Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure-Activity Relationship (HQSAR) Modeling of Amino-Imino Tautomers.

In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity.

Anti-inflammatory activity of essential oils from Syzygium cumini and Psidium guajava.

CONTEXT: Despite the many biological activities reported for essential oils, their anti-inflammatory ability is relatively underexplored considering the wide variation in plant sources and in their volatile composition. Oils from Syzygium cumini Skells (SC) and Psidium guajava L. (PG) (Myrtaceae) have been described as having diverse pharmacological activities. OBJECTIVE: The current study seeks to evaluate the anti-inflammatory activity of the essential oils from the leaves of SC and PG, as well as some of their terpene-enriched fractions (+V = more volatile and -V = less volatile) obtained by vacuum distillation. Both the pharmacological responses and chemical compositions were correlated. MATERIALS AND METHODS: The relative contents of the oils and their fractions were evaluated by gas chromatography. Individual constituents in the oils were characterized by gas chromatography coupled to mass spectrometry. Anti-inflammatory activity was accessed in the lipopolysaccharide-induced pleurisy model, by measuring the inhibition of total leukocyte, neutrophil and eosinophil migration in the mice pleural lavage, after oil treatment with the oils at 100 mg/kg. RESULTS: Eosinophil migration was inhibited by SC (67%), SC (+V) (63%), PG (76%), PG (+V) (67%) and PG (-V) (74%). This efficacy was correlated with the presence of ß-pinene and ß-caryophyllene in the oils, a result that was reinforced by evaluating both these pure components (38 and 50% inhibition, respectively). Synergistic effects associated with the presence of α-pinene were speculated. DISCUSSION AND CONCLUSION: Essential oils from SC and PG may be useful to treat inflammatory diseases by mechanisms that include the inhibition of eosinophil migration.

Synthesis, antimalarial evaluation and molecular modeling studies of hydroxyethylpiperazines, potential aspartyl protease inhibitors, part 2.

The antimalarial acitivity of hydroxyethylamines, synthesized from the reaction of intermediated hydroxyethypiperazines with benzenesulfonyl chlorides or benzoyl chlorides, has been evaluated in vitro against a W2 Plasmodium falciparum clone. Some of the nineteen tested derivatives showed a significant activity in vitro, thus turning into a promising new class of antimalarials. In addition, a molecular modeling study of the most active derivative (5l) was performed and its most probable binding modes within plasmepsin II enzyme were identified.

Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series.

Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X=H, Y=p-NO2, pIC(50)=4.55 M) and 6l (X=F, Y=p-CN, pIC(50)=4.27 M) as the most potent derivatives compared to crystal violet (pIC(50)=3.77 M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising profile with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it.

Synthesis and antimalarial activity of hydroxyethylpiperazine derivatives.

The antimalarial activity of hydroxyethylpiperazine derivatives, synthesized from the reaction of (2S,3S)Boc-phenylalanine epoxide with benzylpiperazines in good yields (76-96%), has been evaluated in vitro against the Plasmodium falciparum W2 clone (chloroquine resistant). The results show that some compounds have moderate activity against this parasite and none of the active compounds showed cytotoxicity at high concentration (100 microg/ml).

Endothelins contribute towards nociception induced by antigen in ovalbumin-sensitised mice.

1. The contribution of endogenous endothelins to nociceptive responses elicited by ovalbumin (OVA) in the hind-paw of mice sensitised to this antigen (50 microg OVA+5 mg Al(OH)(3), s.c., 14 days beforehand) was investigated. 2. Sensitised mice exhibited greater nocifensive responsiveness to intraplantar (i.pl.) OVA (total licking time over first 30 min: 85.2+/-14.6 s at 0.3 microg; 152.6+/-35.6 s at 1 microg) than nonsensitised animals (29.3+/-7.4 s at 1 microg). Nocifensive responses of sensitised mice to 0.3 microg OVA were inhibited by morphine (3 mg kg(-1), s.c.) or local depletion of mast cells (four daily i.pl. injections of compound 48/80). 3. Pretreatment with i.v. bosentan (mixed ET(A)/ET(B) receptor antagonist; 52 micromol kg(-1)) or A-122722.5 (selective ET(A) receptor antagonist; 6 micromol kg(-1)) reduced OVA-induced licking from 124.8+/-20.6 s to 45.7+/-13.0 s and 64.2+/-12.1 s, respectively, whereas A-192621.1 (selective ET(B) receptor antagonist; 25 micromol kg(-1)) enhanced them to 259.2+/-39.6 s. 4. Local i.pl. pretreatment with BQ-123 or BQ-788 (selective ET(A) or ET(B) receptor antagonists, respectively, each at 3 nmol) reduced OVA-induced licking (from 106.2+/-15.2 to 57.0+/-9.4 s and from 118.6+/-10.5 to 76.8+/-14.7 s, respectively). Sarafotoxin S6c (selective ETB receptor agonist, 30 pmol, i.pl., 30 min after OVA) induced nocifensive responses in OVA-sensitised, but not in nonsensitised, animals. 5. Compound 48/80 (0.3 microg, i.pl.) induced nocifensive responses per se and potentiated those induced by i.pl. capsaicin (0.1 microg). Treatment with BQ-123 (3 nmol, i.pl.) reduced only the hyperalgesic effect of compound 48/80, whereas BQ-788 (3 nmol) was ineffective. 6. Thus, immune-mediated Type I hypersensitivity reactions elicit mast cell- and endothelin-dependent nociception in the mouse hind-paw, which are mediated locally by both ET(A) and ET(B) receptors. The nocifensive response to antigen is amenable to blockade by systemic treatment with dual ET(A)/ET(B) or selective ET(A) receptor antagonists, but is sharply potentiated by systemic selective ET(B) receptor antagonist treatment. The apparently distinct roles played by ET(B) receptors in this phenomenon at local and other sites remain to be characterised.