Eufrânio N. da Silva Júnior

What do we know about multicomponent reactions? Mechanisms and trends for the Biginelli, Hantzsch, Mannich, Passerini and Ugi MCRs

The current manuscript describes the importance, mechanism propositions, evidence and controversies associated with multicomponent reactions (MCRs). The following multicomponent reactions are presented and critically evaluated: the Biginelli, Hantzsch, Mannich, Passerini and Ugi reactions. The aim of this review is to highlight what we already know about the mechanisms associated with these MCRs and the evidence supporting the proposed reaction pathways. Controversies and prospects are also discussed herein.

Synthesis of quinoidal molecules: strategies towards bioactive compounds with an emphasis on lapachones.

Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activities of these substances for the development of drugs against the neglected diseases leishmaniasis and Chagas disease as well as malaria, tuberculosis and cancer. Three strategies used to develop bioactive naphthoquinoidal compounds are discussed: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Among these strategies, reactions such as copper-catalysed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, and heterocyclisations will be discussed for the development of naphthoquinoidal compounds against Trypanosoma cruzi, Leishmania and cancer. The aim of derivatisation is the generation of novel molecules that inhibit cellular organelles/processes, generate reactive oxygen species (ROS) and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against neglected diseases and cancer.

Chiral squaramide-catalyzed asymmetric synthesis of pyranones and pyranonaphthoquinones via cascade reactions of 1,3-dicarbonyls with Morita–Baylis–Hillman acetates of nitroalkenes

Cascade reactions of 1,3-dicarbonyls with Morita-Baylis-Hillman acetates of nitroalkenes using a quinine derived chiral squaramide organocatalyst led to the formation of pyranones and pyranonaphthoquinones in good to excellent yields and high diastereo- and enantioselectivities. Representative examples of the reaction scale-up with a much lower catalyst loading without an appreciable loss of selectivities and synthetic transformations of the products are also reported here. The compounds described herein for the first time were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, since the structures are related to bioactive α-lapachones.

1,2,3-triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones.

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.

Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-naphthoquinones against oesophageal cancer cells

Naphthoquinones have been found to have a wide range of biological activities, including cytotoxicity to cancer cells. The secondary metabolites lapachol, α- and β-lapachone and a series of 25 related synthetic 1,4-naphthoquinones were screened against the oesophageal cancer cell line (WHCO1). Most of the compounds exhibited enhanced cytotoxicity (IC50 1.6-11.7 μM) compared to the current drug of choice cisplatin (IC50 = 16.5 μM). This study also established that the two new synthetic halogenated compounds 12a and 16a (IC50 = 3.0 and 7.3 μM) and the previously reported compound 11a (IC50 = 3.9 μM), were non-toxic to NIH3T3 normal fibroblast cells. Cell death of oesophageal cancer cells by processes involving PARP cleavage caused by 11a was shown to be associated with elevated c-Jun levels, suggesting a role for this pathway in the mechanism of action of this cohort of naphthoquinone compounds.

Naphthoquinone-based chalcone hybrids and derivatives: synthesis and potent activity against cancer cell lines

Novel naphthoquinone-based chalcones were prepared from the reaction between 3-bromo-nor-β-lapachone and amino-chalcones. Lapachone derivatives are also described here. All the substances were evaluated against cancer and normal cell lines and several compounds demonstrated potent antitumor activity.

Molecular hybridization as a powerful tool towards multitarget quinoidal systems: synthesis, trypanocidal and antitumor activities of naphthoquinone-based 5-iodo-1,4-disubstituted-, 1,4- and 1,5-disubstituted-1,2,3-triazoles

Quinonoid compounds based on 5-iodo-1,4-disubstituted-, 1,4- and 1,5-disubstituted-1,2,3-triazoles were synthesized using simple methodologies and evaluated against T. cruzi, the etiological agent of Chagas disease, and cancer cell lines PC3, HCT-116, HL-60, MDA-MB-435 and SF-295. The cytotoxic potential of the lapachones was also assayed against peripheral blood mononuclear cells (PBMC). Two compounds 6 and 12 were identified as potential hits against T. cruzi. β-Lapachone-based 1,5-disubstituted-1,2,3-triazole (12) displayed an IC50/24 h = 125.1 μM, similar to benznidazole, the standard drug. Compound 12 was also more active than the precursor β-lapachone against the cancer cell lines. These compounds acting as multitarget quinoidal systems could provide promising new leads for the development of trypanocidal and/or anticancer drugs.

Imidazoles from nitroallylic acetates and α-bromonitroalkenes with amidines: synthesis and trypanocidal activity studies.

Cascade reactions of amidines with nitroallylic acetates and α-bromonitroalkenes provide potentially bioactive imidazoles in good to excellent yields in most cases. While 2,4-disubstituted imidazol-5-yl acetates are formed in the first case, 2,4-disubstituted imidazoles, bearing no substituent at position 5, are the products in the second case. These two series of imidazoles, viz. 2,4,5-trisubstituted and 2,4-disubstituted, were screened for their activity against the protozoan parasite Trypanosoma cruzi which is responsible for Chagas disease. As many as three compounds were as active as the standard benznidazole and two others were 2-3-fold more active highlighting the potential of substituted imidazoles, easily accessible from nitroalkenes, as possible anti-parasitic agents.

Rh-Catalyzed Reactions of 1,4-Benzoquinones with Electrophiles: C–H Iodination, Bromination, and Phenylselenation

Under Rh-catalyzed conditions, typically electrophilic 1,4-benzoquinones exhibit nucleophilic reactivity, such that exposure to appropriate electrophiles generates products of C-H iodination, bromination, and phenylselenation. This provides a mild and general method for direct halofunctionalization, and the first method that can achieve direct C-H phenylselenation of this compound class. The scope and limitations of the new protocols are outlined, and representative derivatizations are highlighted.

On the investigation of hybrid quinones: synthesis, electrochemical studies and evaluation of trypanocidal activity

In our continued search for novel trypanocidal compounds, arylamine, chalcone, triazolic, triazole– carbohydrate and chalcogenium derivatives containing a naphthoquinone scaffold were prepared; in addition to electrochemical studies, these compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Among the thirty-eight compounds herein evaluated, six were found to be more potent against trypomastigotes than the standard drug benznidazole, with IC50/24 h values between 52.9 and 89.5 mM.