Design, synthesis and biological screening of new 4-thiazolidinone derivatives with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile

Khaled R A Abdellatif; Mohamed A Abdelgawad; Heba A H Elshemy; Shahinda S R Alsayed

doi:10.1016/j.bioorg.2015.11.001

Design, synthesis and biological screening of new 4-thiazolidinone derivatives with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile

Bioorg Chem. 2016 Feb:64:1-12. doi: 10.1016/j.bioorg.2015.11.001. Epub 2015 Nov 6.

Authors

Khaled R A Abdellatif¹, Mohamed A Abdelgawad², Heba A H Elshemy³, Shahinda S R Alsayed³

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Beni Suef University, Beni Suef 62514, Egypt. Electronic address: [email protected].
² Department of Pharmaceutical Organic Chemistry, Beni Suef University, Beni Suef 62514, Egypt; Pharmaceutical Chemistry Department, College of Pharmacy, Al Jouf University, Sakaka, Al Jouf 2014, Saudi Arabia.
³ Department of Pharmaceutical Organic Chemistry, Beni Suef University, Beni Suef 62514, Egypt.

PMID: 26561742
DOI: 10.1016/j.bioorg.2015.11.001

Abstract

Two series of new thiazolidin-4-one derivatives 4a-c and 8a-e were designed and prepared. All the synthesized compounds were evaluated for their in vitro COX-2 selectivity and anti-inflammatory activity in vivo. Compounds 8c and 8d showed the best overall in vitro COX-2 selectivity (selectivity indexes of 4.56 and 5.68 respectively) and in vivo activities (edema inhibition %=61.8 and 67 after 3h, respectively) in comparison with the reference drug celecoxib (S.I.=7.29, edema inhibition %=60 after 3h). In addition, 8c and 8d were evaluated for their mean effective anti-inflammatory doses (ED50=27.7 and 18.1 μmol/kg respectively, celecoxib ED50=28.2 μmol/kg) and ulcerogenic liability (reduction in ulcerogenic potential versus celecoxib=85%, 92% respectively. Molecular docking studies were performed and the results were in agreement with that obtained from the in vitro COX inhibition assays.

Keywords: Anti-inflammatory; Cyclooxygenase inhibition; Molecular modeling; Thiazolidinone.

MeSH terms

Animals
Anti-Inflammatory Agents / adverse effects
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / therapeutic use*
Celecoxib / pharmacology
Celecoxib / therapeutic use
Cyclooxygenase 1 / metabolism
Cyclooxygenase 2 / metabolism*
Cyclooxygenase 2 Inhibitors / adverse effects
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / therapeutic use*
Edema / drug therapy
Humans
Ibuprofen / pharmacology
Ibuprofen / therapeutic use
Mice
Molecular Docking Simulation
Sheep
Stomach Ulcer / chemically induced
Sulfonamides / adverse effects
Sulfonamides / chemical synthesis
Sulfonamides / pharmacology*
Thiazolidines / adverse effects
Thiazolidines / chemical synthesis
Thiazolidines / pharmacology
Thiazolidines / therapeutic use*

Substances

3-(4-aminosulfonylphenylamino)-2-(4-chlorophenyl)-5-methyl-4-thiazolidinone
3-(4-aminosulfonylphenylamino)-2-(4-fluorophenyl)-5-methyl-4-thiazolidinone
Anti-Inflammatory Agents
Cyclooxygenase 2 Inhibitors
Sulfonamides
Thiazolidines
Cyclooxygenase 1
Cyclooxygenase 2
PTGS2 protein, human
Celecoxib
Ibuprofen