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：7

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 15g (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. 15g 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, 15g showed nonmutagenic potential against Salmonella typhimurium strains (TA98, TA100, and TA102). Therefore, 3-nitro-1H-1,2,4-triazole 15g is a promising antitrypanosomatid candidate for in vivo studies.

引用

页码：2584 / 2601

页数：18

共 101 条

[1]

Agoram B, 2017, CPT-PHARMACOMET SYST, V6, P355, DOI 10.1002/psp4.12190

[2] Nitroimidazoles: Molecular Fireworks That Combat a Broad Spectrum of Infectious Diseases [J].

Ang, Chee Wei ;

Jarrad, Angie M. ;

Cooper, Matthew A. ;

Blaskovich, Mark A. T. .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (18) :7636-7657

[3] Synthesis and Antitrypanosomal Activity of 1,4-Disubstituted Triazole Compounds Based on a 2-Nitroimidazole Scaffold: a Structure-Activity Relationship Study [J].

Assuncao, Elvis L. F. ;

Carvalho, Diego B. ;

das Neves, Amarith R. ;

Kawasoko Shiguemotto, Cristiane Y. ;

Portapilla, Gisele B. ;

de Albuquerque, Sergio ;

Baroni, Adriano C. M. .

CHEMMEDCHEM, 2020, 15 (21) :2019-2028

[4] Efficient conversion of aromatic amines into azides: A one-pot synthesis of triazole linkages [J].

Barral, Karine ;

Moorhouse, Adam D. ;

Moses, John E. .

ORGANIC LETTERS, 2007, 9 (09) :1809-1811

[5] A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design [J].

Beno, Brett R. ;

Yeung, Kap-Sun ;

Bartberger, Michael D. ;

Pennington, Lewis D. ;

Meanwell, Nicholas A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (11) :4383-4438

[6]

Bern C, 2015, NEW ENGL J MED, V373, P456, DOI [10.1056/NEJMra1410150, 10.1056/NEJMc1510996]

[7] AN EMPIRICAL-APPROACH TO THE STATISTICAL-ANALYSIS OF MUTAGENESIS DATA FROM THE SALMONELLA TEST [J].

BERNSTEIN, L ;

KALDOR, J ;

MCCANN, J ;

PIKE, MC .

MUTATION RESEARCH, 1982, 97 (04) :267-281

[8] Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group [J].

Boechat, Nubia ;

Carvalho, Alcione S. ;

Salomao, Kelly ;

de Castro, Solange L. ;

Araujo-Lima, Carlos F. ;

Mello, Francisco V. C. ;

Felzenszwalb, Israel ;

Aiub, Claudia A. F. ;

Conde, Taline Ramos ;

Zamith, Helena P. S. ;

Skupin, Rolf ;

Haufe, Guenter .

MEMORIAS DO INSTITUTO OSWALDO CRUZ, 2015, 110 (04) :492-499

[9]

Brasil M. D. S., 2017, MANUAL VIGILANCIADA

[10] Evaluating the developmental toxicity of trypanocidal nitroaromatic compounds on zebrafish [J].

Buchanan-Kilbey, Grace ;

Djumpah, Joshua ;

Papadopoulou, Maria V. ;

Bloomer, William ;

Hu, Lonqin ;

Wilkinson, Shane R. ;

Ashworth, Rachel .

ACTA TROPICA, 2013, 128 (03) :701-705

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