Potential of nitrobenzoic acid derivatives as antituberculosis drugs. Insights into the mechanism of action

  • Constantino, Luís (PI)
  • Pais, João P. (CoPI)
  • Do Nascimento Cardoso Guedes, Rita Alexandra R.A. (CoPI)
  • Francisco, Ana Paula Gameiro A.P.G. (CoPI)
  • Dos Santos, Maria Manuel Duque Vieira Marques M.M.D.V.M. (CoPI)
  • Pires, David (Researcher)
  • Dos Santos Anes, Elsa Maria Ribeiro E.M.R. (CoPI)

Project Details

Description

One of the few positive things that the current Covid19 pandemic brought, was to make us all more aware of the urge to address inequalities across the human population. Tuberculosis TB places its heaviest burden on the world’s most poor and vulnerable, aggravating existing inequalities and because of that, the United Nations Sustainable Development Goals SDGs explicitly includes ending the TB epidemic by 2030 under Goal 3.

Every year tuberculosis kills 1.2 million people among HIV negative people and more than 8% are due to multi-drug resistant TB MDR-TB, a form of the disease that is extremely difficult to treat and is regarded as a death sentence in many developing countries.

Alternatives to treat this disease are urgently needed, unfortunately the development of new drugs from scratch is not always seen as feasible for the industry as the target population do not have the power purchase that would allow the return of the large investment that is needed.

We have been developing with success ester prodrugs of pyrazinoic acid that addressed efficiently pyrazinamide resistance and demonstrated activities higher than the reference pyrazinamide molecule. Due to the good results and the fact that other weak acids, also demonstrated activity against TB, but have difficulties penetrating the mycobacterial cell, we decided to apply the same ester prodrug approach to those acids and were able to increase their activity.

We proved that mycobacteria can activate the esters to the corresponding acids and that the rate of hydrolysis can be tuned by modifications in the alcoxy group. An explanation for the activity of weak acids against tuberculosis is the acidification of mycobacterial intracellular environment and the disruption of transport systems. Esters could act as transporters of the acids, hence we prepared esters from organic acids with different pKa and found compounds wit a very interesting activity against M.tuberculosis.

Molecules containing a dinitrobenzamide group like DNB1 are a new group of important candidates to antitubercular drugs Dinitrobenzamides, DNBs, described as inhibitors of the enzyme decaprenylphosphoryl-beta-D-ribose oxidase dprE1. We propose to obtain a library of compounds with structures derived from our compounds and from highly active DNBs, such as DNB1. Hence, we propose an exploratory project to develop the compounds and obtain insights from the mechanism of action of our compounds.

We plan to obtain hibrids of our active compounds with a known dprE1 inhibitor DNB, as well as hybrids with other described DNBs. This library of compounds will allow several biological assays to be performed, aimed at comparing the bioactivity of previously developed and new compounds to a known dprE1 inhibitor, providing essential clues about the mode of action of such compounds.

The assessment will be based in the determination of the minimal inhibitory concentration MIC and minimal bactericidal concentration MBC values and growth curves for all compounds against M. tuberculosis control strain, using well-known methodologies. The antimycobacterial activity of a selected group of compounds will be further studied in multiple mycobacterial strains, namely, M. bovis BCG, M. smegmatis and M. avium, as well as other bacterial strains resistant to dprE1 inhibitors. Also, bacterial kill kinetics will be assessed for the most promising compounds, to select the lead compounds. This data will establish a robust bioactivity profile validating or disproving dprE1 as the molecular target.

As the structure of dprE1 is known we also propose to perform docking studies of our starting compounds and of the whole library aimed at developing optimization strategies for these compounds and propose, at the at the end of the project, new potential compounds to be developed in a further study.

StatusFinished
Effective start/end date1/04/2230/09/23

Collaborative partners

Funding

  • Fundação para a Ciência e a Tecnologia: €49,958.00

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

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