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.

Thrombolysis with recombinant unglycosylated single-chain urokinase-type plasminogen activator (saruplase) in acute myocardial infarction: influence of heparin on early patency rate (LIMITS study). Liquemin in Myocardial Infarction During Thrombolysis With Saruplase.

OBJECTIVES: The Liquemin in Myocardial Infarction During Thrombolysis With Saruplase (LIMITS) study was instituted to evaluate and characterize the effect of a prethrombolytic heparin bolus (5,000 IU) on the efficacy and safety of saruplase in patients with acute myocardial infarction. BACKGROUND: Heparin has been used after thrombolytic therapy for acute myocardial infarction to prevent reocclusion of the infarct-related artery. METHODS: The study was designed as a randomized, parallel-group, double-blind, multicenter trial. Patients were treated within 6 h of onset of symptoms with either a bolus of 5,000 IU of heparin (Liquemin) (n = 56, HSH group) or placebo (n = 62, PSH group) before thrombolytic treatment with saruplase given as a 20-mg bolus followed by an infusion of 60 mg over 60 min. Thirty minutes after completion of thrombolysis, an intravenous heparin infusion was administered for 5 days. Before coronary angiography was performed at 6 to 12 h after start of lysis, an additional bolus of 5,000 IU heparin was given to all patients. End points studied were patency of the infarct-related artery, changes in the hemostatic system and bleeding complications. RESULTS: In the HSH group (heparin-saruplase-heparin), 78.6% of patients had an open infarct-related vessel (Thrombolysis in Myocardial Infarction [TIMI] flow grade 2 or 3) compared with 56.5% in the PSH group (placebo-saruplase-heparin) (intention-to-treat analysis, p = 0.01). No significant difference was observed between the two groups with regard to changes in fibrinogen and fibrin/fibrinogen degradation products. A total of eight bleeding complications (14.3%) were observed in the HSH group and five (8.1%) in the PSH group; no cerebrovascular event occurred, and no allergic reaction was reported. A total of 12 patients died during the hospital stay, 3 in the HSH group (5.4%) and 9 in the PSH group (14.5%). CONCLUSIONS: In acute myocardial infarction, the administration of a heparin bolus before thrombolytic therapy with saruplase is associated with a significantly higher patency at angiography 6 to 12 h after the start of thrombolysis without any appreciable increase in risk of bleeding.

Identification and exploitation of the sigma-opiate pharmacophore.

Certain benzomorphan "sigma-opiates" such as N-allylnormetazocine (NANM) bind at sigma receptors with modest affinity and with little selectivity (i.e., they also bind at phencyclidine or PCP sites). In order to identify the primary pharmacophore of the benzomorphans, we prepared several amine-substituted derivatives of 1-phenyl-2-aminopropane. Several simple alkyl-substituted analogues were shown to bind at sigma sites with affinities comparable to that of NANM itself; among these was the N-benzyl derivative 9 (Ki = 117 nM). Lengthening the spacer between the terminal amine and the phenyl group from one to five methylene units resulted in a significant increase in affinity (e.g. 15, Ki = 6.3 nM). In addition, unlike the benzomorphans, these phenalkylamines do not bind at PCP sites. The results of the present study reveal that (a) the 1-phenyl-2-aminopropane nucleus of the benzomorphans is sufficient for binding at sigma sites provided that the terminal amine is not a primary amine and that (b) introduction of (phenylalkyl)amine substituents affords compounds that represent a new class of high-affinity sigma-selective agents.

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.

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.

Binding of substituted and conformationally restricted derivatives of N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane at sigma-receptors.

Certain benzomorphans, such as N-allylnormetazocine, are classical "sigma-opiates" that bind both at sigma and phencyclidine (PCP) binding sites with modest affinity. Recently, we identified N-substituted 2-phenylaminoethane as being the primary sigma-pharmacophore of the benzomorphans and demonstrated that 1-phenyl-2-aminopropane (2) derivatives, depending upon their terminal amine substituents, constitute a novel class of high-affinity sigma-selective agents. With this pharmacophore, it is shown in the present investigation that the aromatic hydroxyl group (a prime feature of all the sigma-opiates) contributes little to the binding of 2 at sigma-sites. It is also demonstrated that an N-substituted aminotetralin moiety (such as 17, a conformationally restricted analogue of 2) may also be considered a sigma-opiate pharmacophore. Unlike the sigma-opiates, derivatives of 2 and 17 display no affinity for PCP sites and must consequently lack those structural features important for the binding of benzomorphans at PCP sites. Because 3-phenylpiperidines and related sigma-ligands also possess a phenylalkylamine imbedded within their structures, we propose that the 2-phenylaminoethane moiety is a common sigma-pharmacophore for derivatives of 2, the 3-phenylpiperidines, and the sigma-opiates.

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.

[Percutaneous transluminal coronary angioplasty in patients over 75 years old with acute myocardial infarct or unstable angina pectoris]. / Perkutane transluminale Koronarangioplastie bei Patienten über 75 Jahre mit akutem Myokardinfarkt oder instabiler Angina pectoris.

Both increasing frequency and technical improvements of percutaneous transluminal coronary angioplasty (PTCA) have focussed attention on possible applications of PTCA in elderly patients with coronary artery disease. From January 1986 to June 1989, among 1872 patients treated with PTCA in our hospital, 42 patients (2.3%) were 75 or more years old. Of these patients, 14 presented with unstable angina, 28 patients suffered from acute myocardial infarction. PTCA was performed on stenoses of left anterior descending artery (43%), circumflex coronary artery (18%), and right coronary artery (39%), respectively. In patients with unstable angina, PTCA in 81% could reduce diameter stenoses of culprit lesions to 50% or less. 43% of patients with acute myocardial infarction had received previous thrombolytic therapy with streptokinase or urokinase applied either systemically or intracoronarily. On cardiac catheterization, 39% of patients presenting with acute myocardial infarction showed total occlusion of the infarct-related vessel. In 75% of patients with acute myocardial infarction, after PTCA, patency of the infarct-related artery (diameter stenoses 50% or less) was observed. In-hospital mortality of patients with acute myocardial infarction subjected to PTCA was 10%, two patients dying in prolonged cardiogenic shock, one in septic shock. In 20% of cases, coronary dissection was observed after PTCA. Non-Q-wave infarction developed in one patient. Three patients had a peripheral vascular complication, and in one patient a transient ischemic attack was observed. No severe catheter-related complications occurred after thrombolytic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and antiinflammatory activity of novel pyrimidine derivatives.

Hydrazinolysis of ethyl [(4-methyl-6-phenylpyrimidin-2-yl)oxy]acetate (1) gives the unexpected bis(4-methyl-6-phenylpyrimidin-2-yl)hydrazine (2). The desired [(4 methyl-6-phenylpyrimidin-2-yl)oxy]acetohydrazide (3) was prepared from the ester (1) with hydrazine in absolute ethanol. Starting from 3, several new hydrazones, 1,3,4 oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and 1,3-thiazoles have been synthesized. Structure of the new compounds was confirmed by elemental analysis, spectral data and alternative synthesis in certain cases. Some representative examples were evaluated for their antiinflammatory activities.

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).

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.

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.

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.

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.