Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.

Synthesis of some new 2-[[E]-2-furan-2-yl-vinyl]- 3H- quinazolin-4-one derivatives of expected biological activity

A new series of 2-[[E]-2-furan-2-yl-vinyl]-3H-quinazolin-4-ones incorporated into diverse N, O and S heterocyclic moieties of bioavailability as.5-oxo-4,5-dihydropyrazole 4, 3,5-dimethylpyrazole 5, 5-mercapto-1,2,4-triazole 6, substituted thiazolidinones 8 and 1,3,4-thiadiazole 10, were synthesized by cyclization of the starting quinazolinone acid hydrazide 3 or the acid hydrazide Schiff bases 7 using ethyl acetoacetate, acety I acetone, ammoniumthiocyanate, thioglycolic acid and/or phosphorus pentasulphide, respectively. Other related derivatives such as quinazoline thiosemi - carbazides II and 1,3,4-oxadiazoles 12 were also synthesized. The acid hydrazide 3 showed moderate antimicrobial activity While the starting benzoic acid ethyl ester 2 showed promising anti-inflammatory activity but has no effect on liver carcinoma [HePG2] or brain carcinoma [U251] cell lines

Characterization of some arylhydrazone-5-pyrazolones and their chelates with divalent Fe, Co, Ni, Cu, and Zn ions

The pK values of two substituted arylhydrazo-5-pyrazolones are assigned to the dissociation of a proton from the corresponding functional groups. The stability constants of their chelates with some divalent metal ions, viz. Fe [II], Co [II], Ni [II], Cu [II] and Zn [II] have also been determined. The structure of the compounds prepared has been elucidated by IR and NMR spectra which indicate the quinone-hydrazone form rather than the hydroxy-azo or Zwitter ion structures. Solid chelates were isolated and characterized

Spectral and thermal studies of copper [II] and nickel [II] complexes of ethyl cyano [pyridyl hydrazone] acetate

Complexes of copper and nickel with ethyl cyano [pyridyl hydrazono] acetate [EC-3-PyHA and EC-4-PyHA] were synthesized and characterized. Results showed that the Cu [II] complexes are octahedral but the Ni [II] complexes are octahedral and square planar. DTA results indicated greater thermal stability for Ni [EC-3-PyHA]2 than for Cu [EC-3-PyHA]2

Synthesis and spectroscopic studies on nickel [II] complexes of the tetradentate ligand n,n' -di-3- [4,5-dimethylpyrazolyl formyl] hydrazone

N,N'-di-3-[[4,5-dimethylpyrazolyl] formyl] hydrazone, L, reacts with nickel [II] salts to form 1: 1 and 1: 2 complexes. The 1: 1 binuclear systems involve 2 ligands bridging 2 metals, in which L behaves as a tetradentate ligand, and the nickel ions have a pseudo- octahedral stereochemistry. These complexes were formulated

Potential anticancer drugs: synthesis of some fused arylhydrazonoindeno [1,2-d] thiazolo and thiazinopyrimidinones

4-aryl-1,2,3,4-tetrahydro-5-oxoindeno [1,2-d] pyrimidine-2-thiols [I] were synthesized in the laboratories and their corresponding hydrazono derivatives [II] were submitted to react with chloroacetic acid, 2-bromopropionic acid or 3-bromopropionic acid in the presence of fused sodium acetate and acetic anhydride to give 5-aryl-2,3- dihydro-5H, 6-arylhydrazonoindeno [1,2-d] thiazolo [3,2-a] pyrimidin-3-ones [III], its methyl derivatives [IV] and 6-aryl-6H, 7-arylhydrazonoindeno [1,2-d]-pyrimidino-[2,1-b]-1,3-thiazin-4-ones [V], respectively. The indenothiazolopyrimidones [III] condensed with aromatic aldehydes in the presence of acetic anhydride to yield 2-arylmethylene-5 aryl-2,3-dihydro-5H-6-arylhydrazonoimdeno [1,2-d] thiazolo [3,2-a] pyrimidin-3-ones [VI], which was obtained directly from their arylhydrazono derivatives [II] by the reaction of chloroacetic acid in the presence of the corresponding aromatic aldehyde and in refluxing acetic acid/acetic anhydride mixture

Studies on dehydaro-d-erythro-and l-threo-ascorbic acid 2-arylhydrazone-3-oximes and mixed bishydrazones: conversion into substituted triazoles and pyrazolinediones

Reaction of p-nitrophenyltriazole of dehydro-D-erythro-ascorbic acid [I] with hydrazine hydrate in MeOH yielded the corresponding triazole hydrazide [II] which gave the triacetyl derivative [III]. Periodate oxidation of [II] gave the 3-formyltriazole derivative [IV] which formed a triacetyl derivative [VI]. The 3-formyl derivative [IV] was condensed with hydrazine hydrate and O-phenylenediamine to give compounds [VII] and [VIII], respectively. Treatment of [I] with ammonium hydroxide solution and MeOH gave the triazole carboxamide [IX] which produced two different acetyl derivatives [X] and [XI]. The p-nitrophenylhydrazone zone of dehydro-D-erythro-[XII] and dehydro-L- threo-ascorbic acid [XIII], reacted with phenylhydrazine to give the mixed bisarylhydrazones [XIV] and [XV], respectively, which formed the diacetyl derivatives [XVI] and [XVII]. Compound [XIV] underwent rearrangement to the corresponding pyrazole derivative [XVIII] which gave the acetyl product [XIX]. Periodate oxidation of [XVIII] gave the 3-formylpyrazole [XX] which yielded different condensation products [XXI]-[XXV]. Cupric chloride oxidation of [XV] gave the 3,6-anhydro derivative [XXVI] which characterized as its monoacetyl derivative [XXVII]

Some heterocycles from dehydro-l-ascorbic acid bishydrazones

Controlled reaction of dehydro-L-ascorbic acid [I] with one mole of o- tolylhydrazine gave the 2-[o-tolyl] hydrazone II. The reaction of II with phenyl- and o-tolylhydrazine afforded the bis-hydrazones III and V, which underwent acetylation to the di-O-acetyl derivatives IV and VI, respectively. Oxidative cyclization of III and V with cupric chloride gave the 3,6-anhydro derivatives XIII and XV, respectively. The bishydrazone III underwent rearrangement to the pyrazolodione VII by the action of alkali, followed by acidification. Treatment of VII with acetic anhydride in pyridine afforded the tri-O-acetyl derivative VIII. Periodate oxidation of VII led to the aldehyde IX, which was converted to the pyrazole oxime XIX and thiosemicarbazone XXII by treatment with hydroxylamine and thiosemicarbazide, respectively. Acetylation of XXII by boiling with acetic anhydride yielded the thiazoline XXII. Compound II underwent dehydrative acetylation into compound XVII. The latter reacted with methylhydrazine to give XVIII. The IR and PMR of some of the compounds were investigated

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