ABSTRACT
Abstract The modern process of new drug discovery and development is an exciting, yet a challenging, endeavor. Although it can result in significant financial income and meet the medical needs of patients, it ultimately may result in failure. To achieve a fast and successful new product discovery and development process, natural products which are evolutionarily optimized as drug-like molecules have gained great attention as better potential sources of new chemical entities. Historically, plant species containing berberine are used in various traditional phytotherapy. However, despite the various therapeutic effects it exerts, berberine is not yet developed into a drug product. Addressing the barriers that hinder its successful development and the efforts made to overcome them is thus crucial. The toxicological and pharmacokinetic properties of berberine are the main barriers towards its development into a marketed drug product. It has low aqueous solubility, poor absorption, fast metabolism, and wide tissue distribution which lead to low bioavailability limiting its clinical application. Synthetic berberine derivatives with improved properties are suggested as better alternatives for further development and future therapeutic application. Hence, this paper summarizes the preclinical research studies conducted in the last decade to reveal the therapeutic potential of synthetic berberine derivatives for the treatment of various diseases and hence achieve successful berberine-based drug development in the future. To exploit the value of natural products as a source of leads for the development of effective drugs, collaboration among the different discovery and development scientists is essential.