Natural products (NP’s) continue to represent an excellent source for lead structures in drug discovery. In between 1981-2002 only 5% NCE were FDA approved natural products and 23% were natural product derivatives. There are only few cases, where NPs serve directly as drugs, but many of the drugs are the structural analogues and or mimics. For a better drug or lead compound, the molecule should possess not only high potency but also contain other properties like being non-toxic, oral bioavailability (solubility, membrane permeability) and with efficient ADME (Absorption, Distribution, Metabolism, and Excretion). To address these issues, structural modification of NPs has been undoubtedly playing pivotal role for the development of efficient modern medicine. Structural analogues of natural products can give inputs for the clear picture of molecular mechanistic to a medicinal chemist.
Literature is full of examples wherein the modification of a natural product has led to a drug with optimized or minimized toxicities, better drug delivery or higher potency. Artemisinin is only sparingly soluble in water or oil and not well absorbed by the gastro-intestinal tract. Chemical modification of artemisinin led to more potent, better bioavailable analogues such as artemether, arteether, sodium artesunate, fluoroanilide derivative.
Structural modification of betulinic acid resulted in the discovery of most potent anti-HIV drug 3-O-(3’, 3’-dimethylsuccinyl)-betulinic acid (bevirimat, DSB, PA-457), another triterpenoid structural modification led to development of bardoxlone methyl for type 2 diabetes mellitus.
Therapeutic application of unmodified camptothecin is hindered by very low solubility in aqueous media, high toxicity, and rapid inactivation through lactone ring hydrolysis at physiological pH. Chemical modification of camptothecin led to more water-soluble analogs topotecan (Hycamtin), irinotecan (Camptosar).
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