Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as Sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of Sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds.

Sirtuins are nicotinamide adenine dinucleotide (NAD⁺)-dependent class III histone deacetylases and have been linked to the pathogenesis of numerous diseases such as HIV, metabolic disorders, neurodegeneration and cancer. Docking of the virtual pan-African natural products library (p-ANAPL), followed by in vitro testing, resulted in the identification of two inhibitors of sirtuin 1, 2 and 3 (sirt1-3). Two bichalcones; rhuschalcone IV (8) and rhuschalcone I (9), previously isolated from the medicinal plant Rhus pyroides, were shown to be active in the in vitro assay, with rhuschalcone I showing the best activity against sirt1, having an IC₅₀ = 40.8 µM. Based on the docking experiments, suggestions for improving the biological activities of the newly identified hit compounds have been provided.