ConspectusIndole alkaloids, one of the largest classes of alkaloids, serve as an important and rich source of pharmaceuticals and have inspired synthetic chemists to develop novel chemical transformations and synthetic strategies. Many biologically active natural products contain challenging indoline scaffolds, which feature a C3 all-carbon quaternary stereocenter that is often surrounded by a complicated polycyclic ring system. The creation of this quaternary stereocenter creates an inherent synthetic challenge because the substituents on the carbon center cause high steric repulsion. In addition, the presence of nitrogen atoms within the surrounding polycyclic rings can lead to synthetic difficulties.Oxidative coupling between two sp3-hybridized carbon anions provides a unique and powerful method for building C–C single bonds, especially for generating a C–C bond that joins one or two vicinal quaternary stereocenters. Although chemists have known of this transformation for a long time, they have only ap...

Intramolecular dearomative oxidative coupling of indoles: a unified strategy for the total synthesis of indoline alkaloids.

β-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)

Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for new, more affordable and accessible antimalarial agents possessing original modes of action. Natural products have played a dominant role in the discovery of leads for the development of drugs to treat human diseases, and this fact anticipates that new antimalarial leads may certainly emerge from tropical plant sources. This present review covers most of the recently-published non-alkaloidal natural compounds from plants with antiplasmodial and antimalarial properties, belonging to the classes of terpenes, limonoids, flavonoids, chromones, xanthones, anthraquinones, miscellaneous and related compounds, besides the majority of papers describing antiplasmodial crude extracts published in the last five years not reviewed before. In addition, some perspectives and remarks on the development of new drugs and phytomedicines for malaria are succinctly discussed.

https://www.mdpi.com/1420-3049/14/8/3037/pdf

Plant-derived antimalarial agents: new leads and efficient phytomedicines. Part II. Non-alkaloidal natural products.

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined by the WHO. Furthermore, malaria (caused by various Plasmodium species) can be considered a neglected disease in certain countries and with regard to availability and affordability of the antimalarials. Living organisms, especially plants, provide an innumerable number of molecules with potential for the treatment of many serious diseases. The current review attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs. In part I, a general description of the diseases, the current state of therapy and need for new therapeuticals, assay methods and strategies applied in the search for new plant derived natural products against these diseases and an overview on natural products of terpenoid origin with antiprotozoal potential were given. The present part II compiles the current knowledge on natural products with antiprotozoal activity that are derived from the shikimate pathway (lignans, coumarins, caffeic acid derivatives), quinones of various structural classes, compounds formed via the polyketide pathways (flavonoids and related compounds, chromenes and related benzopyrans and benzofurans, xanthones, acetogenins from Annonaceae and polyacetylenes) as well as the diverse classes of alkaloids. In total, both parts compile the literature on almost 900 different plant-derived natural products and their activity data, taken from over 800 references. These data, as the result of enormous efforts of numerous research groups world-wide, illustrate that plant secondary metabolites represent an immensely rich source of chemical diversity with an extremely high potential to yield a wealth of lead structures towards new therapies for NTDs. Only a small percentage, however, of the roughly 200,000 plant species on earth have been studied chemically and only a small percentage of these plants or their constituents has been investigated for antiprotozoal activity. The repository of plant-derived natural products hence deserves to be investigated even more intensely than it has been up to present.

The Potential of Secondary Metabolites from Plants as Drugs or Leads Against Protozoan Neglected Diseases – Part I

Wild Syrian rue (Peganum harmala L. family Zygophyllaceae) is well-known in Iran and various parts of this plant including, its seeds, bark, and root have been used as folk medicine. Recent years of research has demonstrated different pharmacological and therapeutic effects of P. harmala and its active alkaloids, especially harmine and harmaline. Analytical studies on the chemical composition of the plant show that the most important constituents of this plant are beta-carboline alkaloids such as harmalol, harmaline, and harmine. Harmine is the most studied among these naturally occurring alkaloids. In addition to P. harmala (Syrian rue), these beta-carbolines are present in many other plants such as Banisteria caapi and are used for the treatment of different diseases. This article reviews the traditional uses and pharmacological effects of total extract and individual active alkaloids of P. harmala (Syrian rue).

Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids.

Bioassay-guided purification from the seeds of Peganum harmala led to the isolation of harmine (1), harmaline (2), vasicinone (3), and deoxyvasicinone (4). Harmine (1) and harmaline (2) showed a moderate in vitro antiplasmodial activity against Plasmodium falciparum. Quinazoline alkaloid, vasicinone (3), showed a vasorelaxant activity against phenylephrine-induced contraction of isolated rat aorta.

Alkaloids from the seeds of Peganum harmala showing antiplasmodial and vasorelaxant activities

From the fruits of Phaleria macrocarpa, icariside C3 (1), phalerin (2), and mangiferin (3) were isolated and their structures were identified on the basis of spectroscopic data. Icariside C3 (1) showed a slow vasorelaxant activity against noradrenaline-induced contraction of isolated rat aorta. The structure of phalerin (2) was revised as 2,4′,6-trihydroxy-4-methoxybenzophenone-2-O-β-d-glucoside.

Studies on the constituents from the fruits of Phaleria macrocarpa

A cyclic depsipeptide, FR900359, isolated from Ardisia crenata was evaluated for vasorelaxant effects on rat aortic arteries. FR900359 caused concentration-dependent relaxation (1 nM–10 μM) in phenylephrine-precontracted endothelium-intact aortic rings, which was inhibited by addition of l-NMMA, a NOS inhibitor. In endothelium-denuded rings, the relaxant effect of low concentrations of FR900359 was diminished, but remained at high concentrations. In endothelium-denuded rings, FR900359 at 0.1 μM significantly attenuated high-K+-induced contractions and completely inhibited Ca2+-induced contractions. These results suggest that the vasorelaxant effect of FR900359 is mediated through the increased release of NO from endothelial cells at low concentrations, and can be attributed to inhibitory effects on voltage-dependent Ca2+ channel- and receptor-operated Ca2+ channel-dependent Ca2+ influx at high concentrations.

Vasorelaxant effect of FR900359 from Ardisia crenata on rat aortic artery.

Sucutiniranes A and B, new cassane-type diterpenes from Bowdichia nitida.

Four new cassane-type diterpenes, sucutiniranes C-F (3-6), have been isolated from seeds of Bowdichia nitida, and their structures were elucidated by using 2D NMR data, chemical correlations, and X-ray analysis. Sucutiniranes E (5) and F (6) were moderately cytotoxic against human blood premyelocytic leukemia (HL-60), breast adenocarcinoma (MCF-7), and colon cancer (HCT-116) cells.

Yosuke Matsuno

Papers

Alkaloids from the seeds of Peganum harmala showing antiplasmodial and vasorelaxant activities

Studies on the constituents from the fruits of Phaleria macrocarpa

Vasorelaxant effect of FR900359 from Ardisia crenata on rat aortic artery.

Sucutiniranes A and B, new cassane-type diterpenes from Bowdichia nitida.

Sucutiniranes C-F, cassane-type diterpenes from Bowdichia nitida.