abstract
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains one of the top ten causes of death worldwide and the main cause of mortality from a single infectious agent. The upsurge of multi- and extensively-drug resistant tuberculosis cases calls for an urgent need to develop new and more effective antitubercular drugs. As the cinnamoyl scaffold is a privileged and important pharmacophore in medicinal chemistry, some studies were conducted to find novel cinnamic acid derivatives (CAD) potentially active against tuberculosis. In this context, we have engaged in the setting up of a quantitative structure-activity relationships (QSAR) strategy to: (i) derive through multiple linear regression analysis a statistically significant model to describe the antitubercular activity of CAD towards wild-type Mtb; and (ii) identify the most relevant properties with an impact on the antitubercular behavior of those derivatives. The best-found model involved only geometrical and electronic CAD related properties and was successfully challenged through strict internal and external validation procedures. The physicochemical information encoded by the identified descriptors can be used to propose specific structural modifications to design better CAD antitubercular compounds.
keywords
DIFFERENT VALIDATION CRITERIA; REAL EXTERNAL PREDICTIVITY; ISONIAZID DERIVATIVES; APPLICABILITY DOMAIN; MULTIDRUG-RESISTANT; ACID-DERIVATIVES; QSAR MODELS; TUBERCULOSIS; DESIGN; OUTLIERS
subject category
Biochemistry & Molecular Biology; Chemistry
authors
Teixeira, C; Ventura, C; Gomes, JRB; Gomes, P; Martins, F
our authors
Cátia Teixeira
Post-doc Fellowship
José R. B. Gomes
Principal Researcheracknowledgements
This research was funded by Fundacao para a Ciencia e Tecnologia (FCT), Portugal, grants UID/QUI/50006/2019, PTDC/BTM-SAL/29786/2017, PTDC/QUI/67933/2006, and PTDC/MED-QUI/29036/2017.