Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2‐Benzyl‐5‐nitroindazole‐Derived Amines

• Published in: ChemMedChem Vol. 13; no. 12; pp. 1246 - 1259
• Main Authors: Fonseca‐Berzal, Cristina, Ibáñez‐Escribano, Alexandra, Vela, Nerea, Cumella, José, Nogal‐Ruiz, Juan José, Escario, José Antonio, da Silva, Patrícia Bernardino, Batista, Marcos Meuser, Soeiro, Maria de Nazaré C., Sifontes‐Rodríguez, Sergio, Meneses‐Marcel, Alfredo, Gómez‐Barrio, Alicia, Arán, Vicente J.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 20-06-2018
• Subjects: Amastigotes; Amines; antiprotozoal agents; Benznidazole; Chagas disease; Cutaneous leishmaniasis; Derivatives; Epimastigotes; Etiology; leishmaniasis; Mammalian cells; Metronidazole; nitrogen heterocycles; Parasites; Promastigotes; Protozoa; Toxicity; Trichomoniasis; Trophozoites; Tropical diseases; trypanosomiasis; Vector-borne diseases; trypanosomiasis; leishmaniasis; trichomoniasis; antiprotozoal agents; nitrogen heterocycles
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800084

Three different series of new 5‐nitroindazole derivatives—1‐(ω‐aminoalkyl)‐2‐benzylindazolin‐3‐ones (series A; ten compounds), 3‐(ω‐aminoalkoxy)‐2‐benzylindazoles (series B; four compounds) and 3‐alkylamino‐2‐benzylindazoles (series C; five compounds)—have been synthesized and evaluated against the protozoan parasites Trypanosoma cruzi, Leishmania amazonensis, and Trichomonas vaginalis: etiological agents of Chagas disease, cutaneous leishmaniasis, and trichomoniasis, respectively. Many indazoles of series A, B, and C were efficient against T. cruzi. Some compounds in series A, after successfully passing the preliminary screening for epimastigotes, exhibited activity values against amastigotes of several T. cruzi strains that were better than or similar to those shown by the reference drug benznidazole and displayed low nonspecific toxicity against mammalian cells. On the other hand, preliminary studies against promastigotes of L. amazonensis showed high leishmanicidal activity for some derivatives of series A and C. With regard to activity against T. vaginalis, some indazoles of series B and C were rather efficient against trophozoites of a metronidazole‐sensitive isolate and showed low nonspecific toxicities toward Vero cell cultures. Additionally, some of these compounds displayed similar activity against metronidazole‐sensitive and resistant isolates, showing the absence of cross‐resistance between these derivatives and the reference drug.
Attachment of ligands to DNA or RNA delivery systems is a promising strategy for targeted applications. We report the conjugation of a ligand directly onto lipid–nucleic acid complexes using an oximation approach. Simple incubation of DMDK lipoplexes with an aminooxy reagent labeled the lipoplexes without sacrificing transfection efficiency.