A series of 18 1-[(1,2-diphenyl-1H-4-imidazolyl)methyl]-4-piperazines (1a-r) were designed and synthesized as possible ligands with mixed dopamine (DA) D(2)/serotonin 5-HT(1A) affinity, with the aim of identifying novel compounds with neurochemical and pharmacological properties similar to those of clozapine. The binding profile at D(2) like, 5-HT(1A), and 5-HT(2A) receptors of title compounds was determined. Modifications made in the phenyl rings of the parent compound (1a) produced congeners endowed with a broad range of binding affinities for DA D(2) like, serotonin 5-HT(1A), and 5-HT(2A) receptors, with IC(50) values ranging from 25 to >10,000 nM. As for the modification of the piperazine N(4)-phenyl ring, the affinities for both D(2) like and 5-HT(1A) receptors were progressively increased by introduction of ortho-methoxy and ethoxy groups (1b,o, respectively). Data revealed the presence of a para-chloro substituent in 1g to be associated with a relatively high affinity and substantial selectivity for D(2) like receptors, whereas the meta-chloro analogue 1f exhibited preferential affinity for 5-HT(1A) receptors. A quantitative structure-affinity relationship analysis of the measured binding data resulted in regression equations that highlighted substituent physicochemical properties modulating the binding to subtypes 1A and 2A of serotonin 5-HT receptors but not to D(2) like receptors. Thus, besides an electron-withdrawing field effect and ortho substitution, which both influence binding to serotonin 5-HT receptor subtypes, though to a different extent as revealed by regression coefficients in the multiparametric regression equations, the affinity of congeners 1a-r to 5-HT(1A) receptors proved to be linearly correlated with volume/polarizability descriptors, whereas their affinity to 5-HT(2A) receptors correlated with lipophilicity constants through a parabolic relationship. 1-[(1,2-Diphenyl-1H-4-imidazolyl)methyl]-4-(2-methoxyphenyl)piperazine (1b), with a D(2)/5-HT(1A) IC(50) ratio of approximately 1, was selected for a further pharmacological study. In rats, the intraperitoneal administration of compound 1b, like that of clozapine, induced an increase in the extracellular concentration of DA measured in the medial prefrontal cortex. Furthermore, 1b and clozapine each inhibited GABA-evoked Cl(-) currents at recombinant GABA(A) receptors expressed in Xenopus oocytes. These findings suggest that compound 1b may represent an interesting prototype of a novel class of drugs endowed with a neurochemical profile similar to that of atypical antipsychotics.
A series of novel 1,3,4-oxadiazoles was synthesized and evaluated for their cytotoxic activity in in vitro tumor models. Four of the new compounds (2d, 2j, 2k, and 2n) showed growth inhibition in the XTT dye assay. The most active agent, 2j, showed high potency against human cancer cells with ICs ranging from 0.05 to 1.7 μM. Preliminary SAR correlations suggested that the nature of chains on the oxadiazole is important for antitumor potency in vitro. Compound 2j determined a G/M arrest of the cell cycle and also activated a strong apoptotic response. The β-tubulin immunofluorescence analysis indicated that compound 2j effectively inhibited the microtubule organization in all cancer cell lines, causing the formation of abnormal spindle, which did not affect the normal human fibroblast cells NB1, Mrc-5 and IBR3. For all these reasons, compound 2j could be a good candidate in chemopreventive or chemotherapeutic strategies.
Designed as a new group of tricyclic molecules containing the thienocycloheptapyridazinone ring system, a number of 2N-substituted-hexahydrothieno-cycloheptapyridazinone derivatives were synthesized and their biological activity evaluated. Among the synthesized compounds, derivatives 7d and 7h were found to possess cytotoxic activity against non-small cell lung cancer and central nervous system cancer cell lines, respectively.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.