ABSTRACT
Tuberculosis is the leading cause of death due to infectious disease worldwide. There is an urgent need for more effective compounds against this pathogen to control the disease. Investigation of the anti-mycobacterial activity of a deep-water sponge of the genus Plakina revealed the presence of a new steroidal alkaloid of the plakinamine class, which we have given the common name plakinamine P. Its structure is most similar to plakinamine L, which also has an acyclic side chain. Careful dissection of the nuclear magnetic resonance data, collected in multiple solvents, suggests that the dimethyl amino group at the 3 position is in an equatorial rather than axial position unlike previously reported plakinamines. Plakinamine P was bactericidal against M. tuberculosis, and exhibited moderate activity against other mycobacterial pathogens, such as M. abscessus and M. avium. Furthermore, it had low toxicity against J774 macrophages, yielding a selectivity index (SI, or IC50/MIC) of 8.4. In conclusion, this work provides a promising scaffold to the tuberculosis drug discovery pipeline. Future work to determine the molecular target of this compound may reveal a pathway essential for M. tuberculosis survival during infection.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Steroids/chemistry , Steroids/pharmacology , Antitubercular Agents/chemistry , Molecular StructureABSTRACT
Two new indolo[3,2-a]carbazoles (1, 2) were isolated from a deep-water collection of a sponge of the genus Asteropus. The structures of 1 and 2 were determined through the analysis of spectroscopic data including mass spectrometry and 2D-NMR. Compound 1 showed minimum inhibitory concentrations of 25 µg/mL against the fungal pathogen Candida albicans and 50 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 1 and 2 showed no cytotoxicity against the PANC1 human pancreatic carcinoma and NCI/ADR-RES ovarian adenocarcinoma cell lines at our standard test concentration of 5 µg/mL.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Carbazoles/isolation & purification , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Indoles/isolation & purification , Porifera/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bahamas , Candida albicans/drug effects , Carbazoles/chemistry , Carbazoles/pharmacology , Drug Screening Assays, Antitumor , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Methicillin Resistance/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Staphylococcus aureus/drug effectsABSTRACT
As part of our ongoing chemical investigation of biologically active metabolites from marine fungi, three new compounds, p-hydroxyphenopyrrozin (1) and diketopiperazines (3, 4), have been isolated from the marine-derived fungus Chromocleista sp. In addition, the fungus gave the known compound phenopyrrozin (2), four known diketopiperazines (6-9), N-acetyltryptamine (10), and agathic acid (11). Another new diketopiperazine (5) was separated and identified as a decomposition product of 3 and 4. The structures of the new metabolites were determined on the basis of mass spectroscopy, NMR experiments, and derivatization methods. The absolute configuration of 1 was determined by X-ray crystallography studies.
Subject(s)
Ascomycota/chemistry , Pyrroles/chemistry , Pyrroles/isolation & purification , Animals , Candida albicans/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Leukemia P388 , Marine Biology , Mice , Microbial Sensitivity Tests , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Oceans and Seas , Pyrroles/pharmacology , Tumor Cells, CulturedABSTRACT
Discorhabdins S, T, and U (1-3), three new discorhabdin analogues, have been isolated from a deep-water marine sponge of the genus Batzella. These discorhabdin analogues showed in vitro cytotoxicity against PANC-1, P-388, and A-549 cell lines. The isolation and structure elucidation of discorhabdins S, T, and U are described.