Synthesis and biological evaluation of new enantiomerically pure azole derivatives as inhibitors of Mycobacterium tuberculosis (original) (raw)

2009, Bioorganic & medicinal …

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole. Tuberculosis (TB) is a common and deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Over one-third of the world's population has been exposed to the TB bacterium, and new infections occur at a rate of one per second. 1 In 2005, mortality and morbidity statistics included 14.6 million chronic active TB cases, 8.9 million new cases, and 1.6 million deaths, mostly in developing countries. 2 In addition, the rising number of people who are contracting TB because of their immune systems compromised by immunosuppressive drugs or substance abuse or HIV/AIDS, is a serious threat to TB control and prevention. Moreover the emergence of multi-drug resistance TB (MDR-TB), defined as resistance to at least isoniazid and rifampin, and the extensively drug resistant (XDR-TB) strains make the discovery and the development of new drugs a priority. 3 In the last few years, the determination of the genome sequence of Mycobacterium tuberculosis 4,5 (MTB) provided a much needed boost for research into new drug targets against this pathogen. In particular, recent promising data suggest that targeting the lipid metabolism pathways of MTB may provide an excellent route to attenuating or killing the bacterium. The genome of MTB encodes for a relatively large number of cytochrome P450 enzymes. These data indicate important physiological roles for these enzymes which, given that the substrate preference of the majority of P450s is for hydrophobic molecules, most are likely to be involved in lipid metabolism. McLean and co-workers cloned and expressed MTB CYP51 and CYP121, two types of P450 from MTB. 6 They demonstrated that CYP51 and CYP121 bind azole antifungal drugs tightly and that azole compounds are potent inhibitor of cell growth of Mycobacterium bovis and Mycobacterium smegmatis, two mycobacterial species which closely resemble MTB. Azole drugs proved to have also antitubercular activities in mice. 7 Finally, recent studies furnished the crystal structure of MTB cytochrome P450 CYP121 in complex with the fluconazole. 8 It has been found that MTB-CYP121 binds commercially available azole drugs as clotrimazole or econazole and that it may be the true target for the antimycobacterial activity of the azoles in vivo as suggested by gene-knockout studies. In this context, as a continuation of our previous works on the discovery of new antimicrobial agents, 11,12 we decided to focus our attention on the synthesis and preliminary biological evaluation against MTB of novel azole analogues with polycyclic structure A which resemble the classical antifungal/antibacterial azole drugs . Being the target compounds chiral, we were also attracted by the possibility of synthesizing these derivatives in enantiomerically pure form in order to evaluate the biological profile of the single enantiomers.