New series of fused pyrazolopyridines: Synthesis, molecular modeling, antimicrobial, antiquorum-sensing and antitumor activities.

New series of fused pyrazolopyridines were prepared and assessed for antimicrobial, antiquorum-sensing and antitumor activities. Antimicrobial evaluation toward selected Gram-positive bacteria, Gram-negative bacteria and fungi indicated that 5-phenylpyrazolopyridotriazinone 4a has good and broad-spectrum antimicrobial activity. In addition, 5-(4-chlorophenyl)pyrazolopyridotriazinone 4b and 5-(4-(dimethylamino)phenyl)pyrazolopyridotriazinone 4c exhibited good activity against the selected Gram-positive bacteria and A. fumigatus, whereas 5-amino-4-phenylpyrazolopyridopyrimidine 6a demonstrated good activity against B. cereus and P. aeruginosa. Furthermore, 6-amino-5-imino-4-phenylpyrazolopyridopyrimidine 7a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b demonstrated promising activity against the tested Gram-negative bacteria and fungi, and moderate activity against Gram-positive bacteria. Antiquorum-sensing screening over C. violaceum illustrated that 4a, 6a and 7a-c have strong activity. In vitro antiproliferative assessment of the new derivatives against HepG2, HCT-116 and MCF-7 cancer cells revealed that 7a is the most active analog against all tested cell lines. Likewise, 3,7-dimethyl-4-phenylpyrazolopyridopyrimidinone 2a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b manifested strong activity against all examined cell lines. In vivo antitumor testing of 2a, 7a and 7b against EAC cells in mice indicated that 7a has the highest activity. Cytotoxicity toward WI38 and WISH normal cells was also assessed and results assured that all of the investigated analogs have lower cytotoxicity than doxorubicin. DNA-binding affinity and topoisomerase IIß inhibitory activity were evaluated, and results revealed that 5b, 7a and 7b bind strongly to DNA; in addition, 2a, 4a, 7a and 7b manifested higher topoisomerase IIß inhibitory activity than that of doxorubicin. Analogs 5b, 7a and 7b were docked into topoisomerase IIß, and results indicated that 7a and 7b have the highest binding affinity toward topoisomerase IIß. In silico simulation studies referred that most of the new analogs comply with the optimum needs for good oral absorption. Also, computational carcinogenicity evaluation was predicted.

Current progress in antifibrotics.

After years of viewing cirrhosis as the irreversible end-stage of liver fibrosis, it has been shown recently that the possibility of its reversal is no longer a dream. Several studies on experimental animal models showed possible spontaneous resolution of fibrosis after the removal of fibrogenic stimulus. Similar results were also observed in human patients with liver fibrosis due to autoimmune hepatitis and biliary etiology. However, the need for other means of treatment is urgent, especially when the removal of the causative factor is unlikely. Recent antifibrotic strategies were designed to target one or more of the three stages involved in the process of fibrosis. These are the triggering stage, fibrogenesis, and extracellular matrix accumulation. In this review, the classification of the current drugs or agents that showed inhibition of one or more of fibrosis stages with their chemical synthesis are presented.

Novel piperidinedione analogs as inhibitors of breast cancer cell growth.

We previously reported the utility of antineoplaston-A10 (3-phenylacetylamino-2,6-piperidinedione) as an endogenous cancer protector and immune modulator in breast cancer patients (Cancer Lett., 2000, 157, 57). In this study, four new piperidinedione A10 analogs were synthesized and tested for their antimitotic activity on a human breast cancer cell line against the prototype A10 and the antibreast cancer drug tamoxifen. Moreover, the DNA binding capacity of such compounds was evaluated against A10, (E)-3-(4-Nitrocinnamoylamino)-2,6-piperidinedione "3B" and (E)-3-(4-hydroxycinnamoylamino)-2,6-piperidinedione "3D" were several-fold more potent antiproliferative agents than A10 and tamoxifen. They also had significantly higher capacity to bind DNA than A10. Conversely, (E)-3-(cinnamoylamino)-2,6-piperidinedione "3A" and (E)-3-(4-methoxycinnamoylamino)-2,6-piperidinedione) "3C" had weaker biological profiles than the lead compound A10. Detailed synthetic, spectroscopic, and biological data are reported.

Synthesis of some new quinazolines and quinoxalines of potential antiinflammatory activity.

A number of quinazoline derivatives containing basic amine substituents at position 4, as well as new derivatives of triazolo[4,3-alpha]quinoxalines carrying basic amine or carboxylic acid moieties have been synthesized. A tetracyclic imidazotriazoloquinoxaline compound is also reported. Two of the new products (2b and 7b) exhibited good antiinflammatory activity in rats, although inferior to that of indomethacin.

Fused pyrimidines. Synthesis of new derivatives of potential diuretic activity.

Certain derivatives of quinazoline and its bioisostere pyridopyrimidine carrying important structural features that contribute to diuretic activity, such as sulfonamido, morpholino and chlorophenyl, were prepared as potential diuretic agents. Likewise, some tricyclic 1,2,4-triazolo[3,4-b]quinazolines and pyrido[3,2-d][1,2,4]triazolo[4,3-alpha] pyrimidines with the same features were reported. Nine compounds were tested for the diuretic activity in rats and the results showed that the active compound is 7-chloro-2-methyl-3-phthalimido-4(3H)-quinazoline (4).

Structural features important for sigma 1 receptor binding.

Two problems that have hampered sigma receptor research are (i) a lack of high-affinity agents and (ii) the recent identification of multiple populations of sigma receptors (i.e., sigma 1 and sigma 2 sites). Recently, several high-affinity sigma ligands have been identified, and the term superpotent sigma ligands has been coined to describe agents with Ki values of < 1 nM. We have previously shown that appropriately N-substituted phenylalkylamines bind at sigma receptors with high affinity. In the present investigation, we examine the structure-affinity relationships of these phenylalkylamine derivatives for sigma 1 binding and describe some of the first superpotent sigma 1 ligands. A binding model was developed to account for the structural features of the phenylalkylamines that appear to be important for the interaction of these agents with sigma 1 sites.

Novel 1-phenylpiperazine and 4-phenylpiperidine derivatives as high-affinity sigma ligands.

sigma receptors may represent an exciting new approach for the development of novel psychotherapeutic agents. Unfortunately, many of the commonly used sigma ligands lack selectivity (e.g., many bind at phencyclidine or dopamine receptors) or suffer from other serious drawbacks. Recently, we described a series of 2-phenylaminoethanes that bind at sigma receptors with high affinity and selectivity. Because there is evidence that 1-phenylpiperazines can structurally mimic the 2-phenylaminoethane moiety, we prepared a series of 1-phenylpiperazines and related analogues and incorporated structural features already shown to enhance the sigma binding of the 2-phenylaminoethanes. Several of these derivatives bind at sigma receptors with high affinity (Ki = 1-10 nM) and lack appreciable affinity for phencyclidine and dopamine receptors. In as much as certain of these agents structurally resemble the high-affinity, but nonselective, sigma ligand haloperidol, and because they bind with 10 times the affinity of haloperidol, we have apparently identified what appears to be the primary sigma pharmacophore of that agent.

Synthesis and pharmacological study of a thiophene analogue of moprolol and related compounds.

The syntheses of the thiophenic analogue of Moprolol (1d) and of its related compound 1a are described. From a preliminary pharmacological evaluation compound 1d seems worthy of further studies due to its notable beta-blocking activity and its remarkable anti-platelet aggregation action.

Synthesis and biological testing of certain 2-(5-substituted-2-thienylthio)benzoic acid derivatives.

The syntesis of a number of 2-(5-substituted-2-thienylthio)benzoic acid derivatives is described. The synthesized compounds were screened for their muscle relaxant and parasympatholytic activities and the results are reported.

Synthesis and pharmacological evaluation of thiophene analogs of lotucaine.

The syntheses of the three possible thiophene analogs of lotucaine, and of other structurally related derivatives, are described. Preliminary data on their local anesthetic as well as antiplatelet aggregation activities are given.