Spirooxadiazoline-oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells.

Imatinib mesylate was the first representative BCR-ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR-ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR-ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS-1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro-oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8-9.8 µM.

Novel 2-Nitroimidazole and Imidazooxazole Derivatives and their Activity against Trypanosoma cruzi and Mycobacterium tuberculosis.

BACKGROUND: Tuberculosis (TB) is one of the top ten causes of death worldwide, while Chagas disease (CD) is the parasitic disease that kills the largest number of people in the Americas. TB is the leading cause of death for patients with AIDS; it kills 1.5 million people and causes 10 million new cases every year. The lack of newly developed chemotherapeutic agents and insufficient access to health care services for a diagnosis increase the incidence of multidrug-resistant TB (MDRTB) cases. Although CD was identified in 1909, the chronic stages of the disease still lack adequate treatment. OBJECTIVE: The purpose of this work was to design and synthesize two new series of 2-nitroimidazole 5a-e and imidazooxazoles 6a-e with 1H-1,2,3-triazolil nucleus and evaluate their activities against Tc and Mycobacterium tuberculosis (Mtb). METHODS: Two series of five compounds were synthesized in a 3 or 4-step route in moderated yields, and their structures were confirmed by NMR spectral data analyses. The in vitro antitrypanosomal evaluation of products was carried out in an intracellular model using L929 cell line infected with trypomastigotes and amastigote forms of Tc of ß-galactosidase-transfected Tulahuen strain. Their antimycobacterial activity was evaluated against Mtb strain H37Rv. RESULTS: In general, 2-nitroimidazolic derivatives proved to be more potent in regard to antitrypanocidal and antimycobacterial activity. The non-cytotoxic 2-nitroimidazole derivative 5b was the most promising with a half maximum inhibitory concentration of 3.2 µM against Tc and a minimum inhibitory concentration of 65.3 µM against Mtb. CONCLUSION: Our study reinforced the importance of 2-nitroimidazole and 1H-1,2,3-triazole nuclei in antimicrobial activity. In addition, derivative 5b proved to be the most promising, presenting important activity against Tc and Mtb and could be used as a starting point for the development of new agents against these diseases.