A series of N-substituted tetrahydro-β-carbolines were synthesized and screened for antileishmanial activity through an in vitro assay that involves promastigotes and axenic amastigotes of Leishmania ...donovani, the causative agent for visceral leishmaniasis. The thiophen-2-yl analogs 9b and 11f and naphthyl analog 11h were found to show significant activity against promastigotes with IC50 values of 12.7, 9.1 and 22.1 μM, respectively. Analogs 9b and 11h were also effective against axenic amastigotes with IC50 values of 62.8 and 87.6 μM, respectively. The antileishmanial activity of analogs was then tested in human macrophage cell line infected with L. donovani amastigotes and 2-naphthyl linked analog 11h was found to be effective with IC50 value of 28.3 μM. Several analogs also displayed antitrypanosomal activity against Trypanosoma brucei, the causative agent for human African trypanosomiasis. Compounds 11e, 11f and 11h were more effective than others with IC50 values of 1.0, 8.9 and 10.2 μM, respectively. All synthesized analogs were not cytotoxic towards mammalian cell lines including Vero (monkey kidney fibroblasts), HEPG2 (human hepatoma cells), LLC-PK1 (pig kidney epithelial cells) and THP-1 (human macrophages).
Four diterpenes with biological activity were isolated from Salvia deserta roots. Taxodione was considered leishmanicidal, with IC50 value of 0.46 µg/mL against Leishimania donovani and also ...exhibited antifungal and antimicrobial activities. Ferruginol displayed the greatest activity (24-h IC50 1.29 mg/L) against the fish pathogenic bacteria Streptococcus iniae. The crude extract fraction which contained the isolated compounds 7-O-acetylhorminone and horminone showed stronger in vitro antibacterial activity (1.28 µg/mL for Staphylococcus aureus and 1.12 µg/mL for methicillin-resistant S. aureus - MRSA) than the compounds tested alone. 7-O-Acetylhorminone and horminone exhibited a synergistic effect against MRSA (FIC 0.2 µg/mL), and horminone had better activity against S. aureus with respect to other compounds isolated from S. deserta roots. In larvicidal bioassays, these extracts and isolated pure compounds did not show any activity at the highest dose of 125 ppm against 1-d-old Aedes. aegypti larvae.
The metabolic pathways in the apicoplast organelle of
parasites are similar to those in plastids in plant cells and are suitable targets for malaria drug discovery. Some phytotoxins released by plant ...pathogenic fungi have been known to target metabolic pathways of the plastid; thus, they may also serve as potential antimalarial drug leads. An EtOAc extract of the broth of the endophyte
isolated from a seed collected from a
plant with disease symptoms, showed in vitro antimalarial and phytotoxic activities. Bioactivity-guided fractionation of the extract afforded a mixture of two known isomeric phytotoxins, FRT-A and flavipucine (or their enantiomers, sapinopyridione and (-)-flavipucine), and two new unstable
-lactam alkaloids dothilactaenes A and B. The isomeric mixture of phytotoxins displayed strong phytotoxicity against both a dicot and a monocot and moderate cytotoxicity against a panel of cell lines. Dothilactaene A showed no activity. Dothilactaene B was isolated from the active fraction, which showed moderate in vitro antiplasmodial activity with high selectivity index. In spite of this activity, its instability and various other biological activities shown by related compounds would preclude it from being a viable antimalarial lead.
Primaquine (PQ) remains the sole available drug to prevent relapse of Plasmodium vivax malaria more than 60 years after licensure. While this drug was administered as a racemic mixture, prior studies ...suggested a pharmacodynamic advantage based on differential antirelapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel, easily scalable method were given for 7 days to healthy rhesus macaques in a dose-rising fashion to evaluate their effects on the blood, liver, and kidneys. The enantiomers were then administered to Plasmodium cynomolgi-infected rhesus macaques at doses of 1.3 and 0.6 mg/kg of body weight/day in combination with chloroquine. The (-)-PQ enantiomer had higher clearance and apparent volume of distribution than did (+)-PQ and was more extensively converted to the carboxy metabolite. There is evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin (MetHgb) with increasing doses of (+)-PQ greater than that seen for (-)-PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (-)-PQ at 4.5 mg/kg. (-)-PQ in combination with chloroquine was successful in preventing P. cynomolgi disease relapse at doses of 0.6 and 1.3 mg/kg/day, while 1 of 2 animals receiving (+)-PQ at 0.6 mg/kg/day relapsed. While (-)-PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as a clinical concern in humans during >60 years of use. Limited evidence for increased MetHgb generation with the (+) form in the rhesus macaque model suggests that it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.
Calea urticifolia (Asteraceae: Asteroideae) has long been used as a traditional medicine in El Salvador to treat arthritis and fever, among other illnesses. The chloroform extract of the leaves of ...C. urticifolia showed potent inhibition of recombinant human monoamine oxidases (MAO-A and -B). Further bioassay-guided fractionation led to the isolation of a flavonoid, acacetin, as the most prominent MAO inhibitory constituent, with IC50 values of 121 and 49 nM for MAO-A and -B, respectively. The potency of MAO inhibition by acacetin was >5-fold higher for MAO-A (0.121 μM vs 0.640 μM) and >22-fold higher for MAO-B (0.049 μM vs 1.12 μM) as compared to apigenin, the closest flavone structural analogue. Interaction and binding characteristics of acacetin with MAO-A and -B were determined by enzyme-kinetic assays, enzyme–inhibitor complex binding, equilibrium–dialysis dissociation analyses, and computation analysis. Follow-up studies showed reversible binding of acacetin with human MAO-A and -B, resulting in competitive inhibition. Acacetin showed more preference toward MAO-B than to MAO-A, suggesting its potential for eliciting selective pharmacological effects that might be useful in the treatment of neurological and psychiatric disorders. In addition, the binding modes of acacetin at the enzymatic site of MAO-A and -B were predicted through molecular modeling algorithms, illustrating the high importance of ligand interaction with negative and positive free energy regions of the enzyme active site.
Malaria is a major global health threat, with nearly half the world’s population at risk of infection. Given the recently described delayed clearance of parasites by artemisinin-combined therapies, ...new antimalarials are needed to facilitate the global effort toward elimination and eradication. NPC1161 is an 8-aminoquinoline that is derived from primaquine with an improved therapeutic profile compared to the parent compound. The (
R
)-(−) enantiomer (NPC1161B) has a lower effective dose that results in decreased toxic side effects such as hemolysis compared to the (
S
)-(+)-enantiomer, making it a promising compound for consideration for clinical development. We explored the effect of NPC1161B on
Plasmodium falciparum
oocyst and sporozoite development to evaluate its potential transmission-blocking activity viz. its ability to cure mosquitoes of an ongoing infection. When mosquitoes were fed NPC1161B 4 days after
P. falciparum
infection, we observed that total oocyst numbers were not affected by NPC1161B treatment. However, the sporozoite production capacity of the oocysts was impaired, and salivary gland sporozoite infections were completely blocked, rendering the mosquitoes non-infectious. Importantly, NPC1161B did not require prior liver metabolism for its efficacy as is required in mammalian systems, suggesting that an alternative metabolite is produced in the mosquito that is active against the parasite. We performed liquid chromatography–mass spectrometry (LC-MS)/MS analysis of methanol extracts from the midguts of mosquitoes fed on an NPC1161B (434.15
m/z
)-treated blood meal and identified a compound with a mass of 520.2
m/z
, likely a conjugate of NPC1161B or an oxidized metabolite. These findings establish NPC1161B, and potentially its metabolites, as transmission-blocking candidates for the treatment of
P. falciparum
.
Fourteen compounds including vanicoside B (1), vanicoside F (2), vanicoside E (3) and 5,6-dehydrokawain (4), aniba-dimer-A (5), ...6,6′-((1α,2α,3β,4β)-2,4-diphenylcyclobutane-1,3-diyl)bis(4-methoxy-2H-pyran-2-one) (6), (+)-ketopinoresinol (7), isorhamnetin (8), 3,7-dihydroxy-5,6-dimethoxy-flavone (9), isalpinin (10), cardamomin (11), pinosylvin (12), 2-desoxy-4-epi-pulchellin (13) and β-sitosterol (14) were isolated from dichloromethane-soluble portion of Polygonum hydropiper. By using Alamar blue assay, compounds 2, 7, 8, 11 and 12 were found to be active against Trypanosoma brucei with IC
50
values in the range of 0.49-7.77 μg/mL. Cardamomin (11) had most significant activity against T. brucei with IC
50
/IC
90
values of 0.49/0.81 μg/mL compared to the positive control DFMO (IC
50
/IC
90
: 3.02/8.05 μg/mL). Furthermore, in antimalarial, antimicrobial, anti-inflammatory, PPAR and cytotoxic assays, some compounds have demonstrated moderate inhibitory potentials.
Enniatins (ENs), a group of antibiotics commonly produced by various strains of Fusarium, are six-membered cyclic depsipeptides formed by the union of three molecules of D-α-hydroxyisovaleric acid ...and three N-methyl-L-amino acids. The endophyte Fusarium tricinctum Corda was isolated from the fruits of Hordeum sativum Jess. and cultivated on a rice medium. The fungal metabolites were extracted with methanol and were identified, employing liquid chromatography-mass spectrometry as ENs A, A1, B, B1, B2 and Q. EN Q is a new analog of EN A and the occurrence of EN B2 is reported for the first time from this endophyte, in addition to four well-known ENs (A, A1, B and B1). The methanol extract of F. tricinctum showed mild antibacterial and antileishmanial activities. Additionally the tested extract displayed inhibition of the activity of thioredoxin reductase enzyme of Plasmodium falciparum.
The clinical utility of primaquine (PQ), used as a racemic mixture of two enantiomers, is limited due to metabolism-linked hemolytic toxicity in individuals with genetic deficiency in ...glucose-6-phosphate dehydrogenase. The current study investigated differential metabolism of PQ enantiomers in light of the suggestions that toxicity and efficacy might be largely enantioselective.
Stable isotope (13)C-labelled primaquine and its two enantiomers (+)-PQ, (-)-PQ were separately incubated with cryopreserved human hepatocytes. Time-tracked substrate depletion and metabolite production were monitored via UHPLC-MS/MS.
The initial half-life of 217 and 65 min; elimination rate constants (λ) of 0.19 and 0.64 h(-1); intrinsic clearance (Clint) of 2.55 and 8.49 (µL/min)/million cells, which when up-scaled yielded Clint of 6.49 and 21.6 (mL/min)/kg body mass was obtained respectively for (+)- and (-)-PQ. The extrapolation of in vitro intrinsic clearance to in vivo human hepatic blood clearance, performed using the well-stirred liver model, showed that the rate of hepatic clearance of (+)-PQ was only 45 % that of (-)-PQ. Two major primary routes of metabolism were observed-oxidative deamination of the terminal amine and hydroxylations on the quinoline moiety of PQ. The major deaminated metabolite, carboxyprimaquine (CPQ) was preferentially generated from the (-)-PQ. Other deaminated metabolites including PQ terminal alcohol (m/z 261), a cyclized side chain derivative from the aldehyde (m/z 241), cyclized carboxylic acid derivative (m/z 257), a quinone-imine product of hydroxylated CPQ (m/z 289), CPQ glucuronide (m/z 451) and the glucuronide of PQ alcohol (m/z 437) were all preferentially generated from the (-)-PQ. The major quinoline oxidation product (m/z 274) was preferentially generated from (+)-PQ. In addition to the products of the two metabolic pathways, two other major metabolites were observed: a prominent glycosylated conjugate of PQ on the terminal amine (m/z 422), peaking by 30 min and preferentially generated by (+)-PQ; and the carbamoyl glucuronide of PQ (m/z 480) exclusively generated from (+)-PQ.
Metabolism of PQ showed enantioselectivity. These findings may provide important information in establishing clinical differences in PQ enantiomers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A benzo6annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC90 = 1.45 ...μM and viral titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity (CC50 = 169 μM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC90 = 270 nM and VTR of 4.5 log at 10 μM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway.
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