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

Abstract

Abstract:As a continuation of our research and with the aim of obtaining new antituberculosis agents which can improve the current chemotherapeutic antituberculosis treatments, forty-three new 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. Active compounds were also screened to assess toxicity to a VERO cell line. Results indicate that compounds with a methyl moiety substituted in position 3 and un-substituted benzyl substituted on the carboxamide group provide an efficient approach for further development of antituberculosis agents.

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

“…Taking into account the biological values reported in Table 1, it can be concluded that the insertion of a electron-withdrawing moiety, especially that of chlorine atom, is an essential requirement for the anti-tubercular activity, as previously established by our group. [21,22] With the aim of corroborating previous preliminary structure-activity relationship observed by our group and identifying the most suitable length for the aliphatic chain between the carboxamide group and the aromatic ring, three series of compounds (Series 1, 2 and 3) were prepared. Comparing the biological values shown by these compounds, it can be said that the preferred length for the aliphatic chain is one methylene group.…”

“…With regard to position 2, carbonitrile derivatives appeared to be quite toxic [17][18][19][20][21]. Moreover, ketone, carboxylate and carboxamide quinoxaline-1,4-dioxydes derivatives were actually patented in the 70's for their antibacterial activity.…”

“…This modification led to a reduction of the anti-tubercular activity as can be observed by comparing the biological values of compounds from Series 1, 2 and 3 with their analogues containing a methyl group in position 3, described in previous reports. [21,22] Taking into account the biological values of the structures which present a phenyl group substituted in position 3 and the compounds with a methyl group in this position, [22] we decided to keep the methyl moiety in position 3 and modify the substitution on the aromatic ring. Different substituents were introduced on para position of the phenyl ring considering chloro, bromo or trifluoromethyl moiety as electron-withdrawing groups and methyl as electron-releasing group (Series 4, 5, 6, 7).…”

Recent Efforts for the Development of Antitubercular Drug Containing Diazine Ring

“…(61) showed MIC of 6.25 μg/mL against Mtb H37Rv and 0.5 μg/mL against Mtb H37Ra. Which prompted to continue the optimization of quinoxaline 1,4-dioxide [80], a series of quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were evaluated for their in-vitro anti-TB activity against Mtb H37Rv. Among all, compound 62a exhibited best MIC of 0.78 μM, has a solubility problem, while compound (62b) having MIC of 3.13 μM has a best selectivity index (SI=>40.06).…”

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

“…Eleven putative eukaryotic-like protein serine-threonine kinases (Pkn A to L) involved in signal transduction have been identified in M. tuberculosis H37Rv genome (11,(104)(105)(106). Based on this kinase inhibition benzothiophenes (specifically inhibits Pkn G) (107,108) and benzoquinoxalines (inhibitors of Pkn B, Pkn G, and Pkn H) (109)(110)(111)(112) have been reported. Hence this intensive research on signaling kinase inhibitors could also provide target oriented lead molecules for the control of tuberculosis.…”