de Araújo Rodrigo Santos Aquino, Bernardo Vitória Gaspar, Tibúrcio Robert da Silva, Bedor Danilo Cesar Galindo, Campos Michel Leandro de, Pontarolo Roberto, de Sousa Julyanne Maria Saraiva, Rodrigues Klinger Antonio da Franca, Scotti Marcus Tullius, Nayarisseri Anuraj, Marchand Pascal, Mendonça-Junior Francisco Jaime Bezerra
Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraíba, João Pessoa 58071-160, Brazil.
Postgraduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, Brazil.
Pharmaceuticals (Basel). 2025 Jan 17;18(1):125. doi: 10.3390/ph18010125.
: 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. : 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 and for cytotoxicity against macrophages. : Several series of compounds were synthesized, and it was possible to identify some substitution patterns favorable to the activity generating compounds with IC 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. : 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.
根据世界卫生组织的定义，利什曼病是20种被忽视的热带疾病之一，影响着四大洲约1200万人，引发了严重的公共卫生问题。由于缺乏治疗选择，再加上现有药物的毒性和耐药性的出现，开发新的药物选择变得迫在眉睫。在此背景下，本研究的目的是扩展对负责2-氨基噻吩衍生物抗利什曼原虫潜力的药效团基团的认识。因此，除了S-Se生物电子等排体之外，还合成了在2-氨基噻吩环的C-3、C-4和C-5位置含有化学修饰的新化合物。通过Gewald反应依次合成了数十种2-AT和2-氨基硒吩（2-AS）衍生物，然后对其体外抗利什曼原虫活性和对巨噬细胞的细胞毒性进行了评估。合成了几个系列的化合物，并且有可能确定一些有利于活性的取代模式，从而产生IC值低于10 µM的化合物，例如C-3处腈基的存在并非必需；C-4和C-5处环烷基/哌啶基链的存在和大小对调节活性的重要性；以及S/Se生物电子等排体取代在不影响安全性的情况下提高活性。综上所述，这些发现再次证实了2-氨基噻吩在生成抗利什曼病候选药物方面的巨大潜力，并为针对利什曼病问题设计更具前景的化合物提供了帮助。
