1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines (blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC50 values below 2 μM. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). α-Lapachone- and nor-α-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity.

In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8μM. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6μM for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent.

Click chemistry-based strategies for the synthesis of 2-amino-alkyl-1,2,3-triazole-1,4-naphthoquinone derivatives make it possible to obtain desired products from 1,4-naphthoquinone (1,4-NQ), and bio-based lawsone, nor-lapachol and lapachol. The first route (Strategy A) starting from 1,4-NQ and amino alcohols, then 2-amino-alkyl-1,4-NQ alcohols, were tosylated. The azide ion displaced the tosylate group to afford 2-azide-alkyl-1,4-NQ, which was submitted to a copper-catalyzed azide alkyne cycloaddition (CuAAC) condition. The triazole-naphthoquinones were obtained in an overall yield of roughly 47%. Another pathway (Strategy B) substituted bromo-alkyl-phthalimides using NaN 3 as the nucleophile, sequential CuAAC and deprotection of phthalimide group with hydrazine producing amino-triazoles. The subsequent reaction with 1,4-NQ produced 2-amino-alkyl-1,2,3-triazole-1,4-NQ derivatives in an overall yield of 45-76% in four steps. After we developed these two strategies, linear synthesis (Strategy A) was chosen to prepare 2-[(2-(1H-1,2,3-triazol-1-yl)ethylamino)]-3-(3-methylpropenyl)-1,4-naphthoquinones from lawsone with an overall yield of approximately 27% in six steps. On the other hand, convergent synthesis (Strategy B) was employed for the synthesis of 2-[(4-phenyl-1H-1,2,3-triazol-1-yl)alkylamino)]-3-(3-methylbut-2-en-1-yl)-1,4-naphthoquinones from the reaction between 2-methoxylapachol with amino-triazoles with a global yield of about 21%. These synthetic strategies might lead us to new opportunities to build small-molecule libraries for future biological exploration.Keywords: click chemistry, amino-naphthoquinone, lapachol, nor-lapachol, 1,2,3-triazole IntroductionThe synthesis of New Chemical Entities (NCE) remains unaffected by changes in the focus of chemical science. 1A number of synthetic strategies have been developed recently to allow organic chemists to create a great variety of molecules. In order to access novel and diverse chemical libraries of compounds with potential biological activity the use of catalytic methods is prominent.From a synthetic point of view, the Huisgen 1,3-dipolar cycloaddition reaction between organic azides and terminal alkynes has been a straightforward method to assemble a large number of molecules, especially since Sharpless and co-workers 2 and Meldal and co-workers 3 proposed the copper-catalyzed azide-alkyne cycloaddition (CuAAC). This protocol has permitted easy access to molecular diversity of 1,2,3-triazoles and encouraged synthetic chemists to design projects based on this scaffold. [4][5][6][7][8][9][10][11] This reaction has provided the opportunity to synthesize molecules having new properties or biological activities, 12,13 including anti-tuberculosis, 14 antiviral, 15 antitumoral, [16][17][18] antifungal, 19 antibiotic (e.g., tazobactam, see Figure 1a), 20 among others, as can be found in the literature. 21 Moreover, naphthoquinones moieties such as potent trypanocidal and leishmanicidal activities have been synthesized (Figure 1a). [22][23][24] S i n c e m o l ...

Uma série de derivados 1,2,3-triazólicos foi sintetizada a partir de N-alquilftalimida-azidas (A 1 -A 4 ) e alcinos (a-e) sob irradiação de ultrassom na presença de CuI, Et 3 N e DMF como solvente. O presente protocolo forneceu 18 novos 1,2,3-triazóis (1-4) em rendimentos de bons a excelentes (67-98%).A series of 1,2,3-triazole derivatives was synthesized from N-phthalimidoalkyl-azides (A 1 -A 4 ) and alkynes (a-e) under ultrasound irradiation in the presence of CuI, Et 3 N and DMF as solvent. The present protocol afforded 18 new 1,2,3-triazoles (1-4) in good-to-excellent yields (67-98%).