New Strategies for Molecular Diversification of 2-[Aminoalkyl-(1H-1,2,3-triazol-1- yl)]-1,4-naphthoquinones Using Click Chemistry

Abstract

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 ...

Searching Anti-Zika Virus Activity in 1H-1,2,3-Triazole Based Compounds

“…Compounds 1 – 7 ( Figure 2 and Figure 3 , Table 1 ) were prepared according to the methodologies described previously by our research group [ 25 , 26 , 27 ]. Only the compound, 5a, is a new compound.…”

“…Our group has synthesized several heterocycle derivatives and tested their activities against human cancer cell lines [ 23 , 24 , 25 ]. The compounds 1 – 7 (see Figure 2 ), that contain these cited heterocycles, and will be evaluated, were previously synthesized by our research group, except for compound 5a [ 25 , 26 , 27 ]. Here, we expand our initial efforts and evaluate their cytotoxicity to epithelial cells and their antiviral activity against ZIKV.…”

1,2,3- Triazoles: general and key synthetic strategies

“…Additionally, other studies that use ultrasonic energy to prepare compounds containing the 1H-1,2,3triazole unit can be found in the literature. [212][213][214] In all cases the use of ultrasound significantly increased the speed of reactions.…”

Synthesis and Cytotoxicity Evaluation of a Series of 3-Alkenyl-2-Hydroxy1,4-Naphthoquinones Obtained by an Efficient Knoevenagel Condensation

“…1,2 These compounds share structural features with natural lapachol (1), the most abundant quinone found in the core wood of various Bignoniaceae. Lapachol has a long tradition of use as a precursor of modified quinones, particularly for derivatives aimed at trials and screening of their multipurpose biological profiles.…”

“…Lapachol has a long tradition of use as a precursor of modified quinones, particularly for derivatives aimed at trials and screening of their multipurpose biological profiles. 3 Hooker, in 1936, 4 published a systematic synthetic procedure for a series of 3-alkenyl-2-hydroxy-1,4-naphtho quinones using lawsone (2) with suitable aliphatic aldehydes with hydrochloric acid as catalyst. Hooker used propionaldehyde, n-butyraldehyde, valeraldehyde, heptanaldehyde, phenylacetaldehyde and hydrocynamaldehyde (3a-f), obtaining the corresponding products in low to modest yields (23-48%, Table 1).…”