Abstract
In the present study, a series of new hydrazone and sulfonamide derivatives of 1,2,4-triazole were synthesized. Initially three 4-substituted-5-(2-pyridyl)-1,2,4-triazole-3-thiones ZE-1(a–c) were treated with ethyl chloroacetate to get the corresponding thioesters ZE-2(a–c), which were reacted with hydrazine hydrate to the respective hydrazides ZE-3(a–c). The synthesized hydrazides were condensed with different aldehydes and p-toluene sulfonylchloride to furnish the target hydrazone derivatives ZE-4(a–c) and sulfonamide derivatives ZE-5(a–c) respectively. All the synthesized compounds were characterized by FTIR, 1HNMR, 13CNMR and elemental analysis data. Furthermore, the new hydrazone and sulfonamide derivatives ZE-4(b–c) and ZE-5(a–b) were evaluated for their antiplatelet and anticoagulant activities. ZE-4b, ZE-4c, ZE-5a and ZE-5b inhibited arachidonic acid, adenosine diphosphate and collagen-induced platelets aggregation with IC50 values of 40.1, 785 and 10.01 (ZE-4b), 55.3, 850.4 and 10 (ZE-4c), 121.6, 956.8 and 30.1 (ZE-5a), 99.9, 519 and 29.97 (ZE-5b) respectively. Test compounds increased plasma recalcification time (PRT) and bleeding time (BT) with ZE-4c being found most effective, which at 30, 100, 300 and 1000 µM increased PRT to 84.2 ± 1.88, 142 ± 3.51, 205.6 ± 5.37 and 300.2 ± 3.48 s and prolonged BT to 90.5 ± 3.12, 112.25 ± 2.66, 145.75 ± 1.60 s (P < 0.001 vs. saline group) respectively. In silico docking approach was also applied to screen these compounds for their efficacy against selected drug targets of platelet aggregation and blood coagulation. Thus in silico, in vitro and in vivo investigations of ZE-4b, ZE-4c, ZE-5a and ZE-5b prove their antiplatelet and anticoagulant potential and can be used as lead molecules for further development.
Highlights
Thrombotic disorders are responsible for major health problems worldwide [1]
Molecular docking study of synthesized compounds was performed against selected targets of platelet aggregation and blood coagulation pathways to study the binding interactions which can provide an insight into the possible mechanism of action of these new molecules
The intermediate hydrazides were condensed with p-toluene sulfonyl chloride to get the sulfonamide derivatives ZE-5(a–c)
Summary
Thrombotic disorders are responsible for major health problems worldwide [1]. According to global burden of diseases, injuries and risk factors study, ischemic heart diseases caused 7.0 million deaths and stroke up to 5.9 million deaths in 2010 only. Triazole derivatives have wide pharmacological spectrum such as antimicrobial, anti-inflammatory, analgesic, antimalarial, antiviral, antiproliferative, anticancer and various other activities [8]. 1,2,3-triazole derivatives have shown significant inhibitory activity against blood platelet aggregation and coagulation [9]. Hydrazone is a class of organic compounds having azomethine group R1R2C=NNH2, which are known to possess different pharmacological activities like antimicrobial, analgesic, anti-inflammatory, anticonvulsant, antidiabetic, antitumor and antiplatelet activities [10]. The synthesized derivatives ZE-4(b–c) and ZE-5(a–b), as shown, were investigated for their antiplatelet and anticoagulant effects using in vitro and in vivo assays. Molecular docking study of synthesized compounds was performed against selected targets of platelet aggregation and blood coagulation pathways to study the binding interactions which can provide an insight into the possible mechanism of action of these new molecules
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call