Toward innovative therapeutics for the eradication of mycobacterial infections

Abstract

Tuberculosis (TB), brought by M. tuberculosis (Mtb) is one of deadliest diseases that the human kind has faced throughout the centuries, and the toll of deaths caused by this disease is still remarkable. Two main hurdles characterize TB infection: drug-resistance and the presence of persistent strains, that extend the duration of the therapy and make it more difficult to eradicate. Although the hundreds of compounds disclosed, with good in vitro activity against drug-resistant and drug-susceptible Mtb, a different idea is needed to face the disease. Efflux pumps are known to be important means to modulate antibiotic resistance for many bacteria, and for Mtb in particular. Therefore, inhibition of efflux pumps may help in preventing the raise of resistances, in containing its spread, and in re-establish obsolete therapeutic options. Thioridazine (TZ), an old neuroleptic, by virtue of its capability to affect efflux system of macrophage, acts as inhibitors of bacteria efflux pumps but it can also cure resistant TB when administered in combination with other antitubercular agents on compassionate basis. However, TZ, normally administered for schizophrenia, shows general toxicity at the anti-TB therapeutic doses. We report a series of TZ analogues as inhibitors of the mycobacterial efflux pumps. We were pleased to notice that one derivative has lower cytotoxicity than TZ and it was able to enhance up to 64 times the activity of RIF in the combination assay. Meanwhile, in the research group where I have carried out this PhD research a class of anti-TB agents based on the 2-aminothiazole scaffold was developed, and two compounds were chosen as starting points to drive the design of improved analogues. With the aim to improve the activity profile of the 2-aminoarylthiazole, we have now designed and synthesized a library of novel 2-aminothiazole compounds. In our previous work we investigated the positions 2 of the aminothiazole ring, identifying one substituent more active then other. Now, we have modified position 4 of the same ring with different heterocycles, keeping intact the pattern of substitution at position 2. We were pleased to notice that two derivatives were found to be highly active and with a favourable metabolic profile. On a similar vein, we decided to investigate the effect on the anti-TB activity of another heterocycle in place of the 2-aminothiazole, with the aim of assessing the importance of the substitution of the sulphur atom with oxygen in terms of activity, cytotoxicity and metabolic profile. Surprisingly, only a few similar structures are reported in the literature, and the small set of procedures retrieved had many reproducibility issues, therefore being of limited usefulness. Therefore, I have first developed a new synthetic strategy to obtain the 2-aminooxazole scaffold substituted at C-4; then, I have extended the same methodology to other substituent patterns, confirming the versatility of this synthetic strategy. Finally we used this approach to synthesize the 2-aminooxazoles bearing those substituents that grant the best activity in the case of the 2-aminothiazole series