oroidin and clathrodin

We have prepared three alkaloids from the Agelas sponges, clathrodin, hymenidin and oroidin, and a series of their synthetic analogues, and evaluated their inhibitory effect against six isoforms of the K

Topics: Dose-Response Relationship, Drug; Humans; Molecular Structure; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Pyrroles; Structure-Activity Relationship

Marine organisms produce secondary metabolites that may be valuable for the development of novel drug leads as such and can also provide structural scaffolds for the design and synthesis of novel bioactive compounds. The marine alkaloids, clathrodin and oroidin, which were originally isolated from sponges of the genus, Agelas, were prepared and evaluated for their antimicrobial activity against three bacterial strains (Enterococcus faecalis, Staphylococcus aureus and Escherichia coli) and one fungal strain (Candida albicans), and oroidin was found to possess promising Gram-positive antibacterial activity. Using oroidin as a scaffold, 34 new analogues were designed, prepared and screened for their antimicrobial properties. Of these compounds, 12 exhibited >80% inhibition of the growth of at least one microorganism at a concentration of 50 µM. The most active derivative was found to be 4-phenyl-2-aminoimidazole 6h, which exhibited MIC₉₀ (minimum inhibitory concentration) values of 12.5 µM against the Gram-positive bacteria and 50 µM against E. coli. The selectivity index between S. aureus and mammalian cells, which is important to consider in the evaluation of a compound's potential as an antimicrobial lead, was found to be 2.9 for compound 6h.

Topics: Alkaloids; Animals; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Enterococcus faecalis; Escherichia coli; Microbial Sensitivity Tests; Porifera; Pyrroles; Staphylococcus aureus

The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin·(1)/2HCl salt or clathrodin·(1)/2HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure 19. The common process was rationalized from tautomeric precursors I and III.

Topics: Cyclization; Hempa; Imidazoles; Marine Biology; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pyrroles; Stereoisomerism

The total syntheses of oroidin, hymenidin and clathrodin are reported via the intermediacy of an imidazo[1,2-a]pyrimidine derivative. The chemistry described herein obviates the need for expensive guanidine reagents, multiply protected prefunctionalized 2-aminoimidazole synthons, or the need for laborious olefinations thereby achieving synthetic efficiency amenable to scale-up. The approach outlined in this manuscript provides an opportunity for further functionalizations through the imidazo[1,2-a]pyrimidine core and through functional groups placed strategically on the side chain.

Topics: Models, Molecular; Pyrimidines; Pyrroles

In a search for potential target sites for C11N5 compounds obtained from marine sponges of the genus Agelas we evaluated their interaction with muscarinic acetylcholine receptors from rat brain membranes. In competition experiments with 3H-QNB these compounds displayed the following rank order of potency: sceptrin greater than oroidin greater than or equal to dibromosceptrin greater than or equal to clathrodin. Sceptrin (50 microM) was shown to be a competitive inhibitor of 3H-QNB binding as revealed by Scatchard analysis. The results demonstrate the ability of these compounds to interact with multiple target molecules in the micromolar range.

Topics: Alkaloids; Animals; Binding, Competitive; Brain; Cell Membrane; In Vitro Techniques; Parasympatholytics; Porifera; Pyrroles; Radioligand Assay; Rats; Receptors, Muscarinic