Orazio Taglialatela-Scafati

Marine Pharmacology in 2009-2011: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action †

The peer-reviewed marine pharmacology literature from 2009 to 2011 is presented in this review, following the format used in the 1998–2008 reviews of this series. The pharmacology of structurally-characterized compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities were reported for 102 marine natural products. Additionally, 60 marine compounds were observed to affect the immune and nervous system as well as possess antidiabetic and anti-inflammatory effects. Finally, 68 marine metabolites were shown to interact with a variety of receptors and molecular targets, and thus will probably contribute to multiple pharmacological classes upon further mechanism of action studies. Marine pharmacology during 2009–2011 remained a global enterprise, with researchers from 35 countries, and the United States, contributing to the preclinical pharmacology of 262 marine compounds which are part of the preclinical pharmaceutical pipeline. Continued pharmacological research with marine natural products will contribute to enhance the marine pharmaceutical clinical pipeline, which in 2013 consisted of 17 marine natural products, analogs or derivatives targeting a limited number of disease categories.

An NMR Spectroscopic Method to Identify and Classify Thiol‐Trapping Agents: Revival of Michael Acceptors for Drug Discovery?

Although Michael acceptors are traditionally shunned in modern drug discovery, trapping of thiols by covalent coupling represents an important mechanism of bioactivity, and many biologically relevant and druggable pathways are targeted by thiol-reactive compounds. Research on Michael acceptors, long confined to the realm of toxicology, was rekindled by the development of the antioxidant inflammation modulator (AIM) homo-triterpenoid bardoxolone methyl (RTA402, 1). This orally bioavailable biological

Dispacamides, anti-histamine alkaloids from Caribbean Agelas sponges

Abstract Dispacamide 1 and its monobromo derivative 2 , are novel bromopyrrole alkaloids containing an aminoimidazolone moiety. They were isolated from four Caribbean Agelas sponges ( A. conifera, A. longissima, A. clathrodes, A. dispar ), and their structures elucidated on the basis of spectroscopic data. Compounds 1 and 2 exhibit remarkably selective antihistamine activity, tested on the guinea pig ileum.

Two novel pyrrole-imidazole alkaloids from the Mediterranean sponge Agelas oroides

The novel pyrrole-imidazole alkaloids cyclooroidin (7) and taurodispacamide A (8) have been isolated from the Mediterranean sponge Agelas oroides, and their structures established from spectroscopic data. Although both these alkaloids may be conceived as derivatives of the C11N5 skeleton of the known oroidin (1), remarkably cyclooroidin (7) possesses the unprecedented N1/C9 connection. Taurodispacamide A (8) exhibited a good antihistaminic activity, tested on the isolated guinea pig ileum.

Bromopyrrole Alkaloids as Lead Compounds against Protozoan Parasites

In the present study, 13 bromopyrrole alkaloids, including the oroidin analogs hymenidin (2), dispacamide B (3) and dispacamide D (4), stevensine (5) and spongiacidin B (6), their derivatives lacking the imidazole ring bromoaldisin (7), longamide B (8) and longamide A (9), the dimeric oroidin derivatives sceptrin (10) and dibromopalau’amine (11), and the non-oroidin bromopyrrolohomoarginin (12), manzacidin A (13), and agelongine (14), obtained from marine sponges belonging to Axinella and Agelas genera have been screened in vitro against four parasitic protozoa, i.e., two Trypanosoma species (T. brucei rhodesiense and T. cruzi), Leishmania donovani and Plasmodium falciparum (K1 strain, a chloroquine resistant strain), responsible of human diseases with high morbidity and, in the case of malaria, high mortality. Our results indicate longamide B (8) and dibromopalau’amine (11) to be promising trypanocidal and antileishmanial agents, while dispacamide B (3) and spongiacidin B (6) emerge as antimalarial lead compounds. In addition, evaluation of the activity of the test alkaloids (2–14) against three different enzymes (PfFabI, PfFabG, PfFabZ) involved in the de novo fatty acid biosynthesis pathway of P. falciparum (PfFAS-II) identified bromopyrrolohomoarginin (12) as a potent inhibitor of PfFabZ. The structural similarity within the series of tested molecules allowed us to draw some preliminary structure-activity relationships. Tests against the mammalian L6 cells revealed important clues on therapeutic index of the metabolites. This is the first detailed study on the antiprotozoal potential of marine bromopyrrole alkaloids.

Longamide and 3,7-dimethylisoguanine, two novel alkaloids from the marine sponge Agelas longissima

Abstract A purine derivative. 3,7-dimethylisoguanine ( 1 ), and a novel alkaloid with the unusual pyrrolopiperazine nucleus, longamide ( 2 ), were isolated from the sponge Agelas longissima , and their structures established on the basis of spectroscopic data. In addition, 2 exhibited a mild antibacterial activity.

Anti-histaminic activity of bromopyrrole alkaloids isolated from Caribbean Agelas sponges

Abstract Four Caribbean Agelas sponges ( A. clathrodes, A. conifera, A. dispar, A. longissima ) have been investigated for the alkaloid composition. Along with a series of known bromopyrrole alkaloids, two related novel compounds of this class, dispacamides C ( 7 ) and D ( 8 ), were found and their structures determined with spectroscopic methods. All the isolated Agelas bromopyrrole alkaloids have been evaluated for the antihistaminic activity on the guinea pig ileum.

Metabolites from the sponge Plakortis simplex. Determination of absolute stereochemistry of plakortin. Isolation and stereostructure of three plakortin related compounds

Abstract The polyketides dihydroplakortin ( 3 ), and the dodecanoic acid derivatives 4 and 5 , were isolated from the Caribbean marine sponge Plakortis simplex , and their structures fully characterized by spectroscopic and chemical means. The absolute stereochemistries of the known plakortin ( 1 ) and of compounds 3–5 were determined by applying Moshers and Kusumis methods on opportune degradation products. The isolated compounds exhibited cytotoxic activity tested in vitro on WEHI 164, murine fibrosarcoma cell line.

Manadoperoxides A-D from the Indonesian Sponge Plakortis cfr. simplex. Further Insights on the Structure-Activity Relationships of Simple 1,2-Dioxane Antimalarials

The new endoperoxyketal polyketides manadoperoxides A-D (2-5) have been isolated from the Indonesian sponge Plakortis cfr. simplex and their stereostructures established by means of spectroscopic data and semisynthetic transformations. Manadoperoxides were assayed in vitro against D10 and W2 strains of Plasmodium falciparum and showed moderate antimalarial activity compared to that of plakortin (1) and peroxyplakoric B(3) ester (9), the latter differing from manadoperoxide B only by minor structural details. This unexpected difference in the antimalarial activity has been rationalized on the basis of our recently published model for the interaction of 1,2-dioxanes with heme and production of C-centered radicals toxic to the parasite. For the manadoperoxides, either the endoperoxide linkage is inaccessible to the heme iron or the O1 radical cannot evolve to produce a C-centered radical.

Cannabinoids: Occurrence and Medicinal Chemistry

With an inventory of several hundreds secondary metabolites identified, Cannabis sativa L. (hemp) is one of the phytochemically best characterized plant species. The biomedical relevance of hemp undoubtedly underlies the wealth of data on its constituents and their biological activities, and cannabinoids, a class of unique meroterpenoids derived from the alkylation of an olivetollike alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. In addition to the well-known psychotropic properties of Δ(9)-THC, cannabinoids have been reported to show potential in various fields of medicine, with the capacity to address unmet needs like the relief of chemotherapy-derived nausea and anorexia, and symptomatic mitigation of multiple sclerosis. Many of the potential therapeutic uses of cannabinoids are related to the interaction with (at least) two cannabinoid G-protein coupled receptors (CB1 and CB2). However, a number of activities, like the antibacterial or the antitumor properties are non totally dependent or fully independent from the interaction with these proteins. These pharmacological activities are particularly interesting since, in principle, they could be easily dissociated by the unwanted psychotropic effects. This review aims at giving readers a survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology.