Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity.

Tuberculosis, caused by 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 nonreplicating 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 a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.

Synthesis and in vitro biological evaluation of ring B abeo-sterols as novel inhibitors of Mycobacterium tuberculosis.

A series of 3beta-hydroxy steroid analogues possessing a contracted cyclopentane B-ring were prepared based on the initial activity screening of a recently reported naturally occurring marine 5(6-->7)abeo-sterol against Mycobacterium tuberculosis. All of the novel ring B abeo-sterols synthesized showed good inhibitory activity, whereas none of the starting steroids based on the common 3beta-hydroxy-Delta(5)-cholestane nucleus, proved to be active. Therefore, the 5(6-->7)abeo-sterol nucleus present in compounds 3, 5, 7, 9, and 11 represents a novel scaffold for the development of new antitubercular agents.

Ethnopharmacological evaluation of the informant consensus model on anti-tuberculosis claims among the Manus.

Ethnobotanists often utilize predictive models to analyze the potential of indigenously used medicinal plants. The most common of these prognostic models is the informant consensus model. This study evaluates use of this model through the analytical ethnopharmacology of Manus Province, Papua New Guinea (PNG). The informant consensus model enables researchers to prioritize plants for pharmacognostic evaluation, based on the relative frequency of plants cited in anthropological interviews. Fieldwork on Manus Island, PNG, led to the identification of 43 species of plants used in traditional medicine for persistent respiratory symptoms. Plants were collected, dried, micro-extracted using a new technique generated in our laboratory, and evaluated in vitro against Mycobacterium tuberculosis. The results, in the form of IC(50) values and modified selectivity indices (SI), were compared to the results of the anthropological models of informant consensus, and statistically compared through linear regression and t-tests. Results were not statistically significant (alpha=0.1), leading to the conclusions that the informant consensus assumptions were inaccurate in predicting anti-mycobacterial activity among the Manus for anti-TB claims.

Constituents of Senecio chionophilus with potential antitubercular activity.

Two new sesquiterpenoids, (1S,4S,5R,10R)-1-hydroxy-6-isobutyryloxy-10H-9-oxofuranoeremophilane (1) and 1alpha-hydroxy-6beta-(2xi-methylbutyryloxy)-10alphaH-9-oxofuranoeremophilane (2), along with 21 known constituents, were isolated from the n-hexane and dichloromethane extracts of the above-ground biomass and roots of Senecio chionophilus. The structures of 1 and 2 were elucidated on the basis of spectroscopic evidence and chemical transformation methods. The absolute configuration of 1 was determined by Mosher ester methodology. All of the isolates were evaluated for their antitubercular potential against Mycobacterium tuberculosis in a microplate Alamar Blue assay. Compound 2, 6beta-angeloyloxy-1alpha-hydroxy-10alphaH-9-oxofuranoeremophilane (3), and 4'-hydroxyacetophenone (6) exhibited mild antitubercular activity at minimum inhibitory concentrations of 119, 114, and 121 microg/mL, respectively.

Mycobacterium tuberculosis growth inhibition by constituents of Sapium haematospermum.

Four novel compounds consisting of two new pimaranes, lecheronol A (1) and lecheronol B (2), an acylated cycloartane, 3-O-beta-lauroyl-cycloart-(23E)-en-25-ol (10), and a highly oxygenated novel chalconoid, alpha,beta,3,4,5,2',4',6'-octahydroxydihydrochalcone (12), were isolated along with seven known triterpene derivatives and three flavonol glucosides from Mycobacterium tuberculosis growth-inhibiting fractions of the CH(2)Cl(2)/MeOH (1:1) extract of the aerial parts of Sapium haematospermum. Compounds 1, 3 (3 alpha-hydroxyolean-12-ene), 8 [3 alpha-hydroxylup-20(29)-en], and 9 (cycloartanol) were found most active, with MIC values of 4, 12.2, 13.4, and 8 microg/mL, respectively. Cytotoxicity tests in Vero cells for compounds 1, 3, 8, and 9 gave IC(50) values of 104.8, 127.2, 127.2, and 102.4 microg/mL, respectively.

Inhibitory effect of sterols from Ruprechtia triflora and diterpenes from Calceolaria pinnifolia on the growth of Mycobacterium tuberculosis.

Bioactivity-guided fractionation of the CH 2 Cl 2 /MeOH extract of the aerial part of Ruprechtia triflora Griseb. led to the identification of several sterols and a triterpene as the active components against Mycobacterium tuberculosis. This is the first report of a chemical investigation of a member of the genus Ruprechtia. The novel acylated sterol, 5alpha,8alpha-epidioxyergosta-6,22-dien-3beta-yl stearate, was isolated and its structure determined on the basis of spectral evidence including NMR (especially selective 1D NOE, selective 1D TOCSY, HSQC, HMBC) and MS (HR-FAB). In addition, several terpenes obtained from Calceolaria pinnifolia Cav. were also evaluated for their antimycobacterial activity. In a microplate alamar blue assay, sterols from R. triflora were found to be active with MIC values ranging from 2 - 128 microg/mL, with 5alpha,8alpha-epidioxyergost-6,22-dien-3beta-ol, 5alpha,8alpha-epidioxystigmasta-6,22-dien-3beta-ol and stigmast-4-en-6beta-ol-3-one being the most active, each with an MIC value of 2 microg/mL. Among the diterpenes from C. pinnifolia, 19-malonyloxydehydroabietinol and 19-methylmalonyloxy- ent-isopimara-8(9),15-diene were most active each with an MIC value of 4 microg/mL. MIC values for the triterpenes 3-epi-ursolic acid and 3-epi-oleanolic acid from C. pinnifolia were determined to be 8 and 16 microg/mL, respectively.