Structural investigation of two novel classes of quinoloxyacetamide- and hydantoin-based antimycobacterials guided by phenotypic screening and targeted approaches

Date: 2 February 2017

Venue: Universiteit Antwerpen, Stadscampus - Grauwzusters Cloister, Building S, Lange Sint-Annastraat 7 - 2000 Antwerp (route: UAntwerpen, Stadscampus)

Time: 4:30 PM - 6:30 PM

PhD candidate: Eleni Pitta

Principal investigator: Pieter Van der Veken

Co-principal investigator: Koen Augustyns

Short description: PhD defence Eleni Pitta - Department Pharmaceutical Sciences


Tuberculosis (TB) represents an escalating threat for global health, with the increasing prevalence of MDR- and XDR-TB strains. One major obstacle with current TB chemotherapy is the lack of an effective, simple treatment. New anti-TB drugs that shorten the duration of TB chemotherapy are urgently needed.

The present thesis about antimycobacterial drug discovery was performed as part of the OpenMedChem project at the University of Antwerp and GlaxoSmithKline DDW (Tres Cantos, Spain) funded by Marie Skłodowska-Curie Innovative Training Networks.

The research performed can be summarized into two distinct Hit-to-Lead optimization projects of two novel classes of anti-mycobacterial compounds discovered by HTS campaigns performed by GSK. Two series of compounds, namely quinoloxyacetamides and hydantoins were investigated.

During our antimycobacterial research on the first series of quinoloxyacetamides, more than seventy novel derivatives were prepared and evaluated against M. tuberculosis. Apart from the SAR exploration around the initial hits, the optimization processes focused on the improvement of the physicochemical properties, cytotoxicity, cardiotoxicity  and metabolic stability of the series. During this process, several synthetic routes were explored and the alkylation position of heterocyclic N/O-ambident nucleophilic scaffolds was studied using various NMR methods. Several compounds showed potent anti-tubercular activities, no measurable cytotoxicity, and excellent intracellular IC90 values.

The second Hit-to-Lead optimization project was based on a hydantoin-containing primary hit, identified as a potent DprE1 inhibitor with significant cellular potency against M. tuberculosis. During the first round of optimization, it was found that the most potent compounds possessed modifications of the carbonitrile substituent, and that there is a correlation between cellular potency and lipophilic ligand efficiency. Based upon these results, a second round of optimization was initiated. A number of compounds containing variations of the right-hand side of the molecule were synthesized or purchased. Unfortunately, all attempts to reduce the chromlogD values led to a drop of the enzymatic inhibitory activity and the MIC values were moderate. A number of selected compounds were tested for intracellular anti-tubercular activity against infected murine macrophages, in vitro microsomal stability, hERG inhibition and against a panel of Gram-positive and Gram-negative pathogens showing significant specificity. Moreover, selected compounds were evaluated against the DprE1 overexpressor strain, against a number of DprE1 mutant strains and time curves were plotted revealing reversible inhibition. The best compound demonstrated a statistically significant reduction in bacterial load in mice offering an in vivo proof of concept about the potential of this series.