# Anti-inflammatory and Antimicrobial Properties of Ibuprofen Analogues Derived by Photoredox-Catalyzed C–N Scission of Tertiary Amines and Amidation

## TL;DR

This paper shows how modifying ibuprofen using a light-based chemical method creates new compounds with strong anti-inflammatory and antimicrobial effects.

## Contribution

A photoredox-catalyzed method is used to synthesize novel ibuprofen analogues with combined anti-inflammatory and antimicrobial properties.

## Key findings

- Compounds 15 and 16 showed notable antimicrobial activity against Escherichia coli, MRSA, and Candida albicans.
- Several derivatives preserved cell viability better than ibuprofen under inflammatory stress.
- Ibuprofen amide derivatives significantly suppressed pro-inflammatory cytokine production in macrophages.

## Abstract

This manuscript describes the synthesis of ibuprofen-derived
amides,
and their biological evaluation with respect to anti-inflammatory
and antimicrobial properties, including inhibition of biofilm formation.
The compounds were synthesized using a previously developed photoredox-catalyzed
protocol, which proceeds through C–N bond scission of the tertiary
amine building blocks, followed by in situ amide coupling; thus, 16
derivatives of ibuprofen were prepared on 30 to 70 mg scales. Evaluation
in multiple antimicrobial and biofilm-related biological assays revealed
desired activities for many of the compounds. Compounds 9–11 and 14–16 are newly synthesized in the literature, compounds 1–8 have been previously reported by us, and compounds 12–13 are known in the literature. The
broad-spectrum antimicrobial activities of all molecules were evaluated
for the first time in these studies. An initial phenotypic screening
under inflammatory stress was performed using an MTT-based LPS challenge
model, which revealed that several derivatives (2, 4, 7, and 11–16) preserved cell viability more effectively than ibuprofen. Based
on these findings, selected compounds were further evaluated using
direct biochemical assays, demonstrating that ibuprofen amide derivatives
significantly suppressed LPS-induced production of the pro-inflammatory
cytokines IL-1β, TNF-α, and IL-6 in RAW 264.7 macrophages.
Assessment of antimicrobial activity against Escherichia
coli, MRSA, and Candida albicans demonstrated notable inhibitory activities by compounds 15 and 16. The same compounds also showed inhibition of
biofilm growth. Collectively, these results demonstrate that photoredox-catalyzed
modification of the ibuprofen scaffold enables rapid access to newly
synthesized analogues combining confirmed anti-inflammatory activity
with antimicrobial and antibiofilm properties.