Synthesis, anti-inflammatory, analgesic, COX-1/2 inhibitory activities and molecular docking studies of substituted 2-mercapto-4(3H)-quinazolinones.
A new series of 2-substituted mercapto-4(3H)-quinazolinone 1-26 were synthesized and assessed for in vivo anti-inflammatory and analgesic activities and in vitro inhibition of cyclooxygenase COX-1/COX-2. A new series of 2-substituted mercapto-4(3H)-quinazolinone 1-26 were synthesized and assessed for in vivo anti-inflammatory and analgesic activities. The potent anti-inflammatory compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 inhibition assays. Compounds 1, 3, 5, 11, 12, 13, 15, 17, and 25 exhibited potent anti-inflammatory effects, with half-maximal effective dose (ED50) values of 65.7-102.4 mg/kg, (0.16-0.36 mmol/kg), and strong analgesic activities, with ED50 values of 33.3-104.6 mg/kg, (0.07-0.34 mmol/kg). These values were compared with those of diclofenac sodium [ED50 values: 112.2 and 100.4 mg/kg, (0.35 and 0.31 mmol/kg)], and celecoxib [ED50 values: 84.3 and 71.6 mg/kg (0.22 and 0.19 mmol/kg)], respectively as reference drugs. Compounds 1, 11, 12, 13, 15, 17, and 25 exhibited effective COX-2 inhibitory activity, with half-maximal inhibitor concentration (IC50) values of 0.70-2.0 μM and selectivity index (SI) values of more than 50-142.9 compared with celecoxib as reference drugs (IC50 = 0.30 μM and COX-2 SI: >333). Potent COX-2 inhibitors, i.e., compounds 15, 11, and 17 were docked into the binding site pockets of COX-1 and COX-2. These compounds exhibited strong interactions at the COX-2 binding site and poor interactions at COX-1 active site pocket.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: alaa_moenes@yahoo.com.
Alaa A-M
AA
Abdel-Aziz
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Laila A
LA
Abou-Zeid
Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Kamal Eldin H
KEH
ElTahir
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Rezk R
RR
Ayyad
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Magda A-A
MA
El-Sayed
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. Electronic address: adelazaba@yahoo.com.
Adel S
AS
El-Azab
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
C533051:2-mercapto-4(3H)-quinazolinone; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D052999:Quinazolinones; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
2-Mercapto-4(3H)-quinazolinone; Anti-inflammatory activities; Cyclooxygenase-1/cyclooxygenase-2 inhibition assay; Docking study; Synthesis