Identification of novel antitubercular agents from a mixed library comprised of plant extracts and heterocyclic compounds

Date: 10 October 2018

Venue: UAntwerpen - Campus Drie Eiken - Building Q - promotiezaal - Universiteitsplein 1 - 2610 Antwerp (Wilrijk) (route: UAntwerpen, Campus Drie Eiken)

Time: 4:00 PM - 6:00 PM

PhD candidate: Maíra Bidart de Macedo

Principal investigator: Paul Cos - Davie Cappoen

Short description: Phd defence Maíra Bidart de Macedo - Department of Pharmaceutical Sciences



Abstract

Despite the availability of effective chemotherapy for over 60 years, tuberculosis keeps being a life-threatening disease. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, claimed over 1.7 million lives worldwide in 2016. Apart from the socio-economic reasons, the increasing incidence of multi- and extensively-drug resistant strains has pointed out the urgent demand for novel antibiotics for tuberculosis chemotherapy.

The present doctoral thesis reports on the generation of a dual mycobacterial reporter strain, which carries both luminescent and fluorescent plasmids, in order to extract more information in a single experiment by decreasing variance, as well as the biological evaluation of several heterocyclic compounds and plant crude extracts as potential antitubercular agents. Several assays were developed based on state-of-the-art methods.

Thirteen derivatives sharing a common 3-phenyl substituent from a library of substituted 4-hydroxyquinolin-2(1H)-ones showed minimal inhibitory concentrations against the luminescent Mtb H37Ralux reporter strain below 10 μM. Interestingly, 10 of these derivatives were structurally clustered demonstrating the plasticity of the 4-hydroxyquinolin-2(1H)-ones to adjust the physiochemical properties of the derivatives without decreasing their potency.

From results of previous studies with 2- azaanthraquinones derivatives, various “out-of-plane” were synthetized. Further optimization of the scaffold by the addition of protective groups to increase the metabolic stability and improve the antitubercular activity was considered. Results showed that both deletion of the previous substituents as the exchange of those with fluorine or fluorine-containing groups increase the metabolic stability. Acute cytoxicity decreased and no signs of early genotoxicity were assessed. Fifteen novel tetrahydroquinoline based hydrazides were tested for their antitubercular activity against Mtb H37Ralux.

Substitution with a nitro group specially at the ortho position of the phenyl was found favorable for the antitubercular potency with a good safety index. Although the activity was not in the same order as the first line anti-tuberculosis drugs, further elaboration of substitution patterns may lead to new optimization studies. In an attempt to screen for agents from plant-based natural products that inhibit the growth of Mtb, a small library of Brazilian plant crude extracts from the Amazon rain forest was investigated. Twenty vegetal samples belonging to 5 species of Byrsonima genus, widely used in Brazilian traditional medicine, were tested for their anti-infective potential against a broad spectrum of reference strains with clinical relevance and against Mtb H37Ra lab strain. Although a certain level of selectivity could be observed for most of the extracts, no antimycobacterial activity was found.



Link: https://www.uantwerpen.be/en/faculties/fbd/research/departments-and-rese/department-of-pharma/