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.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the most devastating infectious diseases, which currently still has high mortality levels [1]
This is the case of the fluoroquinolones gatifloxacin and moxifloxacin, marketed in 1999 for the treatment of respiratory tract infections, and which are presently the most valuable second-line anti-TB agents according to the World Health Organization (WHO) guidelines [7]
Following our experience in the establishment of biologically relevant quantitative structure–activity relationships (QSAR) [20,21,22,23], we have engaged in the setting up of a QSAR strategy to: (i) derive a statistically significant model to describe the antitubercular activity of cinnamic acid derivatives (CAD) towards wild-type Mtb; and (ii) identify the most relevant properties that have a substantial effect on the antitubercular activity of those derivatives
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the most devastating infectious diseases, which currently still has high mortality levels [1]. As the cinnamoyl scaffold is a privileged and important pharmacophore in medicinal chemistry, in recent years CAD have attracted much attention due to their antitumoral, antioxidative, and antimalarial properties [17,18,19] In this context, and following our experience in the establishment of biologically relevant quantitative structure–activity relationships (QSAR) [20,21,22,23], we have engaged in the setting up of a QSAR strategy to: (i) derive a statistically significant model to describe the antitubercular activity of CAD towards wild-type (wt) Mtb; and (ii) identify the most relevant properties that have a substantial effect on the antitubercular activity of those derivatives. We depict the details of the construction and validation of an MLR-based model to describe the antitubercular activity of a set of CAD and the analysis of the model’s descriptors
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