Novel Kinetic Resolution of Thiazolo-Benzimidazolines Using MAO Enzymes

Abstract

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 (−NO 2 and −CO 2 Et), 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.

Rational Design of Benzobisheterocycle Metallo-β-Lactamase Inhibitors: A Tricyclic Scaffold Enhances Potency against Target Enzymes

“…We also envisaged preparing compound 14 , the nitrogen analogue of BBH 13 , aiming to improve water solubility and cell permeability. Synthesis of compounds (±) 13 and (±) 14 was achieved by double cyclization of 2-aminomercaptobenzene or 2-aminoaniline, respectively, and 1,4-dithiane-2,5-diol using microwave heating at 60 °C (Scheme A) . BBHs (±) 13 and (±) 14 were obtained as a racemic mixture of the syn diastereomer in good yield (85 and 62%, respectively) .…”