A competent synthesis and efficient anti-inflammatory responses of isatinimino acridinedione moiety via suppression of in vivo NF-κB, COX-2 and iNOS signaling

Govindasami Periyasami; Paulrayer Antonisamy; Karthikeyan Perumal; Antony Stalin; Mostafizur Rahaman; Asma A Alothman

doi:10.1016/j.bioorg.2019.103047

A competent synthesis and efficient anti-inflammatory responses of isatinimino acridinedione moiety via suppression of in vivo NF-κB, COX-2 and iNOS signaling

Bioorg Chem. 2019 Sep:90:103047. doi: 10.1016/j.bioorg.2019.103047. Epub 2019 Jun 11.

Authors

Govindasami Periyasami¹, Paulrayer Antonisamy², Karthikeyan Perumal³, Antony Stalin⁴, Mostafizur Rahaman⁵, Asma A Alothman⁵

Affiliations

¹ Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: pkandhan@ksu.edu.sa.
² Department of Korean Physiology, Wonkwang University School of Korean Medicine, 460 Iksan-daero, Iksan City, Jeonbuk 570-749, Republic of Korea.
³ Department of Chemistry, The Ohio State University, 170A CBEC, 151 West Woodruff Avenue, Columbus, OH 43210, United States.
⁴ Department of Traditional Chinese Medicine, Zhejiang A&F University, Hangzhou 311300, China.
⁵ Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.

PMID: 31234130
DOI: 10.1016/j.bioorg.2019.103047

Abstract

A potent Nonsterodial Anti-inflammatory Drug (NSAID) candidates has been conceived and built by an assembly of a hydrophilic, fluorescent and COX-2 inhibiting units in the same molecule. The isatinimino-acridinedione core (TM-7) was achieved in a simple three step synthetic procedure viz (i) a multicomponent reaction between dimedone, aldehyde and amine to furnish the nitroacridinedione (4), (ii) reduction step and (iii) schiff's-base condensation with isatin. The excellent anti-inflammatory pharmacological efficiency of the drug was established by in vivo biological experiments. Accordingly, it was found that the treatment with the synthesized isatinimino analogues (dosage: 30 mg/kg) inhibited protein expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB) as well as production of prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) levels induced by carrageenan. Further, a comparative molecular modeling analysis of TM-7 carried out with the crystal structure of aspirin acetylated human COX-2 suggested effectively binding and efficient accommodation inside the active site's gorge.

Keywords: 5F19 receptor; Acridinedione; Anti-inflammatory; COX-2; Carrageenan; In silico docking; NF-kB; Paw oedema; iNOS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acridones / chemical synthesis
Acridones / metabolism
Acridones / therapeutic use*
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / metabolism
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
Catalytic Domain
Cyclooxygenase 2 / chemistry
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / metabolism
Cyclooxygenase 2 Inhibitors / therapeutic use*
Cytokines / metabolism
Edema / drug therapy
Humans
Indomethacin / therapeutic use
Inflammation / drug therapy*
Isatin / analogs & derivatives*
Isatin / metabolism
Isatin / therapeutic use*
Male
Molecular Docking Simulation
NF-kappa B / metabolism
Nitric Oxide Synthase Type II / metabolism
Protein Binding
Rats, Wistar
Signal Transduction / drug effects

Substances

Acridones
Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Cytokines
NF-kappa B
Isatin
Nitric Oxide Synthase Type II
Nos2 protein, rat
Cyclooxygenase 2
Indomethacin