Isoniazid-N-acylhydrazones as promising compounds for the anti-tuberculosis treatment.

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis complex, still presents significant numbers of incidence and mortality, in addition to several cases of drug resistance. Resistance, especially to isoniazid, which is one of the main drugs used in the treatment, has increased. In this context, N-acylhydrazones derived from isoniazid have shown important anti-Mycobacterium tuberculosis activity. Hence, this work aimed to determine the anti-TB potential of 11 isoniazid-N-acylhydrazones (INH-acylhydrazones). For this purpose, the determination of minimum inhibitory concentration (MIC) against M. tuberculosis H37Rv and clinical isolates was carried out. Drug combination, minimum bactericidal concentration, cytotoxicity, and in silico parameters were also performed. INH-acylhydrazones (2), (8), and (9) had MIC for M. tuberculosis H37Rv similar to or lower than isoniazid, and bactericidal activity was observed. In addition, these compounds showed low cytotoxicity, with a selectivity index greater than 3,000. Interesting results were also obtained in the drug combination assay, with synergistic combinations with isoniazid, ethambutol, and rifampicin. In the in silico study, INH-acylhydrazones behaved similarly to INH, but with improvements in some aspects. Based on these findings, it is concluded that compounds (2), (8), and (9) are considered promising scaffolds and warrant further investigation for designing future antimicrobial drugs.

The chemistry of Vernonanthura nudiflora (Less.) H. Rob. flowers and its antimicrobial activities.

Twenty-one known specialised metabolites were isolated from the flowers of Vernonanthura nudiflora (Less.) H. Rob., the structures of the compounds were established based on 1 D and 2 D NMR spectroscopic experiments. Others 28 compounds were putatively identified using the dereplication technique by UHPLC-HRMS/MS. Twenty-three of the compounds are being reported for the first time in this species. The mixture of sesquiterpene lactones piptocarphins A and B (17 + 18), and the flavone velutin (14) were tested against several microorganisms and showed promising activity against Mycobacterium tuberculosis with MIC of 15.6 µg/mL and 31.2 µg/mL, respectively. Furthermore, 17 + 18 showed greater cytotoxicity against VERO cells (IC50 = 7.0 ± 1.73) compared to compound 14 (IC50 85.0 ± 10.6 µg/mL). These findings reveal the feasibility of using the UHPLC-ESI-HRMS/MS-based dereplication strategy in complex fractions to identify specialised metabolites, moreover to V. nudiflora flowers being a source of compounds with antimycobacterial potential.

Anti-Mycobacterium tuberculosis activity of essential oil and 6,7-dehydroroyleanone isolated from leaves of Tetradenia riparia (Hochst.) Codd (Lamiaceae).

BACKGROUND: The global resurgence of tuberculosis (TB) and the development of drug resistance, as multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis isolates, are a threat to TB control and have created a need for new and more effective anti-TB drugs. AIM: The current study evaluated the in vitro cytotoxicity and activity of Tetradenia riparia essential oil (TrEO) and 6,7-dehydroroyleanone pure compound against M. tuberculosis H37Rv and susceptible and resistant clinical isolates. METHODS: The in vitro activities of TrEO and 6,7-dehydroroyleanone were determined by Resazurin Microtiter Assay Plate (REMA). The cytotoxicity was evaluated in murine peritoneal macrophages by Alamar Blue assay. The cytotoxic effects were expressed as median concentration cytotoxicity (CC50) and the selectivity index (SI) was calculated. RESULTS: TrEO and 6,7-dehydroroyleanone showed activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) 62.5 µg/ml and 31.2 µg/ml, respectively. Both of them exhibited activities against resistant and susceptible M. tuberculosis clinical isolates with MIC values between 31.2 and 62.5 µg/ml. Cytotoxicity assays showed SI 1.9 and 7.9 for TrEO and 6,7-dehydroroyleanone, respectively. CONCLUSION: These results revealed that TrEO isolated from leaves of T. riparia and the pure compound 6,7-dehydroroyleanone display good activity against M. tuberculosis clinical isolates, including MDR isolates, with low cytotoxicity to murine macrophages. The 6,7-dehydroroyleanone compound is a potential candidate for anti-TB drug.

Anti-Mycobacterium tuberculosis activity and cytotoxicity of Calophyllum brasiliense Cambess (Clusiaceae)

We evaluated the in vitro anti-Mycobacterium tuberculosis activity and the cytotoxicity of dichloromethane extract and pure compounds from the leaves of Calophyllum brasiliense. Purification of the dichloromethane extract yielded the pure compounds (-) mammea A/BB (1), (-) mammea B/BB (2) and amentoflavone (3). The compound structures were elucidated on the basis of spectroscopic and spectrometric data. The contents of bioactive compounds in the extracts were quantified using high performance liquid chromatography coupled to an ultraviolet detector. The anti-M. tuberculosis activity of the extracts and the pure compounds was evaluated using a resazurin microtitre assay plate. The cytotoxicity assay was performed in J774G.8 macrophages using the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide colourimetric method. The quantification of the dichloromethane extract showed (1) and (2) at concentrations of 31.86 ± 2.6 and 8.24 ± 1.1 µg/mg of extract, respectively. The dichloromethane and aqueous extracts showed anti-M. tuberculosis H37Rv activity of 62.5 and 125 µg/mL, respectively. Coumarins (1) and (2) showed minimal inhibitory concentration ranges of 31.2 and 62.5 µg/mL against M. tuberculosis H37Rv and clinical isolates. Compound (3) showed no activity against M. tuberculosis H37Rv. The selectivity index ranged from 0.59-1.06. We report the activity of the extracts and coumarins from the leaves of C. brasiliense against M. tuberculosis.

Anti-Mycobacterium tuberculosis activity and cytotoxicity of Calophyllum brasiliense Cambess (Clusiaceae).

We evaluated the in vitro anti-Mycobacterium tuberculosis activity and the cytotoxicity of dichloromethane extract and pure compounds from the leaves of Calophyllum brasiliense. Purification of the dichloromethane extract yielded the pure compounds (-) mammea A/BB (1), (-) mammea B/BB (2) and amentoflavone (3). The compound structures were elucidated on the basis of spectroscopic and spectrometric data. The contents of bioactive compounds in the extracts were quantified using high performance liquid chromatography coupled to an ultraviolet detector. The anti-M. tuberculosis activity of the extracts and the pure compounds was evaluated using a resazurin microtitre assay plate. The cytotoxicity assay was performed in J774G.8 macrophages using the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide colourimetric method. The quantification of the dichloromethane extract showed (1) and (2) at concentrations of 31.86 ± 2.6 and 8.24 ± 1.1 µg/mg of extract, respectively. The dichloromethane and aqueous extracts showed anti-M. tuberculosis H37Rv activity of 62.5 and 125 µg/mL, respectively. Coumarins (1) and (2) showed minimal inhibitory concentration ranges of 31.2 and 62.5 µg/mL against M. tuberculosis H37Rv and clinical isolates. Compound (3) showed no activity against M. tuberculosis H37Rv. The selectivity index ranged from 0.59-1.06. We report the activity of the extracts and coumarins from the leaves of C. brasiliense against M. tuberculosis.

Padronização de modelos experimentais para a investigação de produtos naturais biologicamente ativos com potenciais antidiabético e hipolipemiante em ratos wistar / Standardization of experimental models for the inquiry of biological natural products active with potentials antidiabetic and hipolipemiante in Wister rats

Modelos experimentais empregando animais de laboratório têm um importante papel no desenvolvimento de novos fármacos. Porém, uma escolha apropriada de cada modelo experimental deve ser executada, já que não existe um modelo animal capaz de esclarecer todas as hipóteses. Assim, o objetivo deste trabalho foi padronizar modelos experimentais para investigação de atividade antidiabética e hipolipemiante de produtos naturais biologicamente ativos (PNBAs) em ratos Wistar. Os modelos foram constituídos para avaliar o efeito agudo ou crônico de PNBAs. Observamos que os ratos Wistar responderam a acarbose, clorpropamida, insulina, quitosana ou orlistat de modo semelhante aos humanos, representando modelos para investigação de PNBAs com potencial antidiabético e hipolipemiante. Entretanto a resposta a sinvastatina ou ciprofibrato foi diferente da observada em humanos, mostrando que ratos Wistar poderiam ser empregados em "screenings" farmacológicos para avaliar PNBAs com potencial hipolipemiante desde que se leve em consideração esta diferença. Além disso, ratos Wistar com diabetes induzida por aloxana, apesar da possível reversão parcial do diabetes, poderiam constituir modelos experimentais adequados para investigação de PNBAs com potencial antidiabético. Entretanto, uma tendência à normalização nas concentrações séricas de lipídeos limitam o emprego destes animais diabéticos para avaliação de PNBAs com potencial hipolipemiante. Finalmente, a Solanum melongena e o Cissus sicyoides, empregados em nossos experimentos, não apresentaram efeito antidiabético ou hipolipemiante