Ricardo A. Tapia

Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease.

Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.

Iron complexes of quercetin in aprotic medium. Redox chemistry and interaction with superoxide anion radical

Abstract The redox chemistry of quercetin (Qz) and its iron(II) complexes has been studied in dimethylsulfoxide. In the absence of base an Fe(II):Qz=1:1 complex is formed which presents oxidation processes at 0.28 V vs. S.C.E.; 0.66 V vs. S.C.E. and 0.92 V vs. S.C.E. These processes correspond to the oxidation of Fe(II) to Fe(III), the formation of the quinonic form of the catecholic moiety and the oxidation of the catecholic system regenerated after conjugated addition of an oxygen atom to carbon 6′ on ring B. In the presence of base a stable 1:1 complex is formed with oxidation processes that show up at +0.25 V, +0.64 V and +0.88 V vs. S.C.E. Upon interaction of the complex with superoxide anion radical in dimethylsulfoxide the basic character of this radical anion causes the formation of the monoanion of quercetin leading to a more stable complex of iron(II). The protonated superoxide disproportionates to oxygen and peroxide oxidizing the metal ion to iron(III), precluding the presence of peroxide and iron(II) to produce OH radicals through Fenton chemistry.

Synthesis and antiprotozoal activity of naphthofuranquinones and naphthothiophenequinones containing a fused thiazole ring

The synthesis of tetracyclic quinones 10a,b, 14a,b, 19a,b and 20a,b is described. The preparations involve regioselective Diels-Alder reactions via trapping the thiazole o-quinodimethane 9 with several benzofuranquinones and benzothiophenequinones. The structure of the regioisomers was assigned through 2D NMR 1H-13C HMBC experiments performed on 10a and 14a. Compounds 10a,b, 14a as well as phenol 1 and the starting quinones 2, 5, 7 and 15 are evaluated against Leishmania sp., Toxoplasma gondii and THP-1 cells. Almost all the tested compounds exhibit significant antiprotozoal activities with lower cytotoxicities than the reference compounds. Among them, quinones 2 and 14a possess the best activities towards L. donovani and T. gondii with the lowest toxicities.

Nitric Acid on Silica Gel: A Useful Nitrating Reagent for Activated Aromatic Compounds

Abstract Phenols and arylmethyl ethers are rapidly mononitrated by nitric acid adsorbed in silica gel at room temperature in high yields.

Mechanistic pathways of aromatic nucleophilic substitution in conventional solvents and ionic liquids

Solvation effects on the reaction mechanism of the title reactions have been kinetically evaluated in 21 conventional solvents and 17 ionic liquids. Solvent polarity affects the catalyzed and non-catalyzed SNAr pathways differently. The ambiphilic character of water and formamide, which act as a hydrogen bond donor/acceptor, induces nucleophilic activation at the nitrogen center of the nucleophile. The ionic liquid EMIMDCN appears to be the best solvent for the SNAr route probably due to the high polarizability of the dicyanamide anion.

Synthesis and Antileishmanial Activity of Indoloquinones Containing a Fused Benzothiazole Ring

Pyrazinoindoloquinone 6 was synthesized by alkylation of ethyl 4,7-dimethoxyindole-2-carboxylate (1), followed by cyclization of the N-bromoethyl derivative 2b in the presence of ammonia. Oxidative demethylation of 2b and of the oxopyrazinoindole 3 with silver(II) oxide furnished quinones 5b and 6. Reduction of 3 with lithium aluminium hydride in dioxane provided 4, which was oxidized to afford 7. Quinones 5b, 6, and 7 were then treated in situ with the thiazole o-quinodimethane 9 to afford regioisomeric mixtures of the tetracyclic quinones 10 or the pentacyclic derivatives 11 or 12. The structural assignment was made by 2D NMR 1H-13C HMBC correlation performed on the major regioisomer 10a. In vitro antileishmanial assays showed that dimethoxyindole 2a and quinones 12a + 12b possess good inhibitory activity against two Leishmania sp. without any cytotoxicity towards a THP-1 cell line. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Zinc catechin complexes in aprotic medium. Redox chemistry and interaction with superoxide radical anion

Abstract The redox chemistry of catechin and its zinc(II) complexes has been studied in dimethyl sulfoxide. In the absence of base, catechin undergoes oxidation processes at 0.96 and 1.24 V versus SCE. The first process corresponds to the formation of the quinonic form of the catechol moiety. In the presence of 1 equiv. of base, a stable 1:2 complex is formed with oxidation processes that show up at 0.26 and 0.62 V versus SCE. The voltammetric and spectroscopic characterization of the species produced after the oxidation processes are described. Upon interaction of the complex with superoxide radical anion in dimethyl sulfoxide, its basic character causes the formation of the monoanion of catechin leading to a more stable zinc(II) complex. Protonated superoxide disproportionates to molecular oxygen and peroxide leading to oxidation of the bound ligand. Upon complexation the oxidation potentials decrease, favoring thermodynamically the antioxidant action of this flavonoid.

Specific nucleophile–electrophile interactions in nucleophilic aromatic substitutions

We herein report results obtained from an integrated experimental and theoretical study on aromatic nucleophilic substitution (S(N)Ar) reactions of a series of amines towards 1-fluoro-2,4-dinitrobenzene in water. Specific nucleophile-electrophile interactions in the title reactions have been kinetically evaluated. The whole series undergoes S(N)Ar reactions where the formation of the Meisenheimer complex is rate determining. Theoretical studies concerning specific interactions are discussed in detail. It is found that H-bonding effects along the intrinsic reaction coordinate profile promote the activation of both the electrophile and the nucleophile. Using these results, it is possible to establish a hierarchy of reactivity that is in agreement with the experimental data. Second order energy perturbation energy analysis highlights the strong interaction between the ortho-nitro group and the acidic hydrogen atom of the amine. The present study strongly suggests that any theoretical analysis must be performed at the activated transition state structure, because the static model developed around the reactant states hides most of the relevant specific interactions that characterize the aromatic substitution process.

Studies on quinones. Part 34: The reaction of styrene with activated 1,4-benzoquinones: access to potential antiprotozoal pyranobenzoquinones ☆

Abstract Styrene reacts with highly electrophilic monosubstituted 1,4-benzoquinones to provide pyranobenzoquinone and phenanthrene derivatives, depending on the nature of the quinone substituent. The participation of transient Diels–Alder adduct intermediates in these reactions and their thermal-induced rearrangements are discussed. The in vitro antiparasital effects of the pyranobenzoquinones against Trypanosoma cruzi and Leishmania spp. are reported.

Synthesis of 3,4-Dihydro-4-Hydroxy-2,2-Dimethyl-2H-1-Benzopyran-5 8-Dione. A Potential Key Intermediate for the Preparation of Naphtho[2,3-b]Pyranoquinones

Abstract The synthesis of pyranoquinone 6 and its application to the elaboration of pyranonaphthoquinone 1b is described.