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Protease activated receptor 4 (PAR4) is an important target in antiplatelet therapy to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth, while retaining initial thrombus formation, by acting on the late diffusion stage of platelet aggregation, and may provide a safer alternative to other antiplatelet agents. To date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis. Thus, the development of a potent and selective PAR4 antagonist with a novel chemotype is highly desirable. In this study, we explored the activity of quinazolin-4(3H)-one-based PAR4 antagonists, beginning with their IDT analogues. By repeated structural optimisation, we developed a series of highly selective PAR4 antagonists with nanomolar potency on human platelets. Of these, 13 and 30g, with an 8-benzo[d]thiazol-2-yl-substituted quinazolin-4(3H)-one structure, showed optimal activity (h. PAR4-AP PRP IC 50  = 19.6 nM and 6.59 nM, respectively) on human platelets. Furthermore, 13 and 30g showed excellent selectivity for PAR4 versus PAR1 and other receptors (IC 50 s > 10 μM) on human platelets. And 13 and 30g were lack of cross-reactivity for PAR1 or PAR2 (PAR1 AP FLIPR IC 50  > 3162 nM, PAR2 AP FLIPR IC 50  > 1000 nM) in the calcium mobilization assays. Metabolic stability assays and cytotoxicity tests of 13 and 30g indicated that these compounds could sever as promising drug candidates for the development of novel PAR4 antagonists. In summary, the quinazolin-4(3H)-one-based analogues are the first reported chemotypes with excellent activity and selectivity against PAR4, and, in the current study, we expanded the structural diversity of PAR4 antagonists. The two compounds, 13 and 30g, found in our study could be promising starting points with great potential for further research in antiplatelet therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

A series of adenosine and 2'-deoxyadenosine pairs modified with a 1,12-dicarba-closo-dodecaborane cluster or alternatively with a phenyl group at the same position was synthesized, and their affinity was determined at A 1 , A 2A , A 2B and A 3 adenosine receptors (ARs). While AR affinity differences were noted, a general tendency to preferentially bind A 3 AR over other ARs was observed for most tested ligands. In particular, 5'-ethylcarbamoyl-N 6 -(3-phenylpropyl)adenosine (18), N 6 -(3-phenylpropyl)-2-chloroadenosine (24) and N 6 -(3-phenylpropyl)adenosine (40) showed nanomolar A 3 affinity (K i 4.5, 6.4 and 7.5 nM, respectively). Among the boron cluster-containing compounds, the highest A 3 affinity (K i 206 nM) was for adenosine derivative 41 modified at C2. In the matched molecular pairs, analogs bearing boron clusters were found to show lower binding affinity for adenosine receptors than the corresponding phenyl analogs. Nevertheless, interestingly, several boron cluster modified adenosine ligands showed significantly higher A 3 receptor selectivity than the corresponding phenyl analogs: 7vs. 8, 15vs. 16, 17vs. 18., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Based on the recent observation that the antiplatelet agent ticagrelor and one of its metabolite exert bactericidal activity against gram-positive bacteria, a series of 1,2,3-triazolo[4,5-d]pyrimidines structurally related to ticagrelor were synthesized and examined as putative antiplatelet and antibacterial agents. The aim was to assess the possibility of dissociating the two biological properties and to find novel 1,2,3-triazolo[4,5-d]pyrimidines expressing antiplatelet activity and devoid of in vitro antibacterial activity. The new compounds synthesized were known metabolites of ticagrelor as well as structurally simplified analogues. Some of them were found to express antiplatelet activity and to lose the antibacterial activity, supporting the view that the two activities were not necessarily linked., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Cardiovascular diseases are the leading cause of death in the world. Platelets have a major role in cardiovascular events as they bind to the damaged endothelium activating and forming thrombi. Although some hydroquinone scaffold-containing compounds have known antiplatelet activities, currently there is a lack of evidence on the antiplatelet activity of hydroquinones carrying electron attractor groups. In this work, we evaluate the antiplatelet effect of a series of ortho-carbonyl hydroquinone derivatives on cytotoxicity and function of human platelets, using collagen and thrombin receptor activator peptide 6 (TRAP-6) as agonists. Our structure-activity relationship study shows that gem-diethyl/methyl substitutions and the addition/modifications of the third ring of ortho-carbonyl hydroquinone scaffold influence on the selective index (IC 50 TRAP-6/IC 50 Collagen) and the inhibitory capacity of platelet aggregation. Compounds 3 and 8 inhibit agonist-induced platelet aggregation in a non-competitive manner with IC 50 values of 1.77 ± 2.09 μM (collagen) and 11.88 ± 4.59 μM (TRAP-6), respectively and show no cytotoxicity. Both compounds do not affect intracellular calcium levels and mitochondrial bioenergetics. Consistently, they reduce the expression of P-selectin, activation of glycoprotein IIb/IIIa, and release of adenosine triphosphate and CD63 from platelet. Our findings may be used for further development of new drugs in platelet-related thrombosis diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A novel series of 2-(phenoxyaryl)-3-urea derivatives were designed, synthesized, and biologically evaluated for their anti-thrombotic activity. Most of compounds exhibited good inhibition against P2Y 1 receptor. Among them, three compounds 11, 12, and 13 demonstrated good P2Y 1 receptor antagonistic potency in vitro (IC 50  = 0.62 μM, 0.82 μM, and 0.21 μM, respectively). In antiplatelet aggregation study, four compounds 2, 3, 9, and 13 showed good antiplatelet activity. The possible binding modes of compounds with P2Y 1 receptor were also explored by molecular docking simulation. The docking studies demonstrated that compound 13 interacted well with Phe119 through hydrophobic interaction and modestly improved the P2Y 1 receptor antagonistic activity, making it justifiable for further investigation., (Copyright © 2018. Published by Elsevier Masson SAS.)

Drugs which inhibit platelet function are commonly used to prevent blood clot formation in patients with Acute Coronary Syndromes (ACS) or those at risk of stroke. The thieno[3,2-c]pyridine class of therapeutic agents, of which clopidogrel is the most commonly used, target the P2Y 12 receptor, and are often used in combination with acetylsalicylic acid (ASA). Six thieno[2,3-b]pyridine were assessed for in vitro anti-platelet activity; all derivatives showed effects on both platelet activation and aggregation, and showed synergy with ASA. Some compounds demonstrated greater activity when compared to clopidogrel. These compounds, therefore, represent potential novel P2Y 12 inhibitors for improved treatment for patients., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Cardiovascular diseases (CVDs) account for over 17 million deaths globally each year, with atherosclerosis as the underlying cause of most CVDs. Herein we describe the synthesis and in vitro mechanistic evaluation of novel N'-benzylidene-carbohydrazide-1H-pyrazolo[3,4-b]pyridines (3-22) designed as non-anionic antiplatelet agents and presenting a 30-fold increase in potency compared to aspirin. The mechanism underlying their antiplatelet activity was elucidated by eliminating potential targets through a series of in vitro assays including light transmission aggregometry, clot retraction, and quantitative ELISA, further identifying the reduction in biosynthesis of thromboxane B2 as their main mechanism of action. The intrinsic fluorescence of the compounds permits their binding to platelet membranes to be readily monitored. In silico structure-activity relationship, molecular docking and dynamics studies support the biological profile of the series revealing the molecular basis of their activity and their potential as future molecular therapeutic agents., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

N-aralkylpyroglutamides of substituted bispidine were prepared and evaluated for their ability to inhibit collagen induced platelet aggregation, both in vivo and in vitro. Some compounds showed high anti-platelet efficacy (in vitro) of which six inhibited both collagen as well as U46619 induced platelet aggregation with concentration dependent anti-platelet efficacy through dual mechanism. In particular, the compound 4j offered significant protection against collagen epinephrine induced pulmonary thromboembolism as well as ferric chloride induced arterial thrombosis, without affecting bleeding tendency in mice. Therefore, the present study suggests that the compound 4j displays a remarkable antithrombotic efficacy much better than aspirin and clopidogrel., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

pENW, a three mer peptide derived from Agkistrodon acutus Guenther venom, has been found to be an antagonist of the GPIIb/IIIa receptor and shows antiplatelet aggregation activity. Based on pENW and a GPIIb/IIIa inhibitor Tirofiban, a series of tryptophan derivatives were designed, synthesized and evaluated for their antiplatelet aggregation activity induced by ADP. The most potent compound 87 was also tested for the bleeding time and antithrombotic activity in vivo in comparison with Tirofiban. The results indicated that 87 shows similar antiplatelet aggregation activity as Tirofiban to the aggregation of platelet induced by all of the four agonists, but has lower bleeding risk than Tirofiban, representing a promising lead compound for further study., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

New series of pyridazinone derivatives (4, 5 and 6) were synthesized in good yields following a synthetic strategy based on singlet oxygen oxidation of alkyl furans, in which a suitable β(α)-substituted γ-hydroxybutenolide (10 or 11) or a bicyclic lactone (12 or 13) was the key intermediate. The synthesized compounds were tested in vitro as antiplatelet agents and some of them (compounds 4b, 4d and 5b) exhibited potent inhibitory effects on collagen-induced platelet aggregation with IC50 values in the low μM range. Studies performed with the most active compound of these series (4b) demonstrated its lack of activity as inhibitor of platelet aggregation induced by other agonists as thrombin, ionomycin or U-46619 suggesting a selective action on the biochemical mechanisms triggered by collagen in the platelets., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A new group of 5-(alkylamino)-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine derivatives bearing a CONHR group at the 6-position (1c-g), designed to obtain new effective analgesic and/or anti-inflammatory agents, were synthesized and tested along with three new 9-alkyl-5-(4-alkyl-1-piperazinyl)-N,N-diethyl [1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides (2b-d). Besides, a new class of analogues of compounds 1 and 2, bearing a Mannich base moiety at the 9-position (12a-d), as well as the novel N,N-diethyl-5-(isobutylamino)-8-methyl-10-oxo-10H-pyrimido[1,2-a][1,8]naphthyridine-6-carboxamide (15) were prepared and tested. Compounds 1c-g exhibited very interesting anti-inflammatory properties in rats, whereas compounds 2b-d and 15 proved to be endowed with prevalent analgesic activity frequently associated with sedative effects in mice. On the contrary, the Mannich bases 12a-d resulted inactive. The most effective (80% inhibition of oedema) and potent (threshold dose 1.6 mg kg(-1) with 31% inhibition of oedema) anti-inflammatory compound 1d did not show gastrolesive effects following 100 mg kg(-1) oral administration in rats., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

A series of chiral lactam carboxamides of aminomethylpiperidine were synthesized and investigated for the collagen induced in vitro anti-platelet efficacy and collagen plus epinephrine induced in vivo pulmonary thromboembolism. The compound 31a (30 μM/kg) displayed a remarkable antithrombotic efficacy (60% protection) which was sustained for more than 24 h and points to its excellent bioavailability. The compounds 31a (IC50 = 6.6 μM) and 32a (IC50 = 37 μM), as well as their racemic mixture 28i (IC50 = 16 μM) significantly inhibited collagen-induced human platelet aggregation in vitro. Compound 34c displayed dual mechanism of action against both collagen (IC50 = 3.3 μM) and U46619 (IC50 = 2.7 μM) induced platelet aggregation. The pharmacokinetic study of 31a indicated very faster absorption, prolonged and constant systemic exposure and thereby exhibiting better therapeutic response., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

New series of original 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas were synthesized and evaluated as thromboxane A2 receptor (TP receptor) antagonists. A functional pharmacological test was used, which consisted of measuring the inhibition of intracellular calcium mobilization in a model of mammalian cell line that specifically over-expressed the individual TPα or TPβ isoforms. 2-Arylamino-5-cyanobenzenesulfonylureas exhibited virtually identical affinity and/or functional activity than 2-aryloxy-5-cyanobenzenesulfonylureas for both TPα and TPβ, but some 2-aryloxy-substituted compounds showed increased selectivity for TPβ relative to TPα. Several compounds were found to be as potent as the 2-arylamino-5-nitrobenzenesulfonylurea reference compound BM-573, supporting the view that the bioisosteric replacement of the nitro group by a cyano group was tolerated. TP receptor antagonist activity of the most promising molecules was confirmed in a platelet aggregation assay using the TP receptor agonist U-46619 as a proaggregant. Three compounds (7e, 7h and 8h) were identified as leads for further non-clinical pharmacological and toxicological studies., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Antiplatelet drugs are promising therapeutics to intervene with platelet aggregation in arterial thrombosis, most prominently in myocardial infarction and ischemic stroke. Here, we describe the synthesis and structure-activity relationships of potent inhibitors of platelet aggregation based on the 1,5-diarylpyrazol-3-carboxamide scaffold. Analogs from this series demonstrated potent anti-aggregatory activities against arachidonic acid-induced platelet aggregation, as measured by turbidimetric method of Born. 1,5-Diarylpyrazole-3-carboxamides obtained with small-basic amines (7, 8, 50, 51, 61, 62) displayed the strongest activity with IC50 values in low nanomolar range (5.7-83 nM). On the basis of their high potency in cellular environment, these straightforward pyrazole derivatives may possess potential in the design of more potent compounds for intervention with cardiovascular diseases., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The multistep preparation of the new 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones 6a-o, and of the two isomers 10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one 6p and 10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one 13, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca(2+) ionophore A23187 were here described. Nine out of fifteen 2-(1-piperazinyl)derivatives (6g-o) showed good inhibitory properties towards all the platelet aggregation agonists used. Moreover, a molecular modelling study has been performed on two of the best compounds of this series (6i and 6o) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Esters of 1,4-benzoxazine and 1,4-benzodioxine compounds 1 and 10, which combine thrombin inhibitory and GPIIb/IIIa antagonistic activity in one molecule are shown to inhibit endothelial cell migration and tube formation in vitro and angiogenesis in the chicken chorioallantoic membrane (CAM) assay. The corresponding carboxylic acids 1 (R(2) = H) and 11 were devoid of anti-angiogenic activity, most probably due to their insufficient entry into the cell. Although thrombin inhibition remains the most probable explanation for their inhibition of angiogenesis, VEGFR2 kinase assay suggest that other targets such as VEGFR2 might be involved., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A novel series of prodrugs consisting of dabigatran and 2-hydroxymethyl-3,5,6-trimethylpyrazine (HTMP) were synthesized. The pharmacological results show that all of them possess the effect of anti-platelet aggregation induced by thrombin in vitro. Moreover, one of those compounds, Y-2 (ED(50) = 2.1 ± 1.3 mg/kg) shows more potent activity for inhibiting thrombosis in vivo than that of dabigatran etexilate (ED(50) = 4.4 ± 2.2 mg/kg)., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Thirty-two 2-substituted ethenesulfonic acid ester derivatives were designed, synthesized, and evaluated for their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) and selectivity over T-Cell protein tyrosine phosphatase (TCPTP). Preliminary structure-activity relationship studies demonstrated that the substitution at the aromatic center and the length of linker between the hydrophobic tail and aromatic center markedly affected the inhibitory activity against PTP1B and the selectivity over TCPTP. Specifically, compounds 43 and 36 revealed excellent inhibitory activity to PTP1B with IC(50) = 1.3 μM and 1.5 μM, respectively, and marked 10- and 20-fold selectivity over TCPTP. Cytotoxicity data showed low cytotoxicity for COS-7 cell with IC(50) values >100 μM for most synthesized chemicals., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A number of new 2-(pyridin-3-ylamino)-4H-(substituted) benz[e]-1,3-oxazin-4-ones were synthesized 10a-g. These were then reacted with the hydro-halogen salt of 2, 3 and 4-(halo-methyl) pyridine in the presence of Cs(2)CO(3) to give eighteen new 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11a-i, 13a-c, and 15a-f). X-ray crystallography was used to confirm that the 2-N-substituted structures 11 and 13 were formed rather than the 3-N-substitution analogues 12 and 14. Eleven of the new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active inhibitory compound was 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC(50) of 10 ± 2 μM. DNA-dependent protein kinase (DNA-PK) inhibition data for 12 previously prepared 2-morpholino substituted-1,3-benzoxazines (compounds 19-31) were measured and showed high to moderate activity where the most active compound was compound 27 with an IC(50) of 0.28 μM. Furthermore DNA-PK inhibition data for six newly prepared 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11b, 13a-b, 15a-b and 15e) and 8-methyl-7-(pyridin-3-ylmethoxy)-3-(pyridin-3-ylmethyl)-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 17d were measured and moderate to low inhibitory activity was observed, with the most active of the compounds in this series being 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC(50) of 2.5 μM. PI3K inhibition studies revealed that compound 27 is highly potent (IC(50) for PI3Kα = 0.13 μM, PI3Kβ = 0.14 μM, PI3Kγ = 0.72 μM, PI3Kδ = 2.02 μM). Compound 22 with 7-[2-(4-methylpiperazin-1-yl)ethoxy] group shows greater inhibition of DNA-PK over PI3K. Docking of some 2-morpholino-substituted-1,3-benzoxazine compounds 19-31 within the binding pocket and structure-activity relationships (SAR) analyses were performed with results agreeing well with observed activities., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Nucleoside derivatives are largely synthesized and tested to investigate their influence on platelet aggregation. It's well known that P2Y receptors play an important role in the regulation of platelet function and, as consequence, in controlling atherothrombotic events. The research of compounds that antagonize P2Y(1) and, in particular, P2Y(12) receptors is of great interest in the aim to obtain platelet aggregation inhibitors that are effective in the prevention and treatment of arterial thrombosis. In this study we present the synthesis and in vitro metabolic stability in human blood and rat liver homogenate of a new class of nucleoside derivatives, in particular 5'-phosphonate adenosine, inosine, guanosine and thioadenosine analogues also modified at the ribose moiety. On the basis of the results obtained we can hypothesize compounds 4 and 18 to have in vivo a relatively high stability., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A series of novel N(6)-alkyl(aryl)-2-alkyl(aryl)thioadenosines were synthesized, and their human antiplatelet aggregation activities were evaluated by the stimulation of adenosine 5'-diphosphate (ADP). Some of these compounds showed strong activity, among which compound 5b(11) displayed the highest activity with an IC(50) value of 29 ± 3 μM. Furthermore, five compounds were tested against arachidonic acid (AA)-induced human platelet aggregation. The results showed that compound 5b(10) exhibited the highest activity with an IC(50) value of 3 ± 2 μM. The adenosine derivatives substituted with a phenethyl group at the N(6) position and a methylthio or ethylthio group at the C-2 position displayed high antiplatelet aggregation activity., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A series of 4,6-diaryl-2-aminopyrimidines was developed as antiplatelet agents and their potency was evaluated by in vitro assay. Compound 14k was found to be two times more potent than aspirin. These encouraging results could be helpful for the development of new antiplatelet compounds., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A series of 3-phenyl-2,7-dihydro-1H-pyrrolo[3,2-f]quinazolin-1-one derivatives (3-PPyQZ) was synthesized starting from 5-amino-indoles, via condensation with N-ethoxycarbonylthiobenzamides followed by thermal cyclization. On the basis of their structural analogy with reported anti-thrombin pyrroloquinazolines, the derivatives were first tested for their capacity to inhibit platelet aggregation. Some of them had in vitro inhibitory effects on collagen and thrombin-induced aggregation in the micromolar range, and much higher inhibition than that shown by some phenyl-pyrroloquinolinones. Experiments to determine the mechanism of action of the most potent inhibitor (compound 18) indicated that it acts in at least two sites: one preceding the agonist-induced increase of cytosolic [Ca(2+)], and one following this step of the platelet activation cascade. The compound also inhibited thrombin-evoked protein-Tyr-phosphorylation. Although it is premature to draw definitive conclusions, the present results indicate that 3-PPyQZ structure, with the quite potent inhibitor of platelet aggregation compound 18, might constitute a starting point for the synthesis of potential anti-thrombosis agents., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

High anti-thrombotic activity of aminoacid modified tetrahydro-β-carbolines was generally correlated with a small proximity of the side chain of the aminoacid residue to the carboline-cycle. This paper explored that the aromatization of the tetrahydro-β-carboline-cycle of N-(1-methyl-β-tetrahydrocarboline-3-carbonyl)-N'-(aminoacid-acyl)-hydrazines leaded to N-(1-methyl-β-carboline-3-carbonyl)-N'-(aminoacid-acyl)-hydrazines and decreased the proximity of the side chain of the aminoacid residue to the carboline-cycle. The in vitro activities of inhibiting pig platelet aggregation induced by PAF, ADP, and AA, as well as the in vivo anti-thrombotic activities of inhibiting rat thrombosis of these aromatized derivatives were generally higher than that of N-(1-methyl-β-tetrahydrocarboline-3-carbonyl)-N'-(aminoacid-acyl)-hydrazines. The understanding was also obtained from the 3D QSAR analysis., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

A new series of persulfated compounds was synthesized and assayed for in vitro anticoagulant and antiplatelet activities, which may be useful in the treatment of both venous and arterial thrombosis. Persulfation of polyphenolic components of wine, coumarins and other structurally diverse small molecules was achieved with triethylamine-sulphur trioxide adduct. The derivatives were highly effective in increasing the APTT, being trans-resveratrol 3-ß-D-glucopyranoside persulfate (15) the most potent (APTT2=1.5×10(-4) M), and were able to completely block the clotting process at the highest concentration. Compound 15 showed good stability in human plasma and anticoagulation effects in whole blood. trans-Resveratrol 3-ß-D-glucopyranoside persulfate (15) and a series of polysulfated oligoflavonoids (1-4) also exhibited antiplatelet activity by inhibition of arachidonic acid and ADP-induced platelet aggregation., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

We report the synthesis of collagen related peptides containing the peptide sequence Lys-Hyp-Gly-Glu-Hyp-Gly-Pro-Lys. The anti-thrombotic activity effects of different glycine mutations in this sequence were studied in regard with their different adopted conformations. The biological results could be correlated to the glycine propensity to adopt a more stable polyproline II helix conformation. The incorporation of these sequences in "collagen-like" alpha-triple-helix peptides shows a pro-thrombotic activity compared to a scrambled negative control peptide which possesses no significant activity.

The synthesis, antileukemic and antiplatelet activity evaluation of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines are described. In general, it was found that compound 17o showed moderate antileukemic activity against MOLT3 human leukemic cancer cell lines. An arachidonic acid induced platelet aggregation effect on washed rat platelets was studied. Compound 17i was found to be the most potent. The antiplatelet properties may be mediated by interference with the arachidonic acid pathway.

In this work, we describe a new class of promising anti-platelet drug candidates with significant antithrombotic activity in vivo. This new series of compounds was structurally planned by modification of known thrombin inhibitors based on the use of acylhydrazone subunit, as a nonpeptide scaffold, and variations at P1 moiety. Three different families of arylsulfonate-acylhydrazone derivatives were designed. The bioassays indicated the first class of derivatives represented by 4f (LASSBio-693) and 4j (LASSBio-743), which were active in inhibiting the platelet aggregation induced by thrombin. The second class represented by compounds 4e (LASSBio-774) and 4h (LASSBio-480) that selectively inhibit the platelet aggregation involving TXA(2) formation. Finally, the third class of derivatives was identified acting as a novel symbiotic agent able to inhibit the platelet aggregation induced by collagen or AA and by thrombin, represented by compounds 4b (LASSBio-694) and 4g (LASSBio-770).

A number of 2-morpholino substituted benzoxazines have been prepared in order to test their effectiveness against ADP and collagen induced platelet aggregation. The reaction of 2-thio-1,3-benzoxazines with morpholine has been generalised to enable the use of substituted benzoxazines. Two separate methods were used to prepare 7-O-2-morpholino substituted benzoxazines from 7-hydroxy-2-morpholino benzoxazines. Antiplatelet testing was carried out on 15 of the title compounds. 7-(2-Chloroethoxy)-8-methyl-2-morpholin-4-yl-4H-1,3-benzoxazin-4-one 15d and 7-[2-(4-methylpiperazin-1-yl)ethoxy]-8-methyl-2-morpholin-4-yl-4H-1,3-benzoxazin-4-one 16d showed potent activity against ADP and collagen induced platelet aggregation. The structures of the newly prepared compounds were confirmed by microanalysis as well as the analysis of IR, (1)H and (13)C NMR.

A novel synthetic approach to N-aryl-4-(3-pyridyl)thiazol-2-amine and analogues using HMCM-41, a mesoporous aluminosilicate catalyst and their in vitro ADP-induced platelet aggregation inhibitory activity on human blood platelets is described. Among the test compounds N-(2'-flourophenyl)-4-(3-pyridyl)thiazol-2-amine (9e) was found to be the most potent, IC(50)=4.84x10(-7)M.

Diazeniumdiolates (NONOates), among them a ciprofloxacin-diazeniumdiolate hybrid compound, were synthesized and the pH-, temperature- and structure-dependent liberation of nitric oxide (NO) was monitored by laser magnetic resonance spectroscopy (LMRS). The compounds induced a transient and reversible relaxation (EC(50) 8.3-150 nM) of pulmonary arteries independently from intact endothelium by stimulation of guanylyl cyclase (sGC). Increase in vascular cGMP was observed and blocking sGC with ODQ, an inhibitor of the NO-sensitive guanylyl cyclase, induced a rightward shift of the concentration-response curves. Repeated exposure did not show homologous desensitization. ADP-induced platelet aggregation (IC(50) = 0.15-3 microM, IC(50) for SNP: 2 microM) and collagen-induced aggregation were potently inhibited. Preincubation with ODQ also diminished these inhibitory effects.

New platelet glycoprotein IIb/IIIa (GP IIb/IIIa, integrin alpha(IIb)beta3) antagonists were prepared on a 2H-1,4-benzoxazine-3(4H)-one scaffold. Their anti-aggregatory activities in human platelet rich plasma and their affinity towards alpha(IIb)beta3 and alpha(V)beta3 integrins were assessed. Various substitution positions and side chain variations were studied. In contrast to the generally accepted model, compounds containing ethyl esters as aspartate mimetics were in general more active than the corresponding free acids. We suggest an explanation for the observed behaviour of these new compounds.

Pursuing our chemical and biological studies in this field, we described the multistep preparation of the new 5-, 6-, or 7-alkoxy and 7-alkoxy-8-methyl substituted 4-(1-piperazinyl)coumarins 5d-v, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca(2+) ionophore A23187. Compounds 5h-j,p,r-u showed notably high activity towards all the platelet aggregation inducers used, and the most active one, 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin (5t), proved to be a potent in vitro antiplatelet agent.

Synthesis of 1,3-disubstituted indoles derivatives as potential glycoprotein (GP) IIb/IIIa antagonists was reported. Substitution of the indolic nitrogen atom by piperidino or benzamidino moieties was used as mimics of an arginine residue. The acid carboxylic group was linked to the indole scaffold in position-3 via a methylene unit (compounds 4, 9, 10). Introduction of a beta-alanine chain was carried out on the acids (17-22) which after deprotection and basic hydrolysis afforded the final compounds 39-46. The distance between the indole scaffold and the amide bond was modulated from no methylene unit (compound 39) to 1 (compounds 40, 41) or 2 methylene units (compounds 42-46). The presence of a tosylamino group on the beta-alanine chain (compound 56) slightly increased the inhibiting action on platelet aggregation initiated by collagen.

Naturally occurring saponins 3 and 4 have a normal type F ring and alpha-arranged CH(3)-21 group. Treatments of pseudosaponin peracetates 18 and 19 derived from 3 and 4, respectively, with alcoholic KOH, followed by acidification with acetic acid, gave spirostanols 20 and 22 having iso type F rings as major products. Structural analyses of sapogenins and saponins derived from pseudo derivatives 11, 12, 18 and 19 were performed by comparisons of their 1H-NMR spectral data and the X-ray analytical data of 3-O-p-bromobenzoyl sarsasapogenin 7, 3-O-acetyl diosgenin 13 and saponin 20. The mechanisms of ring-closure reaction of the side chain at C-22 of pseudosapogenins and pseudosaponins were deduced using stereomodels of the spirostanols derived from 11 under various reaction conditions. Inhibitory activities of saponin diglycosides 3, 4, 20, 21 and 25 on human platelet agglutinations induced by ADP and ristocetin were compared.