Imidazole and benzimidazole systems are presented in a large number of common therapeutics agents. They were widely used in organic and medicinal chemistry, but recently the development of N-oxide derivatives got an improvement from the point of view of its chemical and biological activity. Though we will review recent developments in chemical and biological profiles (as antitumoral, antiparasitic, antiviral and antimicrobial agents) of these heterocycle systems and the corresponding N-oxides.

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Background:Mcl-1 inhibits apoptosis and promotes survival of cancer cells. Results: The Hsp70 co-chaperone, BAG3, prevents Mcl-1 degradation by the proteasome. Conclusion: BAG3 sustains Mcl-1 expression in cancer cells, promoting its antiapoptotic activity. Significance: Mcl-1 expression is a major determinant of resistance in human cancer, so BAG3 is a potential target for anticancer drug discovery.

The syntheses and biological evaluation of the first anti-protozoa imidazole N-oxide and benzimidazole N-oxide and their derivatives are reported. They were tested in vitro against two different protozoa, Trypanosoma cruzi and Trichomonas vaginalis. Derivative 7c, ethyl-1-(i-butyloxycarbonyloxy)-6-nitrobenzimid-azole-2-carboxylate, displayed activity on both protozoa. Lipophilicity and redox potential were experimentally determined in order to study the relationship with activity of the compounds. These properties are well related with the observed bioactivity. Imidazole and benzimidazole N-oxide derivatives are becoming leaders for further chemical modifications and advanced biological studies.

Three series of benzimidazole N-oxide derivatives were developed and were examined for their activity against trypanosomatid parasites (Trypanosoma cruzi and Leishmania spp.). 2H-benzimidazole 1,3-dioxides displayed remarkable in vitro activities against both parasites, with derivatives 28, 29, and 32 being the most potent (IC50 < 5 microM) against the epimastigote form of T. cruzi and 28, 33, and 35 the most potent against the promastigote form of Leishmania spp. Unspecific cytotoxicity was evaluated using murine macrophages, and derivative 33 was not toxic at a concentration 30 times that of its IC50 against T. cruzi that was completely toxic for Leishmania spp., implying that the series of 2H-benzimidazole 1,3-dioxides is selective toward both trypanosomatid parasites. Derivatives 33 and 35 were submitted to an in vivo assay using an acute model of Chagas' disease and a short-term treatment (30 mg/kg/day orally administrated as aqueous solution, during 10 days). While in the control (untreated) and Benznidazole (50 mg/kg/day) groups survival fraction was 60.0% and 87.5%, respectively, none of the animals treated with derivatives 33 and 35 died. From the preliminary structure-activity relationship studies reduction potential and electrophilicity were found relevant to anti-T. cruzi activity. Active compounds are better electrophiles and more easily reduced than inactive ones.

Parasitic flatworms are responsible for serious infectious diseases that affect humans as well as livestock animals in vast regions of the world. Yet, the drug armamentarium available for treatment of these infections is limited: praziquantel is the single drug currently available for 200 million people infected with Schistosoma spp. and there is justified concern about emergence of drug resistance. Thioredoxin glutathione reductase (TGR) is an essential core enzyme for redox homeostasis in flatworm parasites. In this work, we searched for flatworm TGR inhibitors testing compounds belonging to various families known to inhibit thioredoxin reductase or TGR and also additional electrophilic compounds. Several furoxans and one thiadiazole potently inhibited TGRs from both classes of parasitic flatworms: cestoda (tapeworms) and trematoda (flukes), while several benzofuroxans and a quinoxaline moderately inhibited TGRs. Remarkably, five active compounds from diverse families possessed a phenylsulfonyl group, strongly suggesting that this moiety is a new pharmacophore. The most active inhibitors were further characterized and displayed slow and nearly irreversible binding to TGR. These compounds efficiently killed Echinococcus granulosus larval worms and Fasciola hepatica newly excysted juveniles in vitro at a 20 µM concentration. Our results support the concept that the redox metabolism of flatworm parasites is precarious and particularly susceptible to destabilization, show that furoxans can be used to target both flukes and tapeworms, and identified phenylsulfonyl as a new drug-hit moiety for both classes of flatworm parasites.

The tautomeric forms of benzimidazole N-oxide derivatives in solution were studied using nuclear magnetic resonance (NMR) techniques. Further insight into the molecular structures was provided by theoretical calculations using density functional theory (DFT). In the gas phase the N-hydroxy tautomer was more stable than the N-oxide, whereas in solution the stabilization of one form or the other depended on hydrogen bond formation involving the N-hydroxy/N-oxide moiety. Derivative 4 (n-butyl-5-nitrobenzimidazole-2-carboxamide 3-oxide), having a 2-carboxamide moiety, was the only compound studied present as a mixture of tautomers, the N-oxide being the predominant one. This was assigned to the formation of an internal hydrogen bond between the N-oxide group and the amide hydrogen atom. The tautomeric form present in the solid state was studied for derivative 1 (ethyl-5-nitrobenzimidazole-2-carboxylate 3-oxide) and was conclusively assigned by X-ray diffraction techniques to the N-hydroxy tautomer. In the crystal a strong O−H···N intermolecular bond gives rise to supramolecular polymeric chains in the lattice. This strong interaction was also seen in the infrared spectrum and was assigned to two broad bands at 2367 and 2526 cm-1. The vibrational spectrum was satisfactorily described by DFT calculations and an example of this is the prediction of the band corresponding to the N−O stretching (N-oxide) just 1% lower than the experimental value. Uncorrelated calculations (HF) were not able to give an unambiguous assignment of this band. The reaction of derivative 1 against different kinds of electrophiles, hard and soft, led only to O-substituted products. This result was explained in terms of the HSAB theory using a local−global approach.

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