Synthesis, characterization, anti-mycobacterial activity and in silico study of new 2,5-disubstituted-1,3,4-oxadiazole derivatives

@#A series of new 2,5-disubstituted-1,3,4-oxadiazole derivatives (5a-j and 6a-j) have been designed and synthesized in four-steps. Sixteen compounds among the twenty compounds are reported for the first time. The compounds were characterized and confirmed by the FTIR, 1D- and 2D-NMR and HRMS analyses, and were tested against Mycobacterium smegmatis and Mycobacterium tuberculosis H37Ra. Compound 5d was the most active against M. smegmatis with MIC value of 25 µM, and exhibited cidal activity with MBC of 68 µM, respectively. The time-kill assay showed the good killing rate at 77% with the combination of isoniazid (INH). In addition, checkboard assay confirmed the interaction of compound 5d was categorised as additive. Docking simulation has been performed to position 5d into the pantothenate synthetase active site with binding free energy value –8.6 kcal mol-1. It also occupied the same active site as that of standard native ligand with similar interactions, which clearly indicate their potential as pantothenate synthetase inhibitor.

Establishment and evaluation of adjuvant-induced arthritis animal model by Mtb in Sprague-Dawley rats / 中国药理学通报

Aim To establish and evaluate the simple and effective animal model of rheumatoid arthritis in SD rats induced by heat-killed mycobacterium tuberculosis H37Ra(Mtb).Methods SD rats were immunized s.c.at the base of the tail with Mtb(1 mg/rat) in mineral oil,and then body weight,blood routine,clinical signs of arthritis were observed regularly.And also hind paw volume in SD rats with AA was tested.Meanwhile,T-lymphocyte subset was determined by flow cytometry in peripheral blood,the level of TNF-?in serum and IL-1 and IL-6 and vascular endothe-lial growth factor(VEGF) in joint tissue were tested by ELISA.The ankle pathological change and radiographic evidence of the hind paws of SD rats were observed to evaluate the AA model effects and availability in SD rats.Results When compared with normal control rats,the total number of white blood cells,platelets and monocytes in peripheral blood and ratio of CD4/CD8 was markedly raised after immunization with Mtb.But body weight of model rats was significantly low from day 14 to 28 after injection of Mtb.The inflammatory arthritic lesions such as edema and erythema in the paws appeared after 9～10 d.The peak of inflammation was 14～16 d.The level of TNF-?in serum and IL-1,IL-6 and VEGF in joint tissue was significantly higher in SD rats with Mtb than that in normal control rats at d 28.The histopathological examination revealed cellular infiltration,synovial and cartilage hyperplasia in ankle joints of SD rats.Conclusions The model induced by Mtb in SD rats is more similar in clinical characterization of rheumatoid arthritis in human being.It is a more efficient and simpler manipulative procedure for screening of new anti-arthritis drugs and experimental studying of anti-rheumatoid arthritis.