Tackling the antibiotic resistance in tuberculosis : synthesis and biological evaluation of novel antitubercular agents and development of novel methodologies for the synthesis of heterocycles

Mycobacterium tuberculosis (Mtb), the etiological agent of Tuberculosis (TB) is developing new multi drug-resistant (MDR) and extensively drug-resistant (XDR) strains to the current drugs used in therapy. Of particular concern the wide spreading of tuberculosis, the high rate of development of resistance, and the high mortality of the patients due to the lack of effective therapy against TB infections. In order to face this problem, two series of novel compounds were designed, synthesised and evaluated against a panel of mycobacterial strains. The first series of compounds includes analogues of the third line drug thioridazine (TZ). TZ is a known antipsychotic drug belonging to the phenothiazine drug group, which showed good activity against MDR-TB infections but causes severe side effects which limit its use in therapy. Among the first series of compounds, five new compounds showed anti-tubercular activity similar or higher than TZ. Moreover, two derivatives showed potent inhibition towards the whole-cell drug efflux pump activity of mycobacteria comparable to that of verapamil, and turning to be promising multi-drug resistance reversal agents. A second series of compounds consist of small molecules which have originally been designed as hybrids of the anti-tubercular drugs BM212 and SQ109. Computational studies revealed a perfect superposition of the structures of SQ109 and BM212 and showed that the two drugs share common features. Five of the resulting compounds showed micromolar anti-tubercular activity on pathogenic TB. Two of them proved to be highly active also against multi-drug resistant clinical isolates and one of these also showed minimal eukaryotic cell toxicity, and therefore would be an excellent lead candidate for preclinical trials. In parallel to the identification of novel compounds active against mycobacteria, new synthetic methodologies for the synthesis of antitubercular heterocyclic scaffolds have been developed. In particular two approaches for the synthesis of pyrrole compounds were developed. Both procedures involve an olefin or enyne metathesis reaction as a key step. The first approach involves the synthesis of 1,2,3-substituted pyrroles, through a tandem enyne cross metathesis-cyclization reaction of propargylamines with ethyl-vinyl ether. The reaction is rapid, procedurally simple and represents a facile entry to the synthetically challenging 4,5-unsubstituted pyrroles. The second methodology allows the synthesis of substituted pyrroles from diallyl-amines via a chemo-enzymatic cascade based on the combination of olefin metathesis together with monoamine oxidase (MAO) biocatalysts. These reactions were carried out in aqueous media and mild temperature leading to the formation of substituted pyrroles in a single step and in high yields.