Novel 5,6-diphenyl-1,2,4-triazine-3-thiol derivatives as dual COX-2/5-LOX inhibitors devoid of cardiotoxicity

Poorvi Saraf; Prabhash Nath Tripathi; Manish Kumar Tripathi; Avanish Tripathi; Himanshu Verma; Digambar Kumar Waiker; Royana Singh; Sushant Kumar Shrivastava

doi:10.1016/j.bioorg.2022.106147

Novel 5,6-diphenyl-1,2,4-triazine-3-thiol derivatives as dual COX-2/5-LOX inhibitors devoid of cardiotoxicity

Bioorg Chem. 2022 Dec:129:106147. doi: 10.1016/j.bioorg.2022.106147. Epub 2022 Sep 13.

Authors

Poorvi Saraf¹, Prabhash Nath Tripathi², Manish Kumar Tripathi¹, Avanish Tripathi³, Himanshu Verma¹, Digambar Kumar Waiker¹, Royana Singh⁴, Sushant Kumar Shrivastava⁵

Affiliations

¹ Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
² Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut 25000, UP, India.
³ Institute of Pharmaceutical Research, GLA University, Mathura 281406, UP, India.
⁴ Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, UP, India.
⁵ Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India. Electronic address: skshrivastava.phe@itbhu.ac.in.

PMID: 36126607
DOI: 10.1016/j.bioorg.2022.106147

Abstract

A novel series of 5,6-diphenyl-1,2,4-triazine-3-thiol derivatives were designed, synthesized, and screened for their inhibitory potential against COX-2 and 5-LOX enzymes. The compounds from the series have shown moderate to excellent inhibitory potential against both targets. Compound 6k showed the inhibitions against COX-2 (IC₅₀ = 0.33 ± 0.02 μM) and 5-LOX inhibition (IC₅₀ = 4.90 ± 0.22 μM) which was better than the standard celecoxib (IC₅₀ = 1.81 ± 0.13 μM) for COX-2 and zileuton (IC₅₀ = 15.04 ± 0.18 μM) for 5-LOX respectively. Further investigation on the selected derivative 6k in rat paw edema models revealed significant anti-inflammatory efficacy. Compound 6k has also shown negligible ulcerogenic liability as compared to indomethacin. Moreover, in vivo biochemical analysis also established the compound's antioxidant properties. Compounds 6c and 6k were also observed to be devoid of cardiotoxicity post-myocardial infarction in rats. The molecular docking and dynamics simulation studies of the most active derivative 6k affirmed their consentient binding interactions with COX-2 specific ravine and cleft of 5-LOX.

Keywords: 1,2,4-triazine; Anti-inflammatory; Cardiotoxicity; Cyclooxygenase; Docking; Dual-inhibition; Lipoxygenase.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Arachidonate 5-Lipoxygenase / metabolism
Cardiotoxicity
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors* / chemistry
Cyclooxygenase 2 Inhibitors* / pharmacology
Cyclooxygenase 2 Inhibitors* / therapeutic use
Edema / chemically induced
Edema / drug therapy
Lipoxygenase Inhibitors* / chemistry
Molecular Docking Simulation
Molecular Structure
Rats
Structure-Activity Relationship
Sulfhydryl Compounds / pharmacology

Substances

Cyclooxygenase 2 Inhibitors
Cyclooxygenase 2
Lipoxygenase Inhibitors
Arachidonate 5-Lipoxygenase
Sulfhydryl Compounds
5,6-diphenyl-1,2,4-triazine-3-thiol
Anti-Inflammatory Agents, Non-Steroidal