Banca de QUALIFICAÇÃO: LUCIANA LUIZ DE AZEVEDO
Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.DISCENTE : LUCIANA LUIZ DE AZEVEDO
DATA : 08/03/2018
HORA: 14:00
LOCAL: Sala 49
TÍTULO:
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW HYBRID COUMARINS PLANNED AS ATP SYNTHASE AND FADD32 INHIBITORS FOR THE TREATMENT OF TUBERCULOSIS
PALAVRAS-CHAVES:
Tuberculosis, Mycobacterium tuberculosis, bedaquiline, coumarine, ATP synthase e FadD32.
PÁGINAS: 20
GRANDE ÁREA: Ciências Exatas e da Terra
ÁREA: Química
RESUMO:
Tuberculosis is a persistent infectious disease caused by mycobacteria that mainly affects the lungs, which Mycobacterium tuberculosis is the main causative agent. Currently, drugs used in tuberculosis therapy, such as rifampicin, pyrazinamide, ethambutol and isoniazid, have undesirable side effects, which makes it difficult for patients compliance to treatment, which is usually long-term. Besides, the emergence of resistant strains of M. tuberculosis to the usual drugs is worrying authorities around the world. Thus, the discovery of new targets and development of new molecules is extremely necessary for the treatment of tuberculosis. Therefore, this work proposes the design, synthesis and biological evaluation of new hybrid coumarins planned as ATP synthase and FadD32 inhibitors, important enzymes for the homeostasis of M. tuberculosis. Two distinct series A and B were planned, inspired by the ATP synthase inhibitor badaquiline, approved in 2012 by FDA for the treatment of tuberculosis, and coumarin CCA34, described in the literature as a potent inhibitor of FadD32 with excellent antimycobacterial activity. The series A and B were proposed in order to evaluate the influence of different functional groups (R1 and R2 = -H, -NH2, -OH, -NO2, -CH3 and -Br) linked to the aromatic rings a and b in biological activity of these compounds. The synthesis of the final hybrid molecules was planned by constructing 3 major subunits: the coumarin subunit, common to A and B series; the a subunit, which corresponds to the modifications of A series; and the b subunit, which corresponds to the modifications of B series. The coumarin subunit was proposed in 4 reactional steps including a Suzuki-Miyaura coupling reaction. This subunit is linked to subunit a through a copper-catalyzed cross-coupling reaction step. Subunit b is then synthesized and linked to the subunits previously described through two distinct routes: the original route, which at the end of the synthesis a standard chromatographic column is performed for the separation of the enantiomeric pairs followed by two chiral columns for the separation of the enantiomers themselves; and the alternative route, which proposes the separation of the enantiomers formed after the second and third reaction stages, through a chiral chromatographic column. After the synthesis, the final products will be evaluated biologically through in vitro inhibition of the ATP synthase and FadD32 enzymes, and against M. tuberculosis H37Rv strain, with a drug resistance and multiresistance profile.
MEMBROS DA BANCA:
Interno - 1220404 - CARLOS MAURICIO RABELLO DE SANTANNA
Externo à Instituição - FLORIANO PAES SILVA JÚNIOR - UFRJ
Presidente - 1058758 - MARCO EDILSON FREIRE DE LIMA
Interno - 1979542 - RENATA BARBOSA LACERDA