Promising hit compounds against resistant trichomoniasis: Synthesis and antiparasitic activity of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:37

Article

Ibanez-Escribano, Alexandra¹  Reviriego, Felipe²  Vela, Nerea²  Fonseca-Berzal, Cristina¹  Jose Nogal-Ruiz, Juan¹  Aran, Vicente J.²  Antonio Escario, Jose¹  Gomez-Barrio, Alicia¹ 

[1] Univ Complutense Madrid UCM, Fac Farm, Dept Microbiol & Parasitol, Plaza Ramon Y Cajal S-N, Madrid 28040, Spain

[2] Inst Quim Med IQM, Consejo Super Invest Cient CSIC, Calle Juan Cierva 3, Madrid 28006, Spain

关键词: Antiprotozoal agents;    Indazole;    Nitrogen heterocycles;    Trichomonas vaginalis;    Resistance;   

DOI  :  10.1016/j.bmcl.2021.127843

来源: Elsevier

【 摘 要 】

A series of 11 3-(omega-aminoalkoxy)-1-benzyl-5-nitroindazoles (2-12) has been prepared starting from 1-benzyl-5-nitroindazol-3-ol 13, and evaluated against sensitive and resistant isolates of the sexually transmitted protozoan Trichomonas vaginalis. Compounds 2, 3, 6, 9, 10 and 11 showed trichomonacidal profiles with IC50 < 20 mu M against the metronidazole-sensitive isolate. Moreover, all these compounds submitted to cytotoxicity assays against mammalian cells exhibited low non-specific cytotoxic effects, except compounds 3 and 9 which displayed moderate cytotoxicity (CC50 = 74.7 and 59.1 mu M, respectively). Those compounds with trichomonacidal effect were also evaluated against a metronidazole-resistant culture. Special mention deserve compounds 6 and 10, which displayed better IC50 values (1.3 and 0.5 mu M respectively) than that of the reference drug (IC50 MTZ = 3.0 mu M). The high activity of these compounds against the resistant isolate reinforces the absence of cross-resistance with the reference drug. The remarkable trichomonacidal results against resistant T. vaginalis isolates suggest the interest of 3-(omega-aminoalkoxy)-1-benzyl-5-nitroindazoles to be considered as good prototypes to continue in the development of new drugs with enhanced trichomonacidal activity, aiming to increase the non-existent drugs to face clinical resistance efficiently for those patients in whom therapy with 5-nitroimidazoles is contraindicated.

【 授权许可】

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