Esther Vicente

Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis.

ABSTRACT This study extends earlier reports regarding the in vitro efficacies of the 1,4-di-N-oxide quinoxaline derivatives against Mycobacterium tuberculosis and has led to the discovery of a derivative with in vivo efficacy in the mouse model of tuberculosis. Quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives were tested in vitro against a broad panel of single-drug-resistant M. tuberculosis strains. The susceptibilities of these strains to some compounds were comparable to those of strain H37Rv, as indicated by the ratios of MICs for resistant and nonresistant strains, supporting the premise that 1,4-di-N-oxide quinoxaline derivatives have a novel mode of action unrelated to those of the currently used antitubercular drugs. Specific derivatives were further evaluated in a series of in vivo assays, including evaluations of the maximum tolerated doses, the levels of oral bioavailability, and the efficacies in a low-dose aerosol model of tuberculosis in mice. One compound, ethyl 7-chloro-3-methylquinoxaline-2-carboxylate 1,4-dioxide, was found to be (i) active in reducing CFU counts in both the lungs and spleens of infected mice following oral administration, (ii) active against PA-824-resistant Mycobacterium bovis, indicating that the pathway of bioreduction/activation is different from that of PA-824 (a bioreduced nitroimidazole that is in clinical trials), and (iii) very active against nonreplicating bacteria adapted to low-oxygen conditions. These data indicate that 1,4-di-N-oxide quinoxalines hold promise for the treatment of tuberculosis.

In vitro and in vivo antimycobacterial activities of ketone and amide derivatives of quinoxaline 1,4-di-N-oxide

OBJECTIVES To evaluate a novel series of quinoxaline 1,4-di-N-oxides for in vitro activity against Mycobacterium tuberculosis and for efficacy in a mouse model of tuberculosis (TB). METHODS Ketone and amide derivatives of quinoxaline 1,4-di-N-oxide were evaluated in in vitro and in vivo tests including: (i) activity against M. tuberculosis resistant to currently used antitubercular drugs including multidrug-resistant strains (MDR-TB resistant to isoniazid and rifampicin); (ii) activity against non-replicating persistent (NRP) bacteria; (iii) MBC; (iv) maximum tolerated dose, oral bioavailability and in vivo efficacy in mice; and (v) potential for cross-resistance with another bioreduced drug, PA-824. RESULTS Ten compounds were tested on single drug-resistant M. tuberculosis. In general, all compounds were active with ratios of MICs against resistant and non-resistant strains of <or=4.00. One compound, 5, was orally active in a murine model of TB, bactericidal, active against NRP bacteria and active on MDR-TB and poly drug-resistant clinical isolates (resistant to 3-5 antitubercular drugs). CONCLUSIONS Quinoxaline 1,4-di-N-oxides represent a new class of orally active antitubercular drugs. They are likely bioreduced to an active metabolite, but the pathway of bacterial activation was different from PA-824, a bioreducible nitroimidazole in clinical trials. Compound 5 was bactericidal and active on NRP organisms indicating that activation occurred in both growing and non-replicating bacteria leading to cell death. The presence of NRP bacteria is believed to be a major factor responsible for the prolonged nature of antitubercular therapy. If the bactericidal activity and activity on non-replicating bacteria in vitro translate to in vivo conditions, quinoxaline 1,4-di-N-oxides may offer a path to shortened therapy.

QSAR analysis for quinoxaline-2-carboxylate 1,4-di-N-oxides as anti-mycobacterial agents.

In a continuing effort of our research group to identify new active compounds against Mycobacterium tuberculosis, we resort to the quantitative structure-activity relationships (QSARs) theory. For this purpose, we employ certain parameters of potency, cytotoxicity and selectivity as given by the Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF) program. The molecular structure of 43 quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives is appropriately represented by 1497 DRAGON type of theoretical descriptors, and the best linear regression models established in this work are demonstrated to result predictive. The application of the QSAR equations developed now serves as a rational guide for the proposal of new candidate structures that still do not have experimentally assigned biological data.

Quinoxaline 1,4-di-N-oxide and the potential for treating tuberculosis.

New drugs active against drug-resistant tuberculosis are urgently needed to extend the range of TB treatment options to cover drug resistant infections. Quinoxaline derivatives show very interesting biological properties (antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal) and evaluation of their medicinal chemistry is still in progress. In this review we report the properties and the recent developments of quinoxaline 1,4-di-N-oxide derivatives as potential anti-tuberculosis agents. Specific agents are reviewed that have excellent antitubercular drug properties, are active on drug resistant strains and non-replicating mycobacteria. The properties of select analogs that have in vivo activity in the low dose aerosol infection model in mice will be reviewed.

Synthesis and Antiplasmodial Activity of 3-Furyl and 3-Thienylquinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives †

The aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenyl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC50 < 1 μM against the 3D7 strain. Derivative 1 demonstrated high potency (IC50= 0.63 µM) and good selectivity (SI=10.35), thereby becoming a new lead-compound.

Anti-T. cruzi activities and QSAR studies of 3-arylquinoxaline-2-carbonitrile di-N-oxides.

In a continuing effort to identify new active compounds for combating Chagas disease and other neglected diseases, our research group synthesized and evaluated 23 3-arylquinoxaline-2-carbonitrile di-N-oxides against Trypanosoma cruzi. Five of them presented IC(50) values of the same magnitude as the standard drug Nifurtimox, making them valid as new lead compounds. The optimized molecular structures of 23 derivatives represented by 1497 types of DRAGON descriptors were subjected to linear regression analysis, and the derived QSAR was shown to be predictive. In this way, we achieved a rational guide for the proposal of new candidate structures whose activities still remain unknown.

Unexpected Reduction of Ethyl 3-Phenylquinoxaline-2- carboxylate 1,4-Di-N-oxide Derivatives by Amines

The unexpected tendency of amines and functionalized hydrazines to reduce ethyl 3-phenylquinoxaline-2-carboxylate 1,4-di-N-oxide (1) to afford a quinoxaline 1c and mono-oxide quinoxalines 1a and 1b is described. The experimental conditions were standardized to the use of two equivalents of amine in ethanol under reflux for two hours, with the aim of studying the distinct reductive profiles of the amines and the chemoselectivity of the process. With the exception of hydrazine hydrate, which reduced compound 1 to a 3-phenyl-2-quinoxalinecarbohydrazide derivative, the amines only acted as reducing agents.

Substitutions of Fluorine Atoms and Phenoxy Groups in the Synthesis of Quinoxaline 1,4-di-N-oxide Derivatives

The unexpected substitution of fluorine atoms and phenoxy groups attached to quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives was based on the classical Beirut reaction. The tendency of fluorine atoms linked to quinoxaline or benzofuroxan rings to be replaced by a methoxy group when dissolved in an ammonia saturated solution of methanol was clearly demonstrated. In addition, 2-phenoxyquinoxaline 1,4-di-N-oxide derivatives became 2-aminoquinoxaline 1,4-di-N-oxide derivatives in the presence of gaseous ammonia.

Exploring 3‐arylquinoxaline‐2‐carbonitrile 1,4‐di‐N‐oxides Activities Against Neglected Diseases with QSAR

This work reveals our efforts to continue identifying new active compounds against neglected diseases, such as malaria and tuberculosis. We took several 3‐arylquinoxaline‐2‐carbonitrile 1,4‐di‐N‐oxide derivative activity results from the reference literature and established useful quantitative structure–activity relationships. We hoped that the development of in silico models would broaden our knowledge regarding the overwhelming problem of drug resistance to both illnesses. The optimized molecular structures of 60 compounds were represented by 1497 DRAGON‐type descriptors and subjected to linear regression analyses; the quantitative structure–activity relationships resulted predictive when searching for new active compounds. We obtained a rational guide for the proposal of new candidate structures whose activities still remain unknown.