Design, Synthesis and Characterization of N-oxide-containing Heterocycles with In vivo Sterilizing Antitubercular Activity

Tuberculosis, caused by the Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide- containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and non- replicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective leading to the reduction of the number of Mtb to undetected levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks the process of translation. Altogether, these results indicated benzofuroxan derivative 8 to be a promising lead compound for the development of a novel chemical class of antitubercular drugs

SCREENING FOR POTENTIAL HAZARD EFFECTS FROM MULTITARGET ANTHRACYCLINE ON THE CARDIOVASCULAR SYSTEM

ATP binding cassette (ABC) transporters can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. Synthetic doxorubicins, modified with moieties containing NO-releasing groups (NitDOX), overcome drug resistance by nitrating critical tyrosine residues of ABC transporters. The introduction of a NO-releasing group made NitDOX also a functionally distinct anthracycline with pharmacologic properties widely different from the parent drug. NitDOX, in fact, accumulates preferentially in the mitochondria, where it affects critical steps of mitochondrial metabolism. The development of clinically useful MDR inhibitors remains a promising strategy for addressing and potentially overcoming MDR. Drug safety, however, is one of the main causes of discontinuation or withdrawal of novel drugs and many reports indicate that cardiovascular toxicity is a significant driver, being more frequent, for example, than hepatotoxicity. In order to develop novel and safe MDR inhibitors and considering the potential use of NitDOX as innovative drugs, the aim of this study was to characterize the mechanism of action and vascular effects of the novel P-gp inhibitors, especially when considering the role of NO in the regulation of vascular tone. Their effects were compared to those of doxorubicin (DOXO) and tariquidar, one of the most potent P-gp inhibitors. The results demonstrated that NitDOX was less toxic than DOXO in human endothelial cells at concentrations comparable to those effective to exert antitumor activities and to accumulate in drug-resistant cells. Both NitDOX and DOXO, however, promoted similar cytotoxic and apoptotic effects in vascular smooth muscle cells, while tariquidar was mostly inactive. In conclusion, NitDOX is a functionally distinct anthracycline with a more favorable toxicity profile and a better efficacy against drug-resistant cells. In the context of earlier attempts to use NO delivery strategies in cancer therapy, NitDOX is worthy of further investigations in preclinical and clinical settings