Novel Kinetic Resolution of Thiazolo-Benzimidazolines Using MAO Enzymes.

The kinetic resolution of racemic 1H,3H-thiazolo[3,4-a]benzimidazoline (TBIM) heterocycles was achieved using E. coli whole cells expressing the MAO-N D11 enzyme. Several cosolvents were screened using TBIM 2a as the substrate. DMF was the best cosolvent, affording the pure enantiomer (+)-2a in 44% yield, 94% ee. The stereochemistry of TBIM was predicted by means of ab initio calculations of optical rotation and circular dichroism spectra. The reaction scope was investigated for 11 substituted (±) TBIM using an optimized protocol. The best yield and % ee were obtained for the nonsubstituted 2a. Among the substituted compounds, the 5-substituted-TBIM showed better % ee than the 4-substituted one. The small electron donor group (Me) led to better % ee than the electron-withdrawing groups (-NO2 and -CO2Et), and the bulky naphthyl group was detrimental for the kinetic resolution. Docking experiments and molecular dynamics (MD) simulations were employed to further understand the interactions between MAO-N D11 and the thiazolo-benzimidazoline substrates. For 2a, the MD showed favorable positioning and binding energy for both enantiomers, thus suggesting that this kinetic resolution is influenced not only by the active site but also by the entry tunnel. This work constitutes the first report of the enzymatic kinetic resolution applied to TBIM heterocycles.

Efficient Access to the Iboga Skeleton: Optimized Procedure to Obtain Voacangine from Voacanga africana Root Bark.

Iboga alkaloids are a group of monoterpenoid indole alkaloids with promising and intriguing biological activities. Ibogaine is the representative member of the series and has become widely known as a potent atypical psychedelic with promising effects to treat substance use disorder. Nowadays, an efficient and scalable enantioselective total synthesis of ibogaine and related iboga alkaloids is still lacking, so direct extraction from natural sources or semi-synthetic schemes are the methods of choice to obtain them in a preparative scale. In particular, ibogaine can be obtained either by a low yielding direct isolation from Tabernanthe iboga or using a semi-synthetic procedure from voacangine, an iboga alkaloid occurring in a higher yield in the root bark of Voacanga africana. In this work, we describe an optimized process to obtain voacangine from V. africana root bark as a precursor of the iboga scaffold. Using a direct acetone-based extraction procedure (0.5 kg of root bark), voacangine was isolated in ∼0.8% of root bark dried weight, while the major alkaloids isolated from the bark were identified as iboga-vobasinyl dimers (∼3.7%) such as voacamine and voacamidine. Since these alkaloids contain the voacangine moiety in their structure, the cleavage of the dimers was further optimized, affording an extra amount of voacangine in ∼50% isolated molar yield. In this manner, the total amount of voacangine obtained by application of the whole procedure to the plant material (extraction and dimer cleavage) could almost duplicate the content originally found in the root bark.

The efficacy of new 2,5-dihydroxybenzyl derivatives against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis.

INTRODUCTION: Chagas disease and Leishmaniasis are among the most important parasitic diseases. They are considered to be within the most relevant group of neglected tropical diseases and have been included as priorities for searching new drugs due to their several treatment limitations. These parasitic diseases caused by flagellated protozoans affect more than 20 million people predominantly in developing countries. METHODOLOGY: In this study, we prepared a series of 2-substituted 1,4-benzenediols by an efficient, green, and lithium salt-free synthesis in water/ethanol as solvent to test their anti-parasitic activity. All 36 phenolic derivatives were evaluated in vitro for their activity against T. cruzi epimastigotes, L. infantum, and L. braziliensis promastigotes, as well as their cytotoxicity on macrophage and fibroblast cell lines. RESULTS: Based on the results obtained, the compounds that presented a methyl, trifluoromethyl or bromo group at the para-position of the second benzene ring were found the most active analogs, with higher selective index values on the three parasites assayed. CONCLUSION: This evidence suggests that the anti-parasitic activity observed in these analogs is affected by the size of the group at the 4-position of the second ring, but not related with electronic factors.This study identified hit compounds with the potential to target several kinetoplastid parasites.