Biological Activities of Libidibia (Caesalpinia) ferrea var. parvifolia (Mart. ex Tul.) L. P. Queiroz Pod Preparations.

Libidibia ferrea has been used in folk medicine throughout Brazil, and this study evaluated the biological activities of crude extract (CE) as well as a partially purified fraction (F80) obtained from its pods. Results from the MTT assay revealed that only F80 inhibited NCI-H292 cell growth; however, neither CE nor F80 reduced HEp-2 cell growth or sarcoma 180 tumor weight with the in vivo assay. Acute oral toxicity of the extract and fraction was evaluated following the steps of Guideline 423, using female mice; LD(50) for both preparations was determined as 2,500 mg/kg body weight. CE and F80 promoted a reduction of the leukocyte number and nitrite level in inflammatory exudates when the anti-inflammatory assay (carrageenan-induced peritonitis) was performed. CE and F80 inhibited writhing regarding antinociceptive activity (acetic acid-induced writhing response in mice). In conclusion, CE and F80 have no significant cytotoxic or antitumor activities in cell lines showing low toxicity and no action against tumors in vivo. Both preparations revealed anti-inflammatory and antinociceptive activities, corroborating the pharmacological basis of L. ferrea for ethnomedical use.

Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases.

AIM: Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N'-substitutedphenylmethylene-1H-pyrazolo[3,4-b]pyridine-carbohydrazide derivatives (3a-3k). METHODS: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPARTAN' 08 program, in silico ADMET screening and the Lipinski " rule of five " using Osiris Property Explorer and molinspiration on-line programs. RESULTS: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c - IC(50)=61 microM and 68 microM respectively) almost 5-fold more potent than aspirin (IC(50)=300 microM). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. CONCLUSION: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases.

Substituded pyrazolylhydrazones: a new class of platelet aggregation inhibitors

A series of 5-pyrazolylhydrazone derivates (I) were designed to be mixed hybrid isosteres of both BW-755C and CBS-1108 which belong to the class of dual cyclooxygenase and 5-lipoxygenase inhibitors. Pharmacological evaluation of some members of this series (Ia, 1-formy 1-3,4-methylenedioxy-6-nitrobenzene-5-(1-phenyl-3-methyl-4-nitropyrazolil)hydrazone; Ib, 2-formylfurane-5-(1-phenyl-3-methyll-4-nitropyrazolyl)hidrazone; Ic, (E)-2-(formylethenylfurane)-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydrazone showed that they inhibit the in vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5µM), collagen (5µg/ml) and arachidonic acid (100 µM). Compounds Ia and Ic at 100 µM concentration showed 49% and 58% inhibition, respectively, of ADP-induced aggregation. In the arachidonic acid-induced aggregation, compounds Ia and Ib at 100 µM concentration fully inhibited platelet aggregation. All compounds significantly inhibited the collagen-induced aggregation. In contrast, indomethacin (10 µM) showed 100% and 85% aggregation inhibition against arachidonic acid and collagen, respectivelym, and was inactive in the ADP- induced aggregation test. These results suggest that the structure-activity relationship in this series of compounds is dependent on the hydrazone moiety at position 5 of the pyrazole ring and on the distance between the aryl ring and the pyrazole ring and that the 2-furyl ring is at the optimal distance for the maximal activity

Antinociceptive property of new 4-acyl-arylhydrazone pyrazole compounds

A series of new 4-acyl-arylhydrazone pyrazole compunds were tested for antinociceptive activity using the inhibition of abdominal contortions induced by acetylcholine (4 mg/Kg, ip) in the mouse. Dipyrone was used for comparison of the antinociceptive potency of the compounds being tested. All drugs wee administered po in saline (dipyrone) or in propylene flycol 94-acyl-arylhydrazones). The maximum response induced by dipyrone (86% inhibition) was assigned an efficacy index of 1.0. Although none of the compounds had an efficacy index greater than 1.0, all three reached 1.0. The two most potent compounds, Wd1 and W1g, which also had an efficacy similar to that of dipyrone, contain a p-N(CH3)2 and m-OH,p-OCH3 group in the aromatic ring of the acyl-hydrazone, respectively. W1d presented the lowest antinociceptive ED50 in the series (1.41 mg/Kg) and was eleven times more potent than dypyrone (ED50 = 15.80 mg/Kg). Other substitutions at the para position had lower potency than W1d. The present results indicate that the introduction of a group at the para postion of the acyl-arylhydrazone ring increases the antinociceptive activity of these compounds to provide compounds of the same efficacy but greater potency than dipyrone to which these new compounds ara structurally related. Other assays of nociceptive activity are veing used to characterize the mechanism of action of the potential new drugs