Development of new drug leads for tuberculosis

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Publication . Campaniço, André Filipe da Silva; Lopes, Francisca Conceição; Moreira, Rui Ferreira Alves; Warner, Digby Francis

Tuberculosis (TB) is a deadly disease caused by a single infectious agent, Mycobacterium tuberculosis (M. tuberculosis). The complexity and duration of the treatment lead to misuse and low compliance by patients, increasing disease burden and the appearance of multidrug-resistant strains of M. tuberculosis. Thus, new antibiotics active against drug-resistant M. tuberculosis and useful for short period therapeutic regimens at lower required doses are urgently needed. A family of azaaurone-based derivatives, from a chemical library developed in iMed.ULisboa, revealed to be active against M. tuberculosis, including multidrug- and extensively drug-resistant clinical isolates, at a submicromolar level. [3] Despite the promising activities, this new scaffold displayed poor ADME properties. In this thesis, we report the complete SAR exploration and ADME profiling of newly synthesized derivatives. All chemical sites of the azaaurone scaffold were extensively explored. More metabolically stable moieties were introduced, generating compounds with improved in vitro half-lives. More hydrophilic groups were inserted and nonaromatic heterocycles were introduced to disrupt the scaffold planarity, two strategies to improve overall solubility. The double bond within the scaffold was also reduced to a single bond, generating a new family of saturated analogues of azaaurones. The new synthesized derivatives displayed improved potency against M. tuberculosis and retained its activity on drug-resistant isolates, remaining non-cytotoxic and selective for the bacteria. Identification of the target was attempted through isolation of resistant mutants, but it was not successful as no azaaurone-resistant isolates were found. Final azaaurones are typically obtained as mixtures of E/Z isomers. The isomers were isolated and differentially studied. Both display similar antitubercular activity. Furthermore, azaaurone isomers were found to isomerize in the presence of mouse liver microsomes (MLM) and under the influence of light. Concerning photoisomerization, it was concluded that this family of azaaurones does not display the optimal characteristics to be used as a photoswitch system.

2022-05Doctoral thesis

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