Design and synthesis of N-containing heterocycles with anti-tuberculosis activity

Cui, Yixin (2023). Design and synthesis of N-containing heterocycles with anti-tuberculosis activity. University of Birmingham. Ph.D.

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Abstract

Nitrogen (N)-containing heterocycles are common structural units in the vast majority of marketed small-molecule drugs. In this work, several novel series of N-containing motifs were successfully synthesised (up to gramme scale) under mild reaction conditions. With the aid of the open-source data-mining software, KNIME, thousands of “druglike” N-containing molecules were synthesised in silico, establishing a virtual compound library. Then, according to the designed structures, a small library of hundreds of novel “drug-like” N-containing molecules was prepared. In vitro high-throughput screening of the library against biological targets and/or cells allowed for identifying hits with potential anti-TB activity. Single enantiomers of hits were obtained to help with the SAR and toxicology study. Along with computational docking studies and imaging studies, several significantly more active compounds were identified without resistance observed, which indicates a promising anti-TB therapy. Furthermore, boron-containing groups as warheads were attached to the leads for the development of potential covalent inhibitors.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):