Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation
Coagulation factor Xa (FXa), a serine endopeptidase is a common coagulation factor activated as a result of the initiation of both intrinsic and extrinsic blood coagulation pathways. Hence, FXa has been regarded as an important pharmaceutical target for the treatment of thrombotic disorders. In this...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Results in Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211715622000741 |
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| author | Rahul H. Rayani Jigar Y. Soni Deepa R. Parmar Rakesh V. Kusurkar Ibrahim.H. Eissae Ahmed M. Metwaly Ahmed Khalil Vishwanath Zunjar Satyanarayana Battula Sarfaraj Niazi |
| author_facet | Rahul H. Rayani Jigar Y. Soni Deepa R. Parmar Rakesh V. Kusurkar Ibrahim.H. Eissae Ahmed M. Metwaly Ahmed Khalil Vishwanath Zunjar Satyanarayana Battula Sarfaraj Niazi |
| author_sort | Rahul H. Rayani |
| collection | DOAJ |
| description | Coagulation factor Xa (FXa), a serine endopeptidase is a common coagulation factor activated as a result of the initiation of both intrinsic and extrinsic blood coagulation pathways. Hence, FXa has been regarded as an important pharmaceutical target for the treatment of thrombotic disorders. In this study, we reported the design and synthesis of pyrazolyl piperidine analogs 4(a–h) as a new class of anticoagulant drug candidates. Among the synthesized analogs 4(a–h), compound 4a consisting of the 4-chlorophenyl substitution displayed the highest in vitro FXa inhibition activity with an IC50 value of 13.4 nM. The PT and aPTT assay indicated that compound 4a showed good anticoagulation activity compared to Heparin. Furthermore, docking studies suggested that the synthesized analogs displayed binding modes similar to the cocrystallized Rivaroxaban ligand. In addition, in-silico ADMET and DFT studies were carried out for all the designed compounds. Together, our study suggests that the compound (4a) displayed anti-coagulant activity through the inhibition of FXa. |
| first_indexed | 2024-04-13T05:53:42Z |
| format | Article |
| id | doaj.art-0abed611090445ab8dda034f1d4afd70 |
| institution | Directory Open Access Journal |
| issn | 2211-7156 |
| language | English |
| last_indexed | 2024-04-13T05:53:42Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Results in Chemistry |
| spelling | doaj.art-0abed611090445ab8dda034f1d4afd702022-12-22T02:59:41ZengElsevierResults in Chemistry2211-71562022-01-014100355Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluationRahul H. Rayani0Jigar Y. Soni1Deepa R. Parmar2Rakesh V. Kusurkar3Ibrahim.H. Eissae4Ahmed M. Metwaly5Ahmed Khalil6Vishwanath Zunjar7Satyanarayana Battula8Sarfaraj Niazi9Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, IndiaDepartment of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, India; Corresponding author.Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, IndiaDepartment of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, IndiaPharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, EgyptPharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al- Azhar University, Cairo, EgyptDepartment of Chemistry, College of Science, King Faisal University, Al-Hofuf, Al-Ahsa 31982, Saudi Arabia; Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, EgyptSchool of Engineering and Technology, Navrachana University, Vadodara, Gujarat, IndiaDepartment of Chemistry, Uka Tarsadia University, Maliba Campus, Bardoli, Gujarat, IndiaPiramal Pharma Limited – Discovery Solutions, Shirish Research Campus, PHARMEZ Plot-18, Sarkhej-Bavla Road, Matoda, Ahmedabad 382213, IndiaCoagulation factor Xa (FXa), a serine endopeptidase is a common coagulation factor activated as a result of the initiation of both intrinsic and extrinsic blood coagulation pathways. Hence, FXa has been regarded as an important pharmaceutical target for the treatment of thrombotic disorders. In this study, we reported the design and synthesis of pyrazolyl piperidine analogs 4(a–h) as a new class of anticoagulant drug candidates. Among the synthesized analogs 4(a–h), compound 4a consisting of the 4-chlorophenyl substitution displayed the highest in vitro FXa inhibition activity with an IC50 value of 13.4 nM. The PT and aPTT assay indicated that compound 4a showed good anticoagulation activity compared to Heparin. Furthermore, docking studies suggested that the synthesized analogs displayed binding modes similar to the cocrystallized Rivaroxaban ligand. In addition, in-silico ADMET and DFT studies were carried out for all the designed compounds. Together, our study suggests that the compound (4a) displayed anti-coagulant activity through the inhibition of FXa.http://www.sciencedirect.com/science/article/pii/S2211715622000741ADMETAnti-coagulationDFT studyFactor XaMolecular dockingPyrazolyl piperidine |
| spellingShingle | Rahul H. Rayani Jigar Y. Soni Deepa R. Parmar Rakesh V. Kusurkar Ibrahim.H. Eissae Ahmed M. Metwaly Ahmed Khalil Vishwanath Zunjar Satyanarayana Battula Sarfaraj Niazi Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation Results in Chemistry ADMET Anti-coagulation DFT study Factor Xa Molecular docking Pyrazolyl piperidine |
| title | Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation |
| title_full | Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation |
| title_fullStr | Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation |
| title_full_unstemmed | Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation |
| title_short | Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation |
| title_sort | identification of new pyrazolyl piperidine molecules as factor xa inhibitors design synthesis in silico and biological evaluation |
| topic | ADMET Anti-coagulation DFT study Factor Xa Molecular docking Pyrazolyl piperidine |
| url | http://www.sciencedirect.com/science/article/pii/S2211715622000741 |
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