Project title

From Design to Synthesis of New Antitubercular Agents

Scientific Coordinator's name:

Filomena Elisabete Lopes Martins Elvas Leitão

Scientific Coordinator's e-mail:

filomena.martins@ciencias.ulisboa.pt

Principal R&D Unit:

Centro de Química e Bioquímica (CQB)

Other R&D Units involved in the project:

Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa; Instituto de Higiene e Medicina Tropical; Faculdade de Farmácia da Universidade de Lisboa

Project keyword(s)

Antitubercular compounds; QSARs; Rational design; Synthesis; Biological activity; Mycobacterium tuberculosis; Resistance; Isoniazid derivatives; Medicinal Chemistry

Short abstract and comments

The project aimed at the development of very robust, predictive and well-validated quantitative structure-activity relationships (QSARs) that assisted us in the design of a series of new potentially active antitubercular compounds from particular relevant core structures, namely, isoniazid, thiobenzanilide, benzimidazole and indole scaffolds. From this QSAR-oriented design approach, the most promising compounds were synthesized and their in vitro antibacterial activities assessed. These experimental values were then confronted with the predicted values provided by our models. In the course of the project, the team became primarily interested on isoniazid derivatives since the first results obtained for these compounds exceeded our expectations. In fact, some of these derivatives were shown to be more active against the H37Rv strain of Mycobacterium tuberculosis (Mtb) than the reference compound, isoniazid (INH). Additionally, and very interestingly, some among these have also proved to be more effective than INH against a Mtb clinical strain carrying only a katG S315Tmutation, the most frequent mutation in clinical settings which is responsible for ca. 50?90% of INH resistance worldwide. One of the most important results of the project was the finding of a compound, N?-decanoylisonicotinohydrazide - an INH derivative with an alkyl chain in C10 - that was six times more active than INH in this resistant strain. This is a remarkable result that makes this compound a very promising lead compound for drug development. This finding cannot be overlooked given the very recent and disturbing update on tuberculosis figures (WHO, Global Tuberculosis Report, 2016): 10.4 million people developed TB in 2014 and 1.8 million died from the disease in the same period of time. Moreover, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mtb all over the world, together with significant levels of co-infection with HIV, makes the search for new antitubercular drugs a major public health challenge.

Potential uses/indications

In spite of a few new antitubercular candidates in phase II and III of the clinical global TB drug pipeline, isoniazid (INH), first synthesized in 1952, is still the treatment of choice for TB and is part of all WHO multidrug recommended regimens. However, Mycobacterium tuberculosis has been showing through the years increased resistance to isoniazid. So, any smart modifications in the INH core structure in order to obtain new compounds both with improved activity and able to circumvent resistance, as is the case of our best compound, and which can be used as alternatives to INH in those multidrug regimens, is certainly of invaluable interest and would have a tremendous worldwide social and economic impact.