Synthesis, hepatotoxic evaluation and antipyretic activity of nitrate ester analogs of the acetaminophen derivative SCP-1

Madhurima Das; Surjyadipta Bhattacharjee; Frank R Fronczek; Nicolas G Bazan; Mark L Trudell

doi:10.1016/j.bmcl.2018.09.020

Synthesis, hepatotoxic evaluation and antipyretic activity of nitrate ester analogs of the acetaminophen derivative SCP-1

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3798-3801. doi: 10.1016/j.bmcl.2018.09.020. Epub 2018 Sep 17.

Authors

Madhurima Das¹, Surjyadipta Bhattacharjee², Frank R Fronczek³, Nicolas G Bazan², Mark L Trudell⁴

Affiliations

¹ Department of Chemistry, University of New Orleans, New Orleans, LA 71048 USA.
² Neuroscience Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
³ Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
⁴ Department of Chemistry, University of New Orleans, New Orleans, LA 71048 USA. Electronic address: mtrudell@uno.edu.

PMID: 30327145
DOI: 10.1016/j.bmcl.2018.09.020

Abstract

A series of nitrate ester analogues of the acetaminophen derivative SCP-1 were prepared by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by nitration with silver nitrate. The chloroesters and corresponding nitrate esters were obtained in high yields. Preliminary hepatotoxicity studies revealed nitrate esters 5b (MD-38) and 5c (MD-39) to be well tolerated by human hepatocytes and had little effect on the three cytochrome P450 enzymes tested (CYP3A4, CYP2E1 and CYP2D6). In addition, the nitrate ester 5c (MD-39) exhibited antipyretic activity similar to acetaminophen.

Keywords: Acetaminophen; Antipyretic activity; Hepatotoxicity; NO donor; Nitrate ester.

Publication types

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

MeSH terms

Acetaminophen / analogs & derivatives*
Acetaminophen / chemical synthesis
Acetaminophen / chemistry
Acetaminophen / therapeutic use
Acetaminophen / toxicity
Animals
Antipyretics / chemical synthesis
Antipyretics / chemistry*
Antipyretics / therapeutic use*
Antipyretics / toxicity
Chemical and Drug Induced Liver Injury / metabolism
Crystallography, X-Ray
Cytochrome P-450 CYP2D6 / metabolism
Cytochrome P-450 CYP2E1 / metabolism
Cytochrome P-450 CYP3A / metabolism
Esterification
Fever / drug therapy*
Fever / metabolism
Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Models, Molecular
Nitrates / chemical synthesis
Nitrates / chemistry
Nitrates / therapeutic use
Nitrates / toxicity
Rats
Saccharin / analogs & derivatives*
Saccharin / chemical synthesis
Saccharin / chemistry
Saccharin / therapeutic use
Saccharin / toxicity

Substances

Antipyretics
Nitrates
SCP 1
Acetaminophen
Cytochrome P-450 CYP2E1
Cytochrome P-450 CYP2D6
Cytochrome P-450 CYP3A
Saccharin