Herein we report a novel strategy for the design and construction of natural and natural product-like libraries based on the principle of privileged structures, a term originally introduced to describe structural motifs capable of interacting with a variety of unrelated molecular targets. The identification of such privileged structures in natural products is discussed, and subsequently the 2,2-dimethylbenzopyran moiety is selected as an inaugural template for the construction of natural product-like libraries via this strategy. Initially, a novel solid-phase synthesis of the benzopyran motif is developed employing a unique cycloloading strategy that relies on the use of a new, polystyrene-based selenenyl bromide resin. Once the loading, elaboration, and cleavage of these benzopyrans was established, this new solid-phase method was then thoroughly validated through the construction of six focused combinatorial libraries designed around natural and designed molecules of recent biological interest.

Natural Product-like Combinatorial Libraries Based on Privileged Structures. 1. General Principles and Solid-Phase Synthesis of Benzopyrans

Coumarin (2H-1-benzopyran-2-one) is a plant-derived natural product known for its pharmacological properties such as anti-inflammatory, anticoagulant, antibacterial, antifungal, antiviral, anticancer, antihypertensive, antitubercular, anticonvulsant, antiadipogenic, antihyperglycemic, antioxidant, and neuroprotective properties. Dietary exposure to benzopyrones is significant as these compounds are found in vegetables, fruits, seeds, nuts, coffee, tea, and wine. In view of the established low toxicity, relative cheapness, presence in the diet, and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.

https://downloads.hindawi.com/journals/bmri/2013/963248.pdf

Review on natural coumarin lead compounds for their pharmacological activity

Several hundred plant and herb species that have potential as novel antiviral agents have been studied, with surprisingly little overlap. A wide variety of active phytochemicals, including the flavonoids, terpenoids, lignans, sulphides, polyphenolics, coumarins, saponins, furyl compounds, alkaloids, polyines, thiophenes, proteins and peptides have been identified. Some volatile essential oils of commonly used culinary herbs, spices and herbal teas have also exhibited a high level of antiviral activity. However, given the few classes of compounds investigated, most of the pharmacopoeia of compounds in medicinal plants with antiviral activity is still not known. Several of these phytochemicals have complementary and overlapping mechanisms of action, including antiviral effects by either inhibiting the formation of viral DNA or RNA or inhibiting the activity of viral reproduction. Assay methods to determine antiviral activity include multiple-arm trials, randomized crossover studies, and more compromised designs such as nonrandomized crossovers and pre- and post-treatment analyses. Methods are needed to link antiviral efficacy/potency- and laboratory-based research. Nevertheless, the relative success achieved recently using medicinal plant/herb extracts of various species that are capable of acting therapeutically in various viral infections has raised optimism about the future of phyto-antiviral agents. As this review illustrates, there are innumerable potentially useful medicinal plants and herbs waiting to be evaluated and exploited for therapeutic applications against genetically and functionally diverse viruses families such as Retroviridae, Hepadnaviridae and Herpesviridae

Novel antiviral agents: a medicinal plant perspective

The mechanism of inhibition of HIV-1 reverse transcriptase by three nonnucleoside inhibitors is described. Nevirapine, O-TIBO, and CI-TIBO each bind to a hydrophobic pocket in the enzyme-DNA complex close to the active site catalytic residues. Pre-steady-state kinetic analysis was used to establish the mechanism of inhibition by these noncompetitive inhibitors. Analysis of the pre-steady-state burst of DNA polymerization indicated that inhibitors blocked the chemical reaction, but did not interfere with nucleotide binding or the nucleotide-induced conformational change. Rather, in the presence of saturating concentrations of the inhibitors, the nucleoside triphosphate bound tightly (Kd, 100 nM), but nonproductively. The data suggest that an inhibitor combining the functionalities of a nonnucleoside inhibitor and a nucleotide analog could bind very tightly and specifically to reverse transcriptase and could be effective in the treatment of AIDS.

https://science.sciencemag.org/content/sci/267/5200/988.full.pdf

Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors

This review examines the recent investigations on the biological activities of extracts and chemicals identified from mangroves (mangroves, mangrove minors and mangal associates). It describes how people have and are using mangroves on a traditional basis. It also describes the world's mangrove resources and products, in terms of their economical importance, medicinal values and other uses and functions. The economical uses of products from mangrove ecosystems are many and varied. Traditionally, the mangroves have been exploited for firewood and charcoal. Use has also been found for mangroves in the construction of dwellings, furniture, boats and fishing gear, tannins for dyeing and leather production. The mangroves provide food and wide variety of traditional products and artefacts for the mangrove dwellers. Extracts and chemicals from mangroves are used mainly in folkloric medicine (e.g. bush medicine), as insecticides and piscicides and these practices continue to this day. However the extraction of novel natural chemical compounds from mangroves, in addition to those already known to the pharmacopoeia of the people is in its infancy. A knowledge of the biological activities and/or chemical constituents of plants is desirable, not only for the discovery of new therapeutic agents, but because such information may be of value in disclosing new sources of already known biologically active compounds. It is of further value to those interested in “deciphering” the actual value of folkloric remedies.

Traditional and medicinal uses of mangroves

As part of a search for novel inhibitors of HIV-1 reverse transcriptase, the acetone extract of the giant African snail, Achatina fulica, was shown to be active. Fractionation of the extract yielded inophyllums A, B, C, and E and calophyllolide (1a, 2a, 3a, 3b, and 6), previously isolated from Calophyllum inophyllum Linn., a known source of nutrition for A. fulica. From a methanol/methylene chloride extract of C. inophyllum, the same natural products in considerably greater yield were isolated in addition to a novel enantiomer of soulattrolide (4), inophyllum P (2b), and two other novel compounds, inophyllums G-1 (7) and G-2 (8). The absolute stereochemistry of inophyllum A (1a) was determined to be 10(R), 11(S), 12(S) from a single-crystal X-ray analysis of its 4-bromobenzoate derivative, and the relative stereochemistries of the other inophyllums isolated from C. inophyllum were established by a comparison of their 1H NMR NOE values and coupling constants to those of inophyllum A (1a). Inophyllums B and P (2a and 2b) inhibited HIV reverse transcriptase with IC50 values of 38 and 130 nM, respectively, and both were active against HIV-1 in cell culture (IC50 of 1.4 and 1.6 microM). Closely related inophyllums A, C, D, and E, including calophyllic acids, were significantly less active or totally inactive, indicating certain structural requirements in the chromanol ring. Altogether, 11 compounds of the inophyllum class were isolated from C. inophyllum and are described together with the SAR of these novel anti-HIV compounds.

The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum Linn

Kinetic and mutational analysis of human immunodeficiency virus type 1 reverse transcriptase inhibition by inophyllums, a novel class of non-nucleoside inhibitors

P B Taylor

Papers

The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum Linn

Kinetic and mutational analysis of human immunodeficiency virus type 1 reverse transcriptase inhibition by inophyllums, a novel class of non-nucleoside inhibitors