Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors
Mohamed A. Shaaban
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Search for more papers by this authorAliaa M. Kamal
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Department of Organic Chemistry, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Giza, Egypt
Search for more papers by this authorSamar I. Faggal
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Search for more papers by this authorCorresponding Author
Nahla A. Farag
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Cairo, Egypt
Correspondence Khaled O. Mohamed, Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, Cairo 11562, Egypt.
Email: [email protected]
Nahla A. Farag, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Km 28 Cairo-Ismailia Road (Ahmed Orabi District), Cairo 11431, Egypt.
Email: [email protected]
Search for more papers by this authorNora M. Aborehab
Department of Biochemistry, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Giza, Egypt
Search for more papers by this authorAyman E. Elsahar
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Search for more papers by this authorCorresponding Author
Khaled O. Mohamed
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Correspondence Khaled O. Mohamed, Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, Cairo 11562, Egypt.
Email: [email protected]
Nahla A. Farag, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Km 28 Cairo-Ismailia Road (Ahmed Orabi District), Cairo 11431, Egypt.
Email: [email protected]
Search for more papers by this authorMohamed A. Shaaban
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Search for more papers by this authorAliaa M. Kamal
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Department of Organic Chemistry, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Giza, Egypt
Search for more papers by this authorSamar I. Faggal
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Search for more papers by this authorCorresponding Author
Nahla A. Farag
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Cairo, Egypt
Correspondence Khaled O. Mohamed, Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, Cairo 11562, Egypt.
Email: [email protected]
Nahla A. Farag, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Km 28 Cairo-Ismailia Road (Ahmed Orabi District), Cairo 11431, Egypt.
Email: [email protected]
Search for more papers by this authorNora M. Aborehab
Department of Biochemistry, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Giza, Egypt
Search for more papers by this authorAyman E. Elsahar
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Search for more papers by this authorCorresponding Author
Khaled O. Mohamed
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Correspondence Khaled O. Mohamed, Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, Cairo 11562, Egypt.
Email: [email protected]
Nahla A. Farag, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Km 28 Cairo-Ismailia Road (Ahmed Orabi District), Cairo 11431, Egypt.
Email: [email protected]
Search for more papers by this authorAbstract
A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1H nuclear magnetic resonance (NMR), 13C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.
CONFLICTS OF INTERESTS
The authors declare that there are no conflicts of interests.
Supporting Information
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| ardp202000027-sup-0001-InChI_Codes_and_biological_activities.doc84 KB | Supporting information |
| ardp202000027-sup-0002-Supplementary_Data.docx5.4 MB | Supporting information |
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