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High-throughput biology has contributed a wealth of data on chemicals, including natural products (NPs). Recently, attention was drawn to certain, predominantly synthetic, compounds that are responsible for disproportionate percentages of hits but are false actives. Spurious bioassay interference led to their designation as pan-assay interference compounds (PAINS). NPs lack comparable scrutiny, which this study aims to rectify. Systematic mining of 80+ years of the phytochemistry and biology literature, using the NAPRALERT database, revealed that only 39 compounds represent the NPs most reported by occurrence, activity, and distinct activity. Over 50% are not explained by phenomena known for synthetic libraries, and all had manifold ascribed bioactivities, designating them as invalid metabolic panaceas (IMPs). Cumulative distributions of ∼200,000 NPs uncovered that NP research follows power-law characteristics typical for behavioral phenomena. Projection into occurrence–bioactivity–effort space produces the hyperbolic black hole of NPs, where IMPs populate the high-effort base.

A recent article by Baell(1) on the problems experienced by medicinal chemists with pan-assay interference compounds (PAINS) and Shoichet’s work(2) on the impact of aggregation occurring in high throughput screening libraries, prompts a consideration of how these and other similar problems are experienced by pharmacognosists with promiscuous invalid metabolites as panaceas (PIMPs). Contrary to the classical definition of secondary metabolites as being species specific (or near specific), several natural products, particularly in the more extensively investigated plant kingdom, are common across species, genera, and even families (e.g. β-sitosterol). In the course of bioactivity-guided fractionation, PIMPs have shown up as major components in active fractions of a wide variety of pharmacological assays, i.e., they have been designated as panaceas. As in the case of PAINS, these assay results are almost invariably invalid and lead enthusiastic young scientists down a garden path. Why does this happen and how can it be avoided? Interestingly, the advances in modern methods of structure determination have exacerbated this problem, because it is possible to determine the structure of a compound when it is quite impure, and residual complexity is characteristic of chromatographic fractionation. That these residuals are often the source of the bioactivity is also frequently overlooked. Classic examples where this has occurred and ways to avoid it will be outlined.

Microglia-driven inflammatory processes are thought to play an important role in ageing and several neurological disorders. Since consumption of a diet rich in polyphenols has been associated with anti-inflammatory and neuroprotective effects, we studied the effects of twenty-five stilbenoids isolated from Milicia excelsa, Morus alba, Gnetum africanum, and Vitis vinifera. These compounds were tested at 5 and 10 µM on BV-2 microglial cells stimulated with bacterial lipopolysaccharide. Ten stilbenoids reduced lipopolysaccharide-induced nitric oxide production at 5 and/or 10 µM. Two tetramers, E-vitisin A and E-vitisin B, were the most effective molecules. Moreover, they attenuated the expression of the inducible NO synthase protein and gene.

The interaction between Vitis vinifera and trunk disease fungi requires better understanding. We studied the role of phenolics as possible plant defense compounds in this context. The impact of 24 grapevine phenolic compounds was determined on 6 major wood decay fungi by an in vitro agar plate assay. Hydroxystilbenoids, especially oligomers such as miyabenol C, isohopeaphenol, and vitisin A and B, greatly reduced the growth of the fungi, except that of Phaeoacremonium aleophilum. A detailed investigation in 10 Botryosphaeriaceae strains revealed that all of the studied members of this family display a common susceptibility to phenolics that is more or less significant. Then we undertook a quantitative analysis of stilbenoid content in grapevine plantlets inoculated with Botryosphaeriaceae to investigate whether in planta these fungi have to counteract the most active phenolics. On the basis of our results, the possible role of phenolics in grapevine defense against trunk disease agents is discussed.