Application of biocatalysts in the synthesis of anti-tuberculosis compounds and analogues

Abstract

The current advancements in genomic engineering and DNA technology have expanded the range and applications of enzymes in synthetic organic chemistry. Biocatalytic transformations continue to replace traditional chemical methods at an exponential rate. With the world now faced with various sustainability and climate change challenges, synthetic chemists need to rethink how we might prepare important target molecules in the future. In this thesis, we present an overview of the design, investigation, and application of enzyme biocatalysts towards the synthesis of important active pharmaceutical ingredients, placing a particular interest in anti-tuberculosis drugs. The target molecules in this work include benzimidazole and benzothiazole fused to triazole rings (part one) and quinazolinone derivatives (part two). The enzymes of focus in this study include commercially available biocatalysts—Laccases (EC1.10.3.2), Nitrile hydratases (EC 4.2.1.84), and Lipases (E.C. 3.1.1.3). The synthesis of hydroxy 2-aryl-1H-benzimidazoles and 2-arylbenzothiazoles from the cyclisation and oxidation reaction of arylamines and hydroxy benzaldehydes was investigated using laccase as an oxidant. Subsequently, the obtained hydroxy heterocycles were treated with potassium carbonate and propargyl bromide in acetone to form 2-aryl-1H-benzimidazole and 2-arylbenzothiazole ether alkynes in decent yields. A novel approach for synthesising triazole rings through the laccase-catalysed 1,3- dipolar cycloaddition reaction between alkynes and azide derivatives was outlined. By treating the obtained 2-aryl-1H-benzimidazole and 2-arylbenzothiazole alkynes with phenyl-azides in the presence of a catalytic amount of laccase (Trametes versicolor), target benzothiazole and benzimidazole fused 1,2,3-triazole derivatives were achieved. Our method effectively catalysed the condensation reaction for a broad range of substrates, yielding both the 1,4-Disubstituted-1H-1,2,3-triazoles and the 1,5- disubstituted-1H-1,2,3-triazoles in adequate to moderate yields. For the first time, we present a novel multistep biocatalytic process for the synthesis of novel quinazolinone derivatives. We effectively catalysed the hydrolysis of nitriles to amides using whole cells containing nitrile hydratase. This is then followed by a condensation reaction between the obtained amides with aldehyde esters using microwave irradiation and a novel laccase/DMSO oxidation to obtain quinazolinone esters in excellent yields. Subsequently, we hydrolysed the quinazolinone esters to acids using immobilised lipase (CAL B). Finally, using HBTU as a coupling reagent, we effectively catalysed the direct amidation reaction of the quinazolinone acid to obtain the target quinazolinone amide derivatives in excellent yields.