ABSTRACT
A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.
Subject(s)
Diterpenes , Quinones , Plant Extracts , Quinones/pharmacologyABSTRACT
Two new isochromans, panowamycins A and B, were purified by solvent extraction, silica gel and octadecylsilyl silica gel (ODS) column chromatography followed by preparative HPLC, from a culture broth of Streptomyces sp. K07-0010, together with the known compounds NFAT-133, conglobatin, piericidin C series and dinactin. Structures of panowamycins were elucidated as new analogs of NFAT-133 by spectroscopic studies including various NMR experiments. Panowamycins A and B showed moderate antitrypanosomal activity, with IC(50) values of 0.40 and 3.30 µg ml(-1), respectively.
Subject(s)
Antiprotozoal Agents/isolation & purification , Chromans/isolation & purification , Streptomyces/chemistry , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Bangladesh , Cell Line , Cell Proliferation/drug effects , Chromans/chemistry , Chromans/pharmacology , Humans , Inhibitory Concentration 50 , Microscopy, Electron, Scanning , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Infrared , Streptomyces/metabolism , Streptomyces/ultrastructure , Trypanosoma brucei brucei/drug effectsABSTRACT
During the course of our screening program to discover new antitrypanosomal compounds, 17 known plant aromatic compounds [12 bis(bibenzyls)s and 5 bibenzyls] were evaluated for in vitro activity against Trypanosoma brucei brucei. Sixteen compounds were found to exhibit antitrypanosomal activity. In particular, three compounds, marchantin A (1), plagiochin A (5) and 2(R)-2-isopropenyl-6,7-dihydroxy-4-(2-phenylethyl)dihydrobenzofuran (16) demonstrated moderate selective and potent antitrypanosomal activities in vitro. We detail here the antitrypanosomal properties and cytotoxicities of the compounds in comparison with two commonly used therapeutic drugs, eflornithine and suramin. Our finding represents the first report of the promising trypanocidal activity of these compounds. The research also provides valuable insight into structure-activity relationships and the possible mode of action of the compounds.
Subject(s)
Bibenzyls/chemistry , Bibenzyls/pharmacology , Hepatophyta/chemistry , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Molecular StructureSubject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Animals , Anti-Bacterial Agents/toxicity , Cell Line , Humans , Molecular Structure , Molecular Weight , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanocidal Agents/toxicityABSTRACT
During our search to discover new antitrypanosomal compounds, eight known plant compounds (three phenolic compounds and five kawa lactones) were evaluated for in vitro activity against Trypanosoma brucei brucei. Among them, we found two phenolic compounds and three kawa lactones possessing an α-pyrone influenced antitrypanosomal property. In particular, ß-phenethyl caffeate, farnesyl caffeate and dihydrokawain exhibited high or moderate selective and potent antitrypanosomal activity in vitro. We detail here the antitrypanosomal activity and cytotoxicities of the compounds, in comparison with two commonly used antitrypanosomal drugs (eflornithine and suramin). Our findings represent the first report of the promising trypanocidal activity of these compounds.
Subject(s)
Kava/chemistry , Lactones/chemistry , Lactones/pharmacology , Propolis/chemistry , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Pyrones/chemistry , Pyrones/pharmacology , Trypanosoma brucei brucei/drug effectsABSTRACT
During the course of screening to discover antitrypanosomal compounds, 24 known plant terpenes (6 sesquiterpenes, 14 sesquiterpene lactones and 4 diterpenes) were evaluated for in vitro antitrypanosomal activity against Trypanosoma brucei brucei. Among them, 22 terpenes exhibited antitrypanosomal activity. In particular, α-eudesmol, hinesol, nardosinone and 4-peroxy-1,2,4,5-tetrahydro-α-santonin all exhibited selective and potent antitrypanosomal activities in vitro. Detailed here in an in vitro antitrypanosomal properties and cytotoxicities of the 24 terpenes compared with two therapeutic antitrypanosomal drugs (eflornithine and suramin). This finding represents the first report of promising trypanocidal activity of these terpenes. Present results also provide some valuable insight with regard to structure-activity relationships and the possible mode of action of the compounds.
Subject(s)
Terpenes/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Diterpenes/chemistry , Diterpenes/isolation & purification , Diterpenes/pharmacology , Eflornithine/pharmacology , Plants/chemistry , Structure-Activity Relationship , Suramin/pharmacology , Terpenes/chemistry , Terpenes/isolation & purification , Trypanocidal Agents/chemistry , Trypanocidal Agents/isolation & purificationABSTRACT
Three novel antitrypanosomal alkaloids, named spoxazomicins A-C, were isolated by silica gel column chromatography and HPLC from the culture broth of a new endophytic actinomycete species, Streptosporangium oxazolinicum K07-0460(T). The structures of the spoxazomicins were elucidated by NMR and X-ray crystal analyses and shown to be new types of pyochelin family antibiotic. Spoxazomicin A showed potent and selective antitrypanosomal activity with an IC50 value of 0.11 µg ml⻹ in vitro without cytotoxicity against MRC-5 cells (IC50=27.8 µg ml⻹).
Subject(s)
Actinobacteria/metabolism , Alkaloids/pharmacology , Oxazoles/pharmacology , Phenols/pharmacology , Thiazoles/pharmacology , Trypanocidal Agents/pharmacology , Alkaloids/chemistry , Alkaloids/isolation & purification , Cell Line , Chromatography/methods , Chromatography, High Pressure Liquid/methods , Humans , Inhibitory Concentration 50 , Oxazoles/chemistry , Oxazoles/isolation & purification , Phenols/chemistry , Phenols/isolation & purification , Silica Gel , Thiazoles/chemistry , Thiazoles/isolation & purification , Trypanocidal Agents/chemistry , Trypanocidal Agents/isolation & purificationSubject(s)
Antimalarials/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/administration & dosage , Dose-Response Relationship, Drug , Drug Resistance , Fatty Alcohols/administration & dosage , Fatty Alcohols/pharmacology , L-Lactate Dehydrogenase/metabolism , Trophozoites/drug effectsABSTRACT
In the course of screening for antimalarial agents, five tropolone compounds were isolated from the culture broth of Penicillium sp. FKI-4410. Two were known compounds, puberulic acid and stipitatic acid. Three were new analogs of puberulic acid, designated viticolins A-C. Among them, puberulic acid exhibited potent antimalarial inhibition, with IC(50) values of 0.01 µg ml(-1) against chloroquine-sensitive and -resistant Plasmodium falciparum strains in vitro. Furthermore, puberulic acid showed weak cytotoxicity against human MRC-5 cells, with an IC(50) value of 57.2 µg ml(-1). The compound also demonstrated a therapeutic effect in vivo, which compared well against the currently used antimalarial drugs, and thus shows promise as a leading candidate for development into a new antimalarial compound.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Penicillium/metabolism , Plasmodium falciparum/drug effects , Animals , Antimalarials/metabolism , Antimalarials/toxicity , Cell Line , Cell Survival/drug effects , Humans , Inhibitory Concentration 50 , Malaria/drug therapy , Mice , Parasitic Sensitivity Tests , Plasmodium berghei/pathogenicity , Treatment OutcomeABSTRACT
Two new nucleotide antibiotics, named sinefungin VA and dehydrosinefungin V, were separated by cation exchange column chromatography and purified by HPLC from the culture broth of Streptomyces sp. K05-0178, together with the known antibiotics, sinefungin, dehydrosinefungin and KSA-9342. The structures of the two novel sinefungin analogs were elucidated by spectroscopic studies, including various NMR and advanced peptide chemical methods. Sinefungin VA consists of adenosine and ornithylvalylalanine, whereas dehydrosinefungin V consists of 4',5'-dehydroadenosine and ornithylvaline. Sinefungin VA showed potent antitrypanosomal activity with an IC(50) value of 0.0026 µg ml(-1) in vitro without cytotoxicity against MRC-5 cells. Dehydrosinefungin V showed moderate antitrypanosomal activity (IC(50)=0.15 µg ml(-1)).
Subject(s)
Adenosine/analogs & derivatives , Streptomyces/metabolism , Trypanocidal Agents/pharmacology , Adenosine/chemistry , Adenosine/isolation & purification , Adenosine/pharmacology , Cell Line , Chromatography, Ion Exchange/methods , Fermentation , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy/methods , Spectrum Analysis/methods , Trypanocidal Agents/chemistry , Trypanocidal Agents/isolation & purificationSubject(s)
Anti-Bacterial Agents/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Cell Line , Drug Design , Humans , Molecular Weight , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/toxicity , Trypanosomiasis, African/drug therapy , Trypanosomiasis, African/parasitologySubject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , In Vitro Techniques , Lysine/analogs & derivatives , Lysine/chemistry , Lysine/pharmacology , Malaria/drug therapy , Pactamycin/chemistry , Pactamycin/pharmacology , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosomiasis, African/drug therapySubject(s)
Antiprotozoal Agents/metabolism , Antiprotozoal Agents/pharmacology , Paecilomyces/metabolism , Pyrones/metabolism , Pyrones/pharmacology , Trypanosoma/drug effects , DNA, Fungal/chemistry , DNA, Fungal/genetics , DNA, Ribosomal Spacer/chemistry , DNA, Ribosomal Spacer/genetics , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Molecular Structure , Paecilomyces/classification , Paecilomyces/isolation & purification , Parasitic Sensitivity Tests , Pyrones/chemistry , Pyrones/isolation & purification , Sequence Analysis, DNA , Soil MicrobiologySubject(s)
Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosomiasis, African/drug therapy , Animals , Disease Models, Animal , Inhibitory Concentration 50 , Mice , Molecular Structure , Parasitic Sensitivity Tests , Phenazines/administration & dosage , Phenazines/pharmacology , Treatment OutcomeSubject(s)
Peptides/pharmacology , Trichoderma/metabolism , Trypanocidal Agents/isolation & purification , Chromatography, High Pressure Liquid , Intercellular Signaling Peptides and Proteins , Peptides/chemistry , Peptides/isolation & purification , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effectsSubject(s)
Antiprotozoal Agents/pharmacology , Macrolides/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Antiprotozoal Agents/chemistry , In Vitro Techniques , Macrolides/chemistry , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effectsABSTRACT
We accomplished the solid-phase total synthesis of malformin C, which is adaptable for the easy preparation of various derivatives. A solid-phase total synthesis of malformin C was achieved by on-resin macrolactamization and disulfide bond formation, with concurrent cleavage from the resin. Antimalarial and antitrypanosomal activities were examined, which helped elucidate partial structure-activity relationships. Results indicate that the disulfide bond is essential and branched amino acids are also crucial components if the compound is to exhibit potent antimalarial and antitrypanosomal properties.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
In the course of our screening for antitrypanosomal compounds from soil microorganisms, as well as from the antibiotics library of the Kitasato Institute for Life Sciences, we found three peptide antibiotics, leucinostatin (A and B), alamethicin I and tsushimycin, which exhibited potent or moderate antitrypanosomal activity. We report here the in vitro and in vivo antitrypanosomal properties and cytotoxicities of leucinostatin A and B, alamethicin I and tsushimycin compared with suramin. We also discuss their possible mode of action. This is the first report of in vitro and in vivo trypanocidal activity of leucinostatin A and B, alamethicin I and tsushimycin.
Subject(s)
Alamethicin/pharmacology , Anti-Bacterial Agents/pharmacology , Lipopeptides/pharmacology , Paecilomyces/metabolism , Peptides/pharmacology , Trypanocidal Agents , Trypanosomiasis, African/drug therapy , Alamethicin/isolation & purification , Alamethicin/therapeutic use , Animals , Anti-Bacterial Agents/therapeutic use , Antimicrobial Cationic Peptides , Cell Line , Cell Survival/drug effects , Female , Fermentation , Lipopeptides/isolation & purification , Lipopeptides/therapeutic use , Mice , Mice, Inbred ICR , Paecilomyces/classification , Peptides/isolation & purification , Peptides/therapeutic use , Peptides, Cyclic , Suramin/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei rhodesiense/drug effects , Trypanosomiasis, African/parasitologyABSTRACT
More than 400 compounds isolated from soil microorganisms, and catalogued in the antibiotic library of the Kitasato Institute for Life Sciences, were screened against African trypanosomes. Ten compounds were found to have selective and potent antitrypanosomal activity in vitro: aureothin, cellocidin, destomycin A, echinomycin, hedamycin, irumamycin, LL-Z 1272beta, O-methylnanaomycin A, venturicidin A and virustomycin A. Results of the in vitro assays using the GUTat 3.1 strain of Trypanosomal brucei brucei and the STIB900 strain of T. b. rhodesiense are presented. Cytotoxicity was determined using a human MRC-5 cell line. This is the first report of antitrypanosomal activities of the 10 microbial metabolites listed above.