Monocarbonyl curcuminoids as antituberculosis agents with their moderate in‐vitro metabolic stability on human liver microsomes

Abstract

Tuberculosis, an airborne infectious disease, results in a high morbidity and mortality rate. The continuous emergence of TB resistance strains including MDR (multidrugresistant tuberculosis), XDR (extensive drug-resistant tuberculosis), and especially TDR (totally drug-resistant tuberculosis) is a major public health threat and has intensified the need to develop new antitubercular agents. A natural product, curcumin, possesses diverse biological activities but suffers due to a lack of water solubility and bioavailability.To overcome these limitations, a series of 17 water-soluble monocarbonyl curcuminoids was synthesized and evaluated for antimycobacterial activity. All compounds exhibited good to moderate anti-TB activity with MIC 99 in the range of 3.12-25.0 µM, out of which 7c and 7p were found the most potent compounds with MIC 99 in the range of 3.12-6.25 µM. Furthermore, these compounds were observed to be nonhaemolytic, nontoxic, and stable under both physiological as well as reducing conditions. In-vitro metabolic stability data of the representative compound 7p with the human liver microsome revealed that these compounds possess a moderate metabolism with a half-life of 1.2 h and an intrinsic clearance of 1.12 ml/h/mg.

Targeted Screening of Curcumin Derivatives as Pancreatic Lipase Inhibitors Using Computer-Aided Drug Design

“…The determination of the structural derivatives of curcumin was obtained through the compilation of relevant research literature. Alterations in the quantity of methoxy and hydroxy groups on the phenyl ring substituents of curcumin exhibited varying degrees of influence on its polarity, water solubility, and pharmacological efficacy. − Monocarbonyl curcumin, dihydrocurcumin, tetrahydrocurcumin, and octahydrocurcumin had been demonstrated to outperform curcumin in terms of stability, bioavailability, and activity. − Based on the aforementioned reasons, we had identified the substitution positions and quantities of methoxy and hydroxy groups on the phenyl ring of curcumin as well as structural modifications of double bonds and β-diketones on the backbone. Ultimately, curcumin derivatives were obtained through a linear arrangement for CADD analysis.…”

Diarylpentanoids, the privileged scaffolds in antimalarial and anti‐infectives drug discovery: A review

“…Moreover, the antimycobacterial activity was decreased by adding a methoxy group to the aromatic ring, while replacing the methoxy group with an ethoxy group had no significant effect. [ 156 ]…”

Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities

“…The authors reported that these compounds are nonhemolytic, nontoxic, and stable under physiological and reducing conditions. Apart from that, compound 89 has moderate in vitro metabolism by liver human microsomes (halflife of 1.2 h; intrinsic clearance of 1.12 mL/h/mg) [69].…”