Raquel Villar

New 3-methylquinoxaline-2-carboxamide 1,4-di-N-oxide derivatives as anti-Mycobacterium tuberculosis agents.

Mycobacterium tuberculosis (M.Tb) is a bacillus capable of causing a chronic and fatal condition in humans known as tuberculosis (TB). It is estimated that there are 8 million new cases of TB per year and 3.1 million infected people die annually. Thirty-six new amide quinoxaline 1,4-di-N-oxide derivatives have been synthesized and evaluated as potential anti-tubercular agents, obtaining biological values similar to the reference compound, Rifampin (RIF).

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.

Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents

We report the synthesis, anti‐inflammatory, and antioxidant activities of novel quinoxaline and quinoxaline 1,4‐di‐N‐oxide derivatives. Microwave‐assisted methods have been used to optimize reaction times and to improve yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase (LOX). Two of the best LOX inhibitors (compounds 7b and 8f) were evaluated as in vivo anti‐inflammatory agents using the carrageenin‐induced edema model. One of them (compound 7b) showed important in vivo anti‐inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug.

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.

Heterocyclic-2-carboxylic Acid (3-Cyano-1,4-di-N-oxidequinoxalin-2-yl)amide Derivatives as Hits for the Development of Neglected Disease Drugs

Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis (TB). Besides TB, Chagas disease, affects approximately 20 million people. Quinoxalines display great activities against TB and Chagas. Forty new quinoxaline 1,4-di-N-oxide derivatives have been prepared and tested against M. tuberculosis and T. cruzi. Carboxylic acid quinoxaline 1,4-di-N-oxides (CAQDOs) 5 and 17 showed MIC values on the same order as the reference antituberculosis drug, rifampicin. Meanwhile, CAQDOs 12 and 22 presented IC50 values in the same order as the anti-chagasic drug, nifurtimox.

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.

DNA strand cleaving properties and hypoxia-selective cytotoxicity of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide

The heterocyclic N-oxide, 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, 1), shows promising antitumor activity in preclinical studies, but there is a continuing need to explore new compounds in this general structural category. In the work described here, we examined the properties of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide (9h). We find that 9h causes redox-activated, hypoxia-selective DNA cleavage that mirrors the lead compound, tirapazamine, in both mechanism and potency. Furthermore, we find that 9h displays hypoxia-selective cytotoxicity against human cancer cell lines.

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.