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An approach to the synthesis of phosphoryl substituted spiro-1,3-dioxolane oxindoles was developed from the base-catalyzed reaction of various isatins with (3-hydroxyprop-1-yn-1-yl)phosphonates. It was found that various aryl-substituted and N-functionalized isatins with the formation of appropriate products with high yields and stereoselectivity when using t -BuOLi are able to react. Cytotoxic activity evaluation suggests that the most significant results in relation to the HuTu 80 cell line were shown by N-benzylated spirodioxolanes. 5-Cloro- N -unsubstituted spirooxindoles exhibit antiaggregational activity exceeding the values of acetylsalicylic acid.

A series of stilbene analogues, in which a phenyl ring was replaced by the pyridazin-3(2H)-one nucleus, was designed and synthesized to be explored as platelet aggregation inhibitors. The proposed stilbene-pyridazinone hybrids were successfully obtained from simple starting materials and by Wittig's reaction. Most of the target compounds displayed improved in vitro activity in comparison with the standard drug, resveratrol, highlighting as the most potent the analogues 10d and 10e, with inhibition percentages of 94.15 % at 100 µM and 100 % at 50 µM, respectively. The pharmacokinetic and toxicity (ADME/T) properties of the novel hybrids were also estimated with the SwissADME and ProTox-II web servers., 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

ACKR3, an atypical chemokine receptor, has been associated with prothrombotic events and the development of cardiovascular events. We designed, synthesized, and evaluated a series of novel small molecule ACKR3 agonists. Extensive structure-activity relationship studies resulted in several promising agonists with potencies ranging from the low micromolar to nanomolar range, for example, 23 (EC 50 = 111 nM, E max = 95%) and 27 (EC 50 = 69 nM, E max = 82%) in the β-arrestin-recruitment assay. These compounds are selective for ACKR3 versus ACKR2, CXCR3, and CXCR4. Several agonists were subjected to investigations of their P-selectin expression reduction in the flow cytometry experiments. In particular, compounds 23 and 27 showed the highest potency for platelet aggregation inhibition, up to 80% and 97%, respectively. The most promising compounds, especially 27 , exhibited good solubility, metabolic stability, and no cytotoxicity, suggesting a potential tool compound for the treatment of platelet-mediated thrombosis.

Thrombosis plays an important role in the occurrence and development of cardiovascular and cerebrovascular diseases that contribute to high mortality and morbidity in patients. L-(-)-Quebrachitol (QCT), a natural product, was first isolated from quebracho bark. It can inhibit PAF receptor and decrease gastric damage induced by indomethacin, as a drug against platelet aggregation. Here, five QCT derivatives were synthesized and investigated for their inhibitory effects on platelet aggregation. Among them, compound 3a showed anticoagulant effects comparable to aspirin, while compound 4b showed dose-independent inhibitory activities in rats that were stronger than aspirin.

Drugs with anti-platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and 6-phenyl-4,5-dihydropyridazin-3(2H)-one hybrids were designed and synthesized. Among them, 6g showed the most effective cytoprotective effect against oxygen-glucose deprivation/reoxygenation-induced damage in BV2 cells and an excellent inhibitory effect on platelet aggregation induced by adenosine diphosphate and arachidonic acid. Additionally, 6g could prevent thrombosis caused by ferric chloride in rats and pose a lower risk of causing bleeding compared with aspirin. It provides better protection against ischemia/reperfusion injury in rats compared with edaravone and alleviates the oxidative stress related to cerebral ischemia/reperfusion by increasing the GSH and SOD levels and decreasing the MDA concentration. Finally, molecular docking results showed that 6g probably acts on PDE3 A and plays an anti-platelet aggregation effect. Overall, 6g could be a potential candidate compound for the treatment of ischemic stroke., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases., Objective: The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits., Methods: Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities., Results: The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC 50 values of 0.13 to 0.05 μM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC 50 value of 0.05 μM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED 50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90., Conclusion: The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sevoflurane was first synthesized independently by Richard Wallin and Bernard Regan at Travenol Laboratories Incorporated and Ross Terrell and Louise Croix at Airco, Inc in the late 1960s, and subsequent animal studies and a phase-1 human trial of the agent published in 1981 showed promising results. Further research in the United States was halted, however, because of concerns regarding potential nephrotoxicity and the introduction of less degradable alternatives. Interest in sevoflurane resumed in Japan when Maruishi Pharmaceutical Company, Limited (Ltd) (Maruishi) decided to continue its development in 1982. They secured approval by the Japanese Ministry of Health, Labor and Welfare for its clinical use in January 1990. Because of its low blood:gas partition coefficient and resulting rapid action, sevoflurane quickly became the anesthetic of choice of Japanese anesthesiologists. In 1992 Abbott Laboratories, now AbbVie, Inc (Abbott, North Chicago, IL) finalized a licensing agreement with Maruishi to seek the US Food and Drug Administration approval for sevoflurane sales in the United States. Approved in June 1995, sevoflurane is now marketed by Abbott in 120 countries and has been administered >120 million times. This report details the Japanese contribution to the development of sevoflurane., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

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.)

To obtain new anticancer agents with antimetastatic adjunct efficacy, a series of novel N 4 -hydrazone derivatives of 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one were designed and synthesized by an eight-step reaction, with appropriate yields. All the synthesized compounds were evaluated for their antiproliferative activity against A549 and MCF-7 cells and for antiplatelet aggregation activity in vitro. The results showed that compounds 25 and 35 not only showed potent antiproliferative activity against the A549 (IC 50  = 15.3 and 21.4 μM) and MCF-7 (IC 50  = 15.6 and 10.9 μM) cell lines but also showed certain antiplatelet aggregation activity (inhibition rates: 47.0% and 45.8%). These results indicated that the structural modification on the N 4 -hydrazone moiety of 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one is promising to obtain novel anticancer compounds with antimetastatic adjunct efficacy. In addition, a molecular docking study was performed to investigate the possible targets, and these results indicated that compounds 25 and 35 have the potential to target EGFR, HER2, and P2Y 12 ., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Background: Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT 2A receptor antagonists could constitute alternative antiplatelet therapy., Methods: Based on the structures of the conventional 5-HT 2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT 2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT 2A receptors using isolated rat aorta and cells expressing human 5-HT 2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT 2A receptor antagonists. Moreover, the structure-activity relationships were studied following molecular docking to the 5-HT 2A receptor model., Results: Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT 2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC 50  = 27.3 μM) being more active than sarpogrelate (IC 50  = 66.8 μM) and comparable with ketanserin (IC 50  = 32.1 μM). Moreover, compounds 2-5, 9-11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation., Conclusions: Our study confirmed that the 5-HT 2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action., (© 2021. The Author(s).)

In order to discover antiplatelet drug with novel structure and expand our research scope, total twenty 1,3-benzenedisulfonyl piperazines, were designed and synthesized. These target compounds were divided into two series, namely 4-methoxy-1,3-benzenedisulfonyl piperazines of series 1 and 4-ethoxy-1,3-benzenedisulfonyl piperazines of series 2. With adenosine diphosphate (ADP), arachidonic acid (AA) and collagen as inducers, respectively, the Born turbidimetric method was used to screen the antiplatelet activity in vitro of all target compounds at a concentration of 1.3 μM, with aspirin and picotamide as positive control drugs. And of which, the activities of five compounds for collagen were higher than both picotamide and aspirin. In ADP or AA channel, compounds with an inhibition rate greater than 33% were selected, and their corresponding IC 50 values were obtained. According to the IC 50 , the in vitro activity of one compound for ADP was higher than picotamide, and for AA, two compounds were higher than two positive control drugs and other two compounds only higher than or equal to aspirin. The preliminary analysis of the structure-activity relationship of the target compounds involved in this study was completed. Further, eight compounds exhibiting higher activity in one or two test channels, were subjected to cytotoxicity test on mouse fibroblasts (L929) by CCK-8 method. The in vitro cytotoxicity of most test compounds showed less than or same to control drug picotamide at 10 μM, but at the higher concentration of 100 μM, merely two compounds exhibited higher cell survival rate than that of picotamide. In addition, compound N 1 ,N 3 -di(4-ethoxy-1,3-phenylenedisulfonyl)bis(1-(m-tolyl)piperazine), which is delivery activity in the three test channels, and another compound N 1 ,N 3 -di(4-methoxy-1,3-phenylenedisulfonyl)bis(1-(m-tolyl)piperazine), which has the lowest cytotoxic in vitro compound among series 1 and series 2, respectively, are found and selected for simulation analysis as two most likely to dock with the receptor P 2 Y 12 . Each of synthesized compounds in silico molecular property and ADME (absorption, distribution, metabolism and excretion) are predicted by using Molinspiration property engine v2018.10 and PreADMET online servers, respectively. Compared with other series of compounds in the previous stage, the two series compounds obtained after the introduction of piperazinyl have a similar in vitro activity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Blood feeding arthropods, such as leeches, ticks, flies and mosquitoes, provide a privileged source of peptidic anticoagulant molecules. These primarily operate through inhibition of the central coagulation protease thrombin by binding to the active site and either exosite I or exosite II. Herein, we describe the rational design of a novel class of trivalent thrombin inhibitors that simultaneously block both exosites as well as the active site. These engineered hybrids were synthesized using tandem diselenide-selenoester ligation (DSL) and native chemical ligation (NCL) reactions in one-pot. The most potent trivalent inhibitors possessed femtomolar inhibition constants against α-thrombin and were selective over related coagulation proteases. A lead hybrid inhibitor possessed potent anticoagulant activity, blockade of both thrombin generation and platelet aggregation in vitro and efficacy in a murine thrombosis model at 1 mg kg -1 . The rational engineering approach described here lays the foundation for the development of potent and selective inhibitors for a range of other enzymatic targets that possess multiple sites for the disruption of protein-protein interactions, in addition to an active site., (© 2020 Wiley-VCH GmbH.)

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.)

The first trans-selective cyanoboration reaction of an alkyne, specifically a 1,3-enyne, is described. The reported palladium-catalyzed cyanoboration of 1,3-enynes is site-, regio-, and diastereoselective, and is uniquely enabled by the 1,4-azaborine-based Senphos ligand structure. Tetra-substituted alkenyl nitriles are obtained providing useful boron-dienenitrile building blocks that can be further functionalized. The utility of our method has been demonstrated with the synthesis of Satigrel, an anti-platelet aggregating agent., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

R-/S-2-(2-hydroxypropanamido) benzoic acid (R-/S-HPABA), marine-derived anti-inflammatory antiplatelet drugs, were initially synthesised in our group. However, preliminary research showed that R-/S-HPABA were eliminated rapidly because of extensive hydroxylation metabolism of phenyl ring in vivo. In order to reduce significant hydroxylation metabolism to improve pharmacological activity and bioavailability, trifluoromethyl group was incorporated into R-/S-HPABA to synthesise R-/S-2-(2-hydroxypropanamido)-5-trifluoromethyl benzoic acid (R-/S-HFBA), respectively. The purposes of this study were to report the synthesis of R-/S-HFBA and compare the anti-inflammatory antiplatelet effect and pharmacokinetic properties of R-/S-HFBA with those of R-/S-HPABA. Carrageenan-induced rat paw edema assay was used for the evaluation of the anti-inflammatory activity. R-/S-HFBA showed better results in inhibiting edema and were able to prolong the anti-inflammatory effect after carrageenan injection. The antiplatelet aggregation activity of R-/S-HFBA and R-/S-HPABA was studied on arachidonic acid-induced platelet aggregation of rabbit platelet-rich plasma. The aggregation inhibition rate of R-/S-HFBA was significantly (p < 0.05) higher than that of R-/S-HPABA, respectively. Molecular docking study revealed that R-/S-HFBA possess more potent binding affinity with COX-1/COX-2 than R-/S-HPABA, respectively, and that the presence of trifluoromethyl group leads to increase in activity of R-/S-HFBA. R-/S-HFBA also afford more favorable pharmacokinetic properties than R-/S-HPABA, respectively, such as higher C max , larger AUC 0-∞ , and longer t 1/2 , which, as expected, are more metabolically stable.

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 series of 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamides 6a-u were designed according to the splicing principle of structural design in the medicinal chemistry theory and were synthesized in five steps: nitration, acylation, ammoniation, reduction, and secondary ammoniation. The structures of the target compounds were characterized and verified by infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and electron spray ionization spectroscopy. Their in vitro antiplatelet aggregation activities induced by adenosine diphosphate (ADP) or arachidonic acid (AA) were assessed by Born's method. The biological evaluation revealed that all compounds exhibited certain levels of activities in both of the antiplatelet aggregation assays; compounds 6c (IC 50  = 3.84 μM) and 6f (IC 50  = 3.12 μM) displayed the strongest antiplatelet aggregation activities in the ADP-induced and AA-induced assay, separately. Moreover, compounds that had stronger activities were chosen for cell toxicity testing via the cell counting kit-8 assay. The results indicated that none of the compounds had obvious cell toxicity against L929 cells at the doses of 10 and 20 μM. It is worth pointing out that compound 6c showed the highest antiplatelet activity and the lowest cell toxicity. In general, 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamides have the potential to become a kind of safer and more effective antiplatelet agents., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

Heterocyclic compounds play a significant role in various biological processes of the human body and many of them are in clinical use due to their diverse, chemical and biological properties. Among these, indole is one of the most promising pharmacologically active molecules. Due to its chemical reactivity, indole has been willingly modified to obtain a variety of new lead molecules, which has been successfully utilized to obtained novel drug candidates for the treatment of different pharmacological diseases. Indole-based compounds such as vincristine (anticancer), reserpine (antihypertensive), amedalin (antidepressant) and many more describe the medicinal and pharmacological importance of the indole in uplifting human life. In this review, we compiled various reports on indole derivatives and their biological significance, including antifungal, antiprotozoal, antiplatelet, anti- Alzheimer's, anti-Parkinson's, antioxidant and anticancer potential from 2015 onwards. In addition, structure-activity relationship studies of the different derivatives have been included. We have also discussed novel synthetic strategies developed during this period for the synthesis of different indole derivatives. We believe that this review article will provide comprehensive knowledge about the medicinal importance of indoles and will help in the design and synthesis of novel indole-based molecules with high potency and efficacy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Both nitric oxide (NO) dysfunction and oxidative stress have been regarded as the important factors in the development and progression of diabetes and its complications. Multifunctional compounds with hypoglycemic, NO supplementation and anti-oxidation will be the promising agents for treatment of diabetes. In this study, six phenylfuroxan nitric oxide (NO) donor phenols were synthesized, which were designed via a combination approach with phenylfuroxan NO-donor and natural phenols. These novel synthetic compounds were screened in vitro for α-glucosidase inhibition, NO releasing, anti-oxidation, anti-glycation and anti-platelet aggregation activity as well as vasodilatation effects. The results exhibited that compound T5 displayed more excellent activity than other compounds. Moreover, T5 demonstrated significant hypoglycemic activity in diabetic mice and oral glucose tolerance test (OGTT) mice. T5 also showed NO releasing and anti-oxidation in diabetic mice. Based on these results, compound T5 deserves further study as potential new multifunctional anti-diabetic agent with antioxidant, NO releasing, anti-platelet aggregation and vasodilatation properties., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Platelet aggregation is the central event in hemostasis and thrombosis. Up to now, many agents inhibiting platelet aggregation have been approved for the treatment of thrombotic disorders. In this review, we mainly summarized the progress in the research of platelet aggregation inhibitors based on different design strategies. The advantage and challenge of corresponding targets are also discussed in this article. We hope more platelet aggregation inhibitors with efficacy and safety will be discovered in the future.

Aspirin is currently the most widely used drug worldwide, and has been clearly one of the most important pharmacological achievements of the twentieth century. Historians of medicine have traced its birth in 1897, but the fascinating history of aspirin actually dates back >3500 years, when willow bark was used as a painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece and Rome. The modern history of aspirin precursors, salicylates, began in 1763 with Reverend Stone - who first described their antipyretic effects - and continued in the 19th century with many researchers involved in their extraction and chemical synthesis. Bayer chemist Felix Hoffmann synthesized aspirin in 1897, and 70 years later the pharmacologist John Vane elucidated its mechanism of action in inhibiting prostaglandin production. Originally used as an antipyretic and anti-inflammatory drug, aspirin then became, for its antiplatelet properties, a milestone in preventing cardiovascular and cerebrovascular diseases. The aspirin story continues today with the growing evidence of its chemopreventive effect against colorectal and other types of cancer, now awaiting the results of ongoing primary prevention trials in this setting. This concise review revisits the history of aspirin with a focus on its most remote origins., (Copyright © 2018 Elsevier Inc. All rights reserved.)

BMS-986120 is a PAR4 antagonist that is being investigated as an antiplatelet agent in phase I clinical trial. An improved synthesis of BMS-986120 has been developed. Based on the novel synthetic approach to BMS-986120, a series of deuterated derivatives of BMS-986120 have been synthesized and biologically evaluated to search for more potent antiplatelet agents. The in vitro antiplatelet assay by turbidimetry demonstrated that PC-2 and PC-6 had IC 50 values of 6.30 nM and 6.97 nM, respectively, versus BMS-986120 with an IC 50 of 7.80 nM. The result of in vitro metabolic stability study showed that all of the deuterated compounds had similar half-life (T 1/2 ) and intrinsic clearance (Clint) in comparison with BMS-986120. Further probing the metabolic profile of BMS-986120 is worth being conducted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This research based on the anti-inflammatory and antiplatelet aggregation properties of some new thiazolyl hydrazone derivatives of 1-indanone. In this regard a thiosemicabazone and twelve thiazolyl derivatives of 1-indanone have been synthesized. Out of these synthetic compounds seven derivatives 1-3, 6, 11-13 exhibited varying degree of anti-inflammatory action with IC 50 esteems going from 5.1±1.3 - 78.8±4.6μM/mL. Compound 1 (IC50 =5.1±1.9μM) displayed potent result than standard ibuprofen (IC50 = 11.2±1.9 μM). In antiplatelet aggregation assay, five compounds 1, 5, 6, 8 and 11 were observed to be dynamic with IC50 esteems observed in the range of 38.34-255.7±4.1μM, wher eas, aspirin (IC 50 = 30.3±2.6 μM) was used as standard. However, compound 11 was found to be good active for both anti-inflammatory and antiplatelet aggregation activities (IC 50 = 13.9±4.9μg/mL) (IC 50 = 38.60±3.1μM), respectively.

In order to discover novel compounds with anti-platelet aggregation activities, a series of novel 2-methoxy-5-arylamido-N-(pyridin-3-ylmethyl)benzamides (1a-n) were synthesized and their anti-platelet aggregation activities were evaluated by the turbidimetric method in response to the following agonists: adenosine diphosphate (ADP) (5 mM/L), arachidonic acid (AA) (20 µM/L), and collagen (1 mg/mL). Those synthesized compounds that have better in vitro activities were subjected to cell toxicity tests via cell counting kit-8 (CCK-8) assay. The biological evaluation revealed that compound 1a (IC 50 : 0.21 µM/L) exhibited the highest anti-platelet aggregation activities when ADP was selected as an inducer, and compound 1b (IC 50 : 0.23 µM/L) showed the best activities when AA was selected as inducer, and compound 1m (inhibition rate: 55.06%) had significant anti-platelet aggregation activities when collagen was selected as inducer among all target compounds. Moreover, the effect of cell toxicity exhibited that none of the compounds had obvious cell toxicity against L929 cells. Therefore, 2-methoxy-5-arylamido-N-(pyridin-3-ylmethyl)benzamides have the potential to become a novel kind of anti-platelet drugs and deserve further study., (© 2018 Deutsche Pharmazeutische Gesellschaft.)

Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC 50 value of 0.060 μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC 50 of 26.9 μM and 20.5 μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.

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.)

To explore the potential of aporphine alkaloids, a novel series of functionalized aporphine analogues with alkoxy (OCH 3 , OC 2 H 5 , OC 3 H 7 ) functional groups at C1/C2 of ring A and an acyl (COCH 3 and COPh) or phenylsulfonyl (SO 2 Ph and SO 2 C 6 H 4 -3-CH 3 ) functionality at the N6 position of ring B of the aporphine scaffold were synthesized and evaluated for their arachidonic acid (AA)-induced antiplatelet aggregation inhibitory activity and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging antioxidant activity, with acetylsalicylic acid and ascorbic acid as standard references, respectively. The preliminary structure-activity relationship related to AA-induced platelet aggregation inhibitory activity results showed that the aporphine analogues 1-[1,2,9,10-tetramethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone and 1-[2-(benzyloxy)-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone to be the best compounds of the series. Moreover, the DPPH free-radical-scavenging antioxidant activity results demonstrated that the aporphine analogues 1,2,9,10-tetramethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2-ethoxy-1,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 1-ethoxy-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2,9,10-trimethoxy-6-(methylsulfonyl)-1-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, and 1-(benzyloxy)-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline were the best compounds of the series. Moreover, in silico molecular docking simulation studies of the active analogues were also performed., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Thus, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of FFA1 agonist and NO donor were design to obtain dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the induced-fit docking study suggested that it is feasible for our design strategy to hybrid NO donor with compound 1. These hybrids exhibited moderate FFA1 agonistic activities and anti-platelet aggregation activities, and their anti-platelet effects mediated by NO were also confirmed in the presence of NO scavenger. Moreover, compound 3 revealed significantly hypoglycemic effect and even stronger than that of TAK-875 during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 3, is expected as a potential candidate with additional cardiovascular benefits for the treatment of T2DM., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth., Methods: For this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)- β -carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors., Results: The synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 μmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver., Conclusion: Therefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

A series of 2-oxo-2-phenylethylidene linked 2-oxo-benzo[1,4]oxazine analogues 17a-x and 18a-o, incorporated with a variety of electron-withdrawing as well as electron-donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a-x and 18a-o were evaluated for their arachidonic acid (AA)-induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC 50  = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i, 17x, 18f, 18g, 18h, 18i, 18l, and 18o, were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T 3 fibroblast cell lines by MTT assay of the promising compounds (17i, 17x, 18f-18i, 18l, and 18o) were also performed and the compounds were found to be non-toxic in nature. Furthermore, the results on the AA-induced platelet aggregation inhibitory activities of these compounds (17i, 17x, 18f-18i, 18l, and 18o) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non-peptide-based functionalized 2-oxo-benzo[1,4]oxazines as platelet aggregation inhibitors., (© 2018 Deutsche Pharmazeutische Gesellschaft.)

During the past few decades the emergence of inorganic medicinal chemistry has been developed novel therapeutic agents. Researcher's perseverance in this branch of chemistry has led them to explore further valuable chemical spaces by synthesizing metal complexes already known pharmacological agents for their potential use. However, it is in its early stage, this methodology has demonstrated metal complexes with better bioactivities than the parent ligand molecules. In this study, transition metal complexes of pyrazinamide (PZ), isoniazid (INH), fluconazole (FCZ), metformin (dimethylbiguanide, DMBG) and losartan potassium (LS-K) were selected to evaluate for their possible anti-platelets aggregation in the light of reports on divalent and trivalent cations like calcium, copper, manganese, magnesium, and cadmium may influence the process of thrombocytic activity and aggregation. The required evaluation was carried out on human plasma through an APACT 4004 platelet aggregation analyzer. Arachidonic acid (ADP) was used to gauge any alteration in platelet shape and aggregation process. The parent drugs showed some anti-platelets aggregation, however, their metal complexes demonstrated better efficacy.

Background: Arterial thrombosis has been associated with a series of pathological conditions, and the discovery of arterial thrombosis inhibitor is of clinical importance., Methods: By analyzing the pharmacophores of anti-platelet agents, thrombus targeting peptide and anti-thrombotic nano-systems 3S-1,2,3,4-tetrahydroisoquino-line-3-carbonyl-Thr-Ala-Arg-Gly-Asp(Val)-Val (IQCA-TAVV) was designed and prepared as a nano-scaled arterial thrombosis inhibitor., Results: In vitro the nanoparticles of IQCA-TAVV were able to adhere onto the surface of activated platelets, attenuate activated platelets to extend pseudopodia and inhibit activated platelets to form aggregators. In vivo IQCA-TAVV targeted arterial thrombus, dose dependently inhibited arterial thrombosis with a 1 nmol/kg of minimal effective dose, and the activity waŝ1670 folds of that of aspirin., Conclusion: IQCA-TAVV represented the design, preparation and application of nanomedicine capable of adhering on the surface of activated platelets, attenuating platelet activation, targeting arterial thrombus and inhibiting arterial thrombosis., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The regulation of platelet function by pharmacological agents that modulate platelet signaling has proven to be a positive approach to the prevention of thrombosis. Ruthenium complexes are fascinating for the development of new drugs, as they possess numerous chemical and biological properties. The present study aims to evaluate the structure-activity relationship (SAR) of newly synthesized ruthenium (II) complexes, TQ-1, TQ-2 and TQ-3 in agonists-induced washed human platelets. Silica gel column chromatography, aggregometry, immunoblotting, NMR, and X-ray analyses were performed in this study. Of the three tested compounds, TQ-3 showed a concentration (1-5 μM) dependent inhibitory effect on platelet aggregation induced by collagen (1 μg/mL) and thrombin (0.01 U/mL) in washed human platelets; however, TQ-1 and TQ-2 had no response even at 250 μM of collagen and thrombin-induced aggregation. TQ-3 was effective with inhibiting collagen-induced ATP release, calcium mobilization ([Ca 2+ ]i) and P-selectin expression without cytotoxicity. Moreover, TQ-3 significantly abolished collagen-induced Lyn-Fyn-Syk, Akt-JNK and p38 mitogen-activated protein kinases (p38 MAPKs) phosphorylation. The compound TQ-3 containing an electron donating amino group with two phenyl groups of the quinoline core could be accounted for by its hydrophobicity and this nature might be the reason for the noted antiplatelet effects of TQ-3. The present results provide a molecular basis for the inhibition by TQ-3 in collagen-induced platelet aggregation, through the suppression of multiple machineries of the signaling pathway. These results may suggest that TQ-3 can be considered a potential agent for the treatment of vascular diseases., Competing Interests: The authors declare no conflict of interest.

Background: Currently, used oral antiplatelet drugs are both limited and associated with the risk of treatment failure/resistance. Research in this area is hence highly desired. A series of xanthene-3-ones derivatives, we had synthesized, showed us that these derivatives had antiplatelet activity. As far as we know, no research on the effects of xanthen-3-ones in this area has been done., Objective: The aim was to study the antiplatelet potential of a series of synthesised 9-phenylxanthene- 3-ones and to find the ideal structural feature(s) for antiplatelet potential and determine the mechanism of action., Methods: The compounds were synthesized from 1,2,4-triacetoxybenzene and various benzaldehydes. The reaction proceeded smoothly under acidic alcoholic conditions, furnishing the desired products in good yields. The compounds were first screened in whole human blood where platelet aggregation was induced by arachidonic acid. Further analysis was targeted at search of the mechanism of action., Results: Initial screening showed that a majority of the synthesized derivatives had substantial antiplatelet potential. None of the compounds were able to block cyclooxygenase 1 or thromboxane synthase. The mechanism appeared to be based on antagonism of thromboxane effects. The most potent compound 9-(4'-dimethylaminophenyl)-2,6,7-trihydroxy-xanthene-3-one had better potential to block collagen induced platelet aggregation than clinically used acetylsalicylic acid., Conclusion: The last mentioned derivative is promising for further in vivo testing., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Aim: To find novel platelet aggregation inhibitors, two new series of 1,4-benzodioxine derivatives were synthesized and screened for the ability to inhibit platelet aggregation., Materials & Methods: The synthesized compounds were evaluated for antiplatelet aggregation activity using human blood platelet and GPIIb/IIIa antagonistic activity., Results: Compound 9-2p showed significant antiplatelet activity with the IC 50 values of 41.7 and 22.2 μM induced by ADP and thrombin, respectively, more potent than that of LX2421. Compound 9-2p exhibited GPIIb/IIIa antagonistic activity with the IC 50 value of 2.3 μM, as potent as RGDs. In vivo study showed that 9-2p displayed remarkable antithrombotic activity, more effective than LX2421, but less effective than tirofiban., Conclusion: Compound 9-2p showed moderate antiplatelet activity and antithrombotic activity, which could be further optimized based on the target of GPIIb/IIIa.

Background: Prostaglandins are a family of eicosanoids biosynthesized from arachidonic acid through cyclooxygenase (COX) pathway. Two isoforms of COX are well established: COX-1, COX-2. Evidence supports the notion that cyclooxygenase-2, plays a crucial role in some pathological conditions such as inflammation and cancer., Objective: A new group of 1,3-diphenyl-3-(phenylamino)propan-1-ones was designed and synthesized to investigate for their COX-2 inhibitory activity and inhibition of platelet aggregation., Method: Docking study was performed using AutoDock vina software. In vitro COX-1 and COX- 2 isozyme inhibition studies were accomplished to obtain structure activity relationship data. The in vitro antiplatelet aggregation activity was determined by turbidimetric procedure., Results: In vitro COX inhibition assay showed that except compound 8c, all derivatives were selective COX-2 inhibitors with IC50 values in the potent 0.20-0.35 µM range with high COX-2 selectivity indexes (SI). Molecular modeling and docking studies indicated that synthesized compounds had a binding similar to that of the known inhibitor SC-558 and the SO2Me group was inserted into the COX-2 secondary pocket (Val523, Phe518, Ile517, Arg513 and His90) and C=O of the central α, β-unsaturated-carbonyl moiety was oriented toward the entrance to the COX-2 binding site (Tyr355 and Arg120)., Conclusion: The 1,3-diphenyl-3-(phenylamino)propan-1-ones are novel COX-2 inhibitors with good COX-2 inhibitory and low affinity for COX-1 isoenzyme. Also our results demonstrated that majority of these compounds inhibited AA-induced platelet aggregation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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.)

The aim of the present study was to report on a complete synthetic approach, namely benzylation-hydrolysis-acylation‑hydrogenation, to the synthesis of regioselectively acylated quercetin analogues using low‑cost rutin as a starting material. Three quercetin analogues, quercetin‑3‑O‑propionate (Q‑pr), quercetin‑3‑O‑butyrate (Q‑bu) and quercetin‑3‑O‑valerate (Q‑va), containing 3‑, 4‑ and 5‑carbon aliphatic acyl chains, respectively, were synthesized and characterized with 1H nuclear magnetic resonance (NMR), 13C NMR and mass spectrometry. Compared with quercetin, all three analogues exhibited improved lipophilicity. The lipophilicity of the analogue increased with increasing acyl chain length. Q‑va exhibited the highest lipophilicity among the three analogues, but a lower water solubility compared with quercetin. By contrast, Q‑pr and Q‑bu exhibited 8.2‑ and 4.7‑fold higher water solubility compared with quercetin, respectively. The in vitro and in vivo studies demonstrated that Q‑pr and Q‑bu were more effective whereas Q‑va was less effective in inhibiting platelet aggregation compared with quercetin. These results indicated that the water solubility and the lipophilicity of the analogues must be improved in order to achieve higher antiplatelet activity, and an optimal acyl chain length is crucial for the synthesized quercetin analogues to be more effective.

Myocardial infarction, i.e., heart attack, is a fatal condition which is on the increase all over the world. It is reported that a large number of heart attack occur in morning hours which are attributable to platelet aggregation. Chronotherapy at this stage can be crucial. Clopidogrel bisulfate (CLB) is an antiplatelet agent and has become a drug of choice for prevention of heart attack. It is soluble in acidic pH and has a narrow absorption window. So, its long residence time in stomach is desirable. Therefore, a novel high density tablet was developed comprising multiparticulate pellets with pulsatile release necessary to maintain chronotherapy of heart attack. The pellets were prepared by extrusion-spheronization and coated in fluidized bed processor with different coating material to achieve pulsatile release. The size, shape of pellets, and drug release were evaluated. High density tablet containing coated pellets was formulated and evaluated for retention in stomach. Quality by design tools was used to design and optimize the processes. Timed release observed by dissolution study showed lag time of 6 h followed by burst release of drug up to 94% in 1 h. Density of tablets was found to be 2.2 g cm -3 which is more than gastric fluid. In vivo x-ray studies in rabbit revealed 8 h of gastric retention of tablet at the bottom of the stomach. Thus, CLB high density pulsatile system looks to open up a window of opportunity for developing formulations with drugs that are stable in gastric region and needed chronotheraupetic activity.

Background: The current standard-of-care antiplatelet therapy in cardiovascular disease patients is consisted of cyclooxygenase-1 (COX-1) inhibitor aspirin, along with a platelet receptor P2Y 12 antagonist. Recently, the triple antiplatelet therapy with aspirin, a P2Y 12 receptor antagonist and a protease activated receptor-1 (PAR-1) antagonist, has been suggested for the secondary prevention of atherothrombotic events, however presented an increased risk of bleeding. Therefore, the quest for novel antiplatelet agents simultaneously targeting the three pathways with improved efficacy/safety profile is of immense importance. Flavonoids as pre-validated ligands for numerous targets could serve as scaffolds targeting the three platelet activation pathways., Methods: Computational methods, Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) plasma stability and in vitro platelet aggregation experiments were used to establish the antiplatelet activity of the flavonoid naringenin and its conjugates., Results: In silico studies indicated that naringenin could bear a potent triple antiplatelet activity by inhibiting different platelet aggregation mechanisms. However, we found that in human platelets naringenin has diminished activity. We rationally designed and synthesized different naringenin conjugates aiming to amplify the antiplatelet activity of the parent compound. UHPLC-MS/MS revealed a slow degradation rate for a docosahexaenoic acid (DHA) - naringenin conjugate in human plasma. The antiplatelet profile of the new analogues was evaluated against in vitro platelet aggregation induced by several platelet agonists., Conclusions: The DHA - naringenin hybrid presented triple antiplatelet activity simultaneously targeting PAR-1, P2Y 12 and COX-1 platelet activation pathways., General Significance: Natural products could offer a rich source for novel bioactives as a powerful alternative to the current combinatorial use of three different antiplatelet drugs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

S-(+)-Methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate, also known as (S)-clopidogrel, is marketed under the trade names Plavix and Iscover. It is a potent thienopyridine-class of antithrombotic and antiplatelet drug (antiaggregant). Among the two available stereoisomers of clopidogrel, for pharmaceutical activities only the S-enantiomer is applicable, as no antithrombotic activity is observed in the R-enantiomer and causes political upheavals and social turmoil in animal experiments. Worldwide sales of Plavix amounted to $6.4 billion yearly, which ranks second. Attributed to the increased demand of (S)-clopidogrel drug, it provoked the synthetic community to devise facile synthetic approaches. This review aims to summarize the synthetic methods of (S)-clopidogrel drug reported in the literature. The present review discusses the pros and cons of each synthetic methodology, which would be beneficial to the scientific community for further developments in the synthetic methodologies for (S)-clopidogrel. In addition, the compilation approach of literature-reported synthetic strategies of (S)-clopidogrel in one platform is advantageous, supportive, and crucial for the synthetic community to elect the best synthetic methodology of (S)-clopidogrel and to create new synthesis ideas., (© 2017 Wiley Periodicals, Inc.)

A series of 40 7-(O-substituted)-2-morpholino-8-aryl-4H-benzo[e][1,3]oxazin-4-one derivatives was synthesized. They were prepared via synthesis of a key precursor, 8-bromo-7-hydroxy-2-morpholino-4H-benzo[e][1,3]oxazin-4-one 13 which was amenable to ether synthesis at the 7-position and Suzuki coupling at the 8-position. The 2 protons of 7-OCH 2 in compounds 18g, 18h, 18i, 18l and 18m prove to be magnetically non-equivalent, atropisomerism (axial chirality), as result of sterically hindered rotation of the bulky 8-aryl-substituent. The products were evaluated for their activities against PI3K isoforms, DNA-PK and PDE3. The results showed that this substitution pattern has a deleterious effect on PI3K activities, which may arise from steric hindrance in the active site. PI3Kδ was somewhat more tolerant of this substitution particularly where 8-(4-methoxylphenyl) substituents were present (IC 50 s∼2-3μM). Good activities against PDE3 were also obtained for compounds, with particular members of the 7-(2-pyridinyl) methoxy series 19 showing good inhibition (IC 50 s∼2-3μM), comparable to previously described analogues. A piperazinyl derivative 26a effectively inhibited ADP-induced platelet aggregation with an IC 50 of 8μM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Ten new cinnamic acid derivatives containing a 2-aminothiazole substructure were designed and synthesized. This series of compounds exhibited good thermostabilities as demonstrated by thermogravimetric analysis. In coagulation assays (prothrombin time, activated partial thromboplastin time and thrombin time) in vitro, most compounds demonstrated excellent activities to promote blood coagulation. Among the studied series, compounds N1, N4, N5 and W5 exhibited a significant coagulation activity. Further studies indicated that compound N5 (IC 50 =1.87μmol/L) displayed the most suitable efficacy of promoting platelet aggregation than the clinically used haemostatic drug etamsylate (IC 50 =46.22μmol/L). Furthermore, the relationship between the functional groups of the compounds and the corresponding blood coagulant activity was explored in this study., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Protease-activated receptor-1 (PAR1), a G-protein-coupled receptor, plays a critical role in thrombin-mediated platelet aggregation. It is regarded as a promising antithrombosis target that is unlikely to result in bleeding. Here, we describe the synthesis of a series of novel PAR1 antagonists by borrowing the chiral fragment of andrographolide, an easily accessible natural molecule from Andrographis paniculata, to produce natural product/synthesis hybrids. An in vitro PAR1 inhibition assay and an in vivo pharmacokinetic profile led to the identification of compound 39 as the best PAR1 inhibitor. The further in vitro and ex vivo antiplatelet aggregation assays of compound 39 indicated that compound 39 was a potent antiplatelet agent. In addition, this compound is metabolically stable and displays a favorable pharmacokinetic profile with an elimination half-life of 3.1 h, which could be treated as a promising candidate for further clinical development.

Phenylsulfonyfuroxan nitric oxide (NO)-donor phenols were designed, synthesized and evaluated. The compounds were designed through a symbiotic approach using selected phenols and phenylsulfonylfuroxan NO-donor. The antioxidant activities of the hybrid compounds T 2 -T 6 showed to be good in vivo. Compounds T 4 and T 6 revealed excellent yeast α-glucosidase inhibitory activity and anti-glycosylation activity. All of the compounds exhibited strong NO releasing activity and significant anti-platelet aggregation activity. The inhibition of platelet aggregation was more than 50% at low concentration (1.5μM) and 95% at higher concentration (15μM and 150μM). The vasodilatation experiment demonstrated that the six compounds under test exhibited definite vasodilation activity (pIC 50 ranged from 5.698 to 6.383), especially compound T 6 (pIC 50 was 6.383) which was similar to sodium nitroprusside (pIC 50 was 6.786). Both anticoagulant and vasodilatation effects were correlated with their NO releasing activities. These hybrid phenylsulfonyfuroxan-based NO-donor phenols offer a multifunctional prodrug design concept for the development of therapeutic or preventive agents for metabolic syndrome., (Copyright © 2017. Published by Elsevier Ltd.)

In situ methylene capping is introduced as a practical and broadly applicable strategy that can expand the scope of catalyst-controlled stereoselective olefin metathesis considerably. By incorporation of commercially available Z-butene together with robust and readily accessible Ru-based dithiolate catalysts developed in these laboratories, a large variety of transformations can be made to proceed with terminal alkenes, without the need for a priori synthesis of a stereochemically defined disubstituted olefin. Reactions thus proceed with significantly higher efficiency and Z selectivity as compared to when other Ru-, Mo-, or W-based complexes are utilized. Cross-metathesis with olefins that contain a carboxylic acid, an aldehyde, an allylic alcohol, an aryl olefin, an α substituent, or amino acid residues was carried out to generate the desired products in 47-88% yield and 90:10 to >98:2 Z:E selectivity. Transformations were equally efficient and stereoselective with a ∼70:30 Z-:E-butene mixture, which is a byproduct of crude oil cracking. The in situ methylene capping strategy was used with the same Ru catechothiolate complex (no catalyst modification necessary) to perform ring-closing metathesis reactions, generating 14- to 21-membered ring macrocyclic alkenes in 40-70% yield and 96:4-98:2 Z:E selectivity; here too, reactions were more efficient and Z-selective than when the other catalyst classes are employed. The utility of the approach is highlighted by applications to efficient and stereoselective syntheses of several biologically active molecules. This includes a platelet aggregate inhibitor and two members of the prostaglandin family of compounds by catalytic cross-metathesis reactions, and a strained 14-membered ring stapled peptide by means of macrocyclic ring-closing metathesis. The approach presented herein is likely to have a notable effect on broadening the scope of olefin metathesis, as the stability of methylidene complexes is a generally debilitating issue with all types of catalyst systems. Illustrative examples of kinetically controlled E-selective cross-metathesis and macrocyclic ring-closing reactions, where E-butene serves as the methylene capping agent, are provided.

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.)