Comparative acute systemic toxicity of several quinoxaline 1,4-di-N-oxides in Wistar rats.

The acute toxicity of six quinoxaline 1,4-di-N-oxides has been evaluated in an attempt to determine: a) the feasibility of testing systemic toxicity of these compounds in a very preliminary phase without an adequate formulation for in vivo administration, b) the LD50 range and the toxic target organ of these compounds in order to have an approximation of the structure-activity relationship. Quinoxaline 1,4-di-N-oxides have shown a great variety of biological activities with potential therapeutic application in cancer, malaria, etc. Problems of toxicity hinder the progression of these compounds to clinical phases. The compounds dissolved in DMSO at their solubility limit were administered i.v. to female Wistar rats (8 weeks, 160 g), using an infusion pump (300 microL; 20 microl/min). Animals were observed for a period of 14 days. This dose of the vehicle (1.7 ml/kg) was well tolerated by the animals. The LD50 could not be determined, but a marked hypoactivity was induced by the treatment. The same compounds were also injected intraperitoneally, suspended in 0.01% Tween 80/0.09 % saline, and the animals that did not die were observed for a period of 14 days. The LD50 could be estimated to be in a range between 30 and 120 mg/kg, except for one of the compounds. A decrease in the evolution of body weight and hypoactivity were the principal symptoms induced by the treatment. In both assays, histopathologic study of heart, liver, kidney, lung, spleen and ovaries indicated that the target organs may be heart and spleen. In conclusion, the i.v. route is not adequate for estimating the LD50 of these compounds due to solubility problems; by i.p. route, the LD50 interval is between 30 and 120 mg/kg. The data did not permit the deduction of any specific structure-activity relationship.

Antiplasmodial activity of 3-trifluoromethyl-2-carbonylquinoxaline di-N-oxide derivatives

The in vitro antiplasmodial activity of some 3-trifluoromethyl-2-carbonylquinoxaline di-N-oxide derivatives is reported. The evaluation was performed on cultures of FcB1 strain (chloroquine-resistant) of P. falciparum and the most interesting compounds were then evaluated on MCF7 tumor cells in order to evaluate an index of selectivity. The 7-methyl (2b, 4b, 5b, 6b) and nonsubstituted (3c, 4c, 5c) quinoxaline 1,4-dioxide derivatives presented the best level of activity.

Neste artigo descreve-se a atividade anti-Plasmodium falciparum de derivados 3-trifluorometil-2-carbonilquinoxalinas di-N-óxidos (2a-6g). A avaliação das propriedades farmacológicas dos derivados 2a-6g foi realizada em modelo in vitro de inibição de cepas P. falciparum FcB1 (cloroquina resistente) em cultura celular, e sobre culturas de células tumorais MCF7, com a finalidade de estabelecer o índice de seletividade para os compostos mais promissores. Os derivados 7-metil (2b, 4b, 5b, 6b) e não-substituído (3c, 4c, 5c) apresentaram o melhor perfil de atividade.

Synthesis of new quinoxaline-2-carboxylate 1,4-dioxide derivatives as anti-Mycobacterium tuberculosis agents.

Twenty-nine new 6(7)-substituted quinoxaline-2-carboxylate 1,4-dioxide derivatives were synthesized and evaluated for in vitro antituberculosis activity. In general, the in vitro activity is significantly affected by substituents on the quinoxaline nucleus. It has been observed that the presence of a chloro, methyl, or methoxy group in position 7 of the benzene moiety reduces the MIC and IC(50) values. However, antituberculosis activity principally depends on the substituents in the carboxylate group, improving in the following order: benzyl > ethyl > 2-methoxyethyl > allyl > tert-butyl. Fourteen compounds have been selected for macrophage assay, and the results show that ethyl and benzyl 3-methylquinoxaline-2-carboxylate 1,4-dioxide derivatives with the chlorine group in position 7 of the benzene moiety (compounds 10 and 26) and the unsubstituted derivatives (compounds 11 and 27) have good antitubercular activity, including activity in macrophages. In addition, compounds 7 and 28 (the only ones tested up to now) are active against drug-resistant strains of M. tuberculosis H(37)Rv. In conclusion, the potency, selectivity, and low cytotoxicity of these compounds make them valid leads for synthesizing new compounds that possess better activity.

Synthesis and antimalarial activity of new 3-arylquinoxaline-2-carbonitrile derivatives.

New series of 3-arylquinoxaline-carbonitrile derivatives have been synthesized from various 5-substituted or 5,6-disubstituted benzofuroxanes and tested for their in vitro and in vivo activity against the erythrocytic development of Plasmodium falciparum strain with different chloroquine-resistance status. Quinoxaline 1,4-dioxide derivatives showed superior antimalarial activity in respect to reduced quinoxaline analogues. The best activity was observed with nonsubstituted quinoxaline 1,4-dioxides in positions 6 and 7 of the aromatic ring and with a hydrogen or chloro substituent in para position of the phenyl group.

Synthesis and anticancer activity evaluation of new 2-alkylcarbonyl and 2-benzoyl-3-trifluoromethyl-quinoxaline 1,4-di-N-oxide derivatives.

As a continuation of our research in quinoxaline 1,4-di-N-oxide and with the aim of obtaining new anticancer agents, which can improve the current chemotherapeutic treatments, new series of 2-alkylcarbonyl and 2-benzoyl-3-trifluoromethylquinoxaline 1,4-di-N-oxide derivatives have been synthesized and evaluated for in vitro antitumor activity against a 3-cell line panel, consisting of MCF7 (breast), NCI-H460 (lung), and SF-268 (CNS). These active compounds were then evaluated in the full panel of 60 human tumor cell lines derived from nine cancer cell types. The results have shown that, in general, anticancer activity depends on the substituents in the carbonyl group, improving in the order: ethyl

Quinoxaline N,N'-dioxide derivatives and related compounds as growth inhibitors of Trypanosoma cruzi. Structure-activity relationships.

Quinoxaline derivatives presented good inhibitor activity of growth of Trypanosoma cruzi in in vitro assays. The 50% inhibitory doses were of the same order of that of Nifurtimox. Derivative 13, a quinoxaline N,N'-dioxide derivative, and the reduced derivatives 19 and 20 were the most cytotoxic compounds against the protozoan. Structural requirements for optimal activity were studied by computational methods. From statistical analysis we could establish a multiple correlation between activity and lipophilic properties and LUMO energy.

Synthesis of new 2-acetyl and 2-benzoyl quinoxaline 1,4-di-N-oxide derivatives as anti-Mycobacterium tuberculosis agents.

A series of 2-acetyl and 2-benzoyl-6(7)-substituted quinoxaline 1,4-di-N-oxide derivatives were synthesized and evaluated for in vitro antituberculosis activity. The results show that 2-acetyl-3-methylquinoxaline 1,4-di-N-oxide derivatives with chlorine, methyl or methoxy group in position 7 of the benzene moiety (compounds 2, 4 and 6, respectively) and unsubstituted (3) have good antitubercular activity, exhibiting EC(90)/MIC values between 0.80 and 4.29. In conclusion, the potency, selectivity and low cytotoxicity of these compounds make them valid leads for synthesizing new compounds that possess better activity.

Synthesis and antimycobacterial activity of new quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives.

As a continuation of our research and with the aim of obtaining new antituberculosis agents which can improve the current chemotherapeutic antituberculosis treatments, new series of quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis strain H(37)Rv, using the radiometric BACTEC 460-TB methodology. Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line. The results indicate that some compounds exhibited a good antituberculosis activity and the arylcarboxamide analogues 3, 8, and 9 were the most active compounds (EC(90)/MIC1). Also, the cytotoxic effects indicate that these compounds have a good Selectivity Index (SI).

Pyrazolo[3,4-b]quinoxalines. A new class of cyclin-dependent kinases inhibitors.

Protein kinases are involved in most physiological processes and in numerous diseases. Therefore, inhibitors of protein kinases have therefore a wide therapeutic potential. While screening for inhibitors of cyclin-dependent kinases (CDK's) and glycogen synthase kinase-3 (GSK-3), we identified pyrazolo[3,4-b]quinoxalines as sub-micromolar inhibitors of CDK1/cyclin B. A preliminary structure-activity relationship study suggests that this family of compounds can be optimized to inhibit CDK's and GSK-3. Compounds were tested for their anti-proliferative activity and the results show that several of them displayed a significant inhibitory effect on CDK1/cyclin B. The most active compound (1) was also tested against the brain kinases CDK5/p25 and GSK-3, and proved to be a good inhibitor of both of them. On the contrary, none of the compounds showed any activity in the CDC25 phosphatase assay. As an additional approach, affinity chromatography on immobilized pyrazolo[3,4-b]quinoxalines will be used to identify the intracellular targets of this family of compounds.

Anti-Mycobacterium tuberculosis agents derived from quinoxaline-2-carbonitrile and quinoxaline-2-carbonitrile 1,4-di-N-oxide.

In this paper new quinoxaline derivatives with different substituents in positions 3, 6, 7 and 8 are reported. Their biological activities against Mycobacterium tuberculosis have been assessed and most of the 1,4-di-N-oxide derivatives have been shown to strongly inhibit the bacteria growth in the first in vitro screening. One of these N-oxides (4) is a promising candidate due to its good Selectivity Index (7.95). On the other hand, those compounds without N-oxide moieties showed no or very low activity (growth inhibition: 17% and 39%).