Design and Synthesis of Novel 3-Nitro-1H-1,2,4-triazole-1,2,3-triazole-1,4-disubstituted Analogs as Promising Antitrypanosomatid Agents: Evaluation of In Vitro Activity against Chagas Disease and Leishmaniasis

被引：6

作者：

Pelizaro, Bruno I. ^{[1
]}

Batista, Jaqueline C. Z. ^{[2
]}

Portapilla, Gisele B. ^{[3
]}

das Neves, Amarith R. ^{[1
,2
,4
]}

Silva, Fernanda ^{[2
]}

Carvalho, Diego B. ^{[1
]}

Shiguemoto, Cristiane Y. K. ^{[1
]}

Pessatto, Lucas R. ^{[5
]}

Paredes-Gamero, Edgar J. ^{[5
]}

Cardoso, Iara A. ^{[6
]}

Luccas, Pedro H. ^{[5
]}

Nonato, M. Cristina ^{[6
]}

Lopes, Norberto P. ^{[7
]}

Galvao, Fernanda ^{[8
]}

Oliveira, Kelly M. P. ^{[9
]}

Cassemiro, Nadla S. ^{[10
]}

Silva, Denise B. ^{[10
]}

Piranda, Eliane M. ^{[2
]}

Arruda, Carla C. P. ^{[2
]}

de Albuquerque, Sergio ^{[11
]}

Baroni, Adriano C. M. ^{[1
]}

机构：

[1] Univ Fed Mato Grossso do Sul UFMS, Fac Ciencias Farmaceut Alimentos & Nutr, Lab Sintese & Quim Med LASQUIM, BR-79070900 Campo Grande, MS, Brazil

[2] Univ Fed Mato Grossso do Sul UFMS, Lab Parasitol Humana, Inst Biociencias, BR-79070900 Campo Grande, MS, Brazil

[3] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, BR-14040900 Ribeirao Preto, Brazil

[4] Univ Fed Mato Grossso do Sul UFMS, Inst Biociencias, Lab Parasitol Humana, BR-79070900 Campo Grande, MS, Brazil

[5] Univ Fed Mato Grosso do Sul, Fac Ciencias Farmaceut Alimentos & Nutr, Lab Biol Mol BioMol & Cult Celulares, BR-79070900 Campo Grande, MS, Brazil

[6] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias Biomol, Lab Cristalog Prot, BR-14040903 Ribeirao Preto, SP, Brazil

[7] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias Biomol, Nucleo Pesquisas Prod Naturais & Sintet, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP, Brazil

[8] Fundacao Univ Fed Grande Dourados, Fac Ciencias Saude, BR-79804970 Dourados, MS, Brazil

[9] Fundacao Univ Fed Grande Dourados, Fac Ciencias Saude, BR-79804970 Dourados, MS, Brazil

[10] Univ Federalde Mato Grossso do Sul UFMS, Fac Ciencias Farmaceut Alimentos & Nutr, Lab Prod Naturais & Espectrometria Massas LAPNEM, BR-79070900 Campo Grande, MS, Brazil

[11] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, BR-14040900 Ribeirao Preto, SP, Brazil

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 04期

关键词：

MEDICINAL CHEMISTRY; AROMATIC-AMINES; DRUG DISCOVERY; BROAD-SPECTRUM; BENZNIDAZOLE; METABOLISM; TOXICITY; CYTOCHROME-P450; TRANSMISSION; POSACONAZOLE;

D O I：

10.1021/acs.jmedchem.3c01745

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 28 compounds, 3-nitro-1H-1,2,4-triazole, were synthesized by click-chemistry with diverse substitution patterns using medicinal chemistry approaches, such as bioisosterism, Craig-plot, and the Topliss set with excellent yields. Overall, the analogs demonstrated relevant in vitro antitrypanosomatid activity. Analog <bold>15g</bold> (R-1 = 4-OCF3-Ph, IC50 = 0.09 mu M, SI = >555.5) exhibited an outstanding antichagasic activity (Trypanosoma cruzi, Tulahuen LacZ strain) 68-fold more active than benznidazole (BZN, IC50 = 6.15 mu M, SI = >8.13) with relevant selectivity index, and suitable LipE = 5.31. <bold>15g</bold> was considered an appropriate substrate for the type I nitro reductases (TcNTR I), contributing to a likely potential mechanism of action for antichagasic activity. Finally, <bold>15g</bold> showed nonmutagenic potential against Salmonella typhimurium strains (TA98, TA100, and TA102). Therefore, 3-nitro-1H-1,2,4-triazole <bold>15g</bold> is a promising antitrypanosomatid candidate for in vivo studies.

引用

页码：2584 / 2601

页数：18

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