aminothiophenedrug designbioisosterismpharmacomodulation |
| spellingShingle | Rodrigo Santos Aquino de Araújo Vitória Gaspar Bernardo Robert da Silva Tibúrcio Danilo Cesar Galindo Bedor Michel Leandro de Campos Roberto Pontarolo Julyanne Maria Saraiva de Sousa Klinger Antonio da Franca Rodrigues Marcus Tullius Scotti Anuraj Nayarisseri Pascal Marchand Francisco Jaime Bezerra Mendonça-Junior 2-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity Pharmaceuticals leishmaniasis 2-aminothiophene drug design bioisosterism pharmacomodulation |
| title | 2-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity |
| title_full | 2-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity |
| title_fullStr | 2-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity |
| title_full_unstemmed | 2-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity |
| title_short | 2-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity |
| title_sort | 2 aminothiophene derivatives new drug candidates against leishmaniasis drug design synthesis pharmacomodulation and antileishmanial activity |
| topic | leishmaniasis 2-aminothiophene drug design bioisosterism pharmacomodulation |
| url | https://www.mdpi.com/1424-8247/18/1/125 |
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