Abstract
A series of nineteen novel ring-substituted N-arylcinnamanilides was synthesized and characterized. All investigated compounds were tested against Staphylococcus aureus as the reference strain, two clinical isolates of methicillin-resistant S. aureus (MRSA), and Mycobacterium tuberculosis. (2E)-N-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide showed even better activity (minimum inhibitory concentration (MIC) 25.9 and 12.9 µM) against MRSA isolates than the commonly used ampicillin (MIC 45.8 µM). The screening of the cell viability was performed using THP1-Blue™ NF-κB cells and, except for (2E)-N-(4-bromo-3-chlorophenyl)-3-phenylprop-2-enamide (IC50 6.5 µM), none of the discussed compounds showed any significant cytotoxic effect up to 20 μM. Moreover, all compounds were tested for their anti-inflammatory potential; several compounds attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. The lipophilicity values were specified experimentally as well. In addition, in silico approximation of the lipophilicity values was performed employing a set of free/commercial clogP estimators, corrected afterwards by the corresponding pKa calculated at physiological pH and subsequently cross-compared with the experimental parameters. The similarity-driven property space evaluation of structural analogs was carried out using the principal component analysis, Tanimoto metrics, and Kohonen mapping.
Highlights
Inflammatory diseases of visceral organs, joints, bones, etc. can be based on an infectious or autoimmune basis, but the body always aims to eradicate noxious agents and restore tissue homeostasis [1]
All compounds compoundswere weresynthesized synthesized from cinnamic a microwave reactor: The carboxyl
All from cinnamic acidacid in a in microwave reactor: The carboxyl group group was converted with phosphorus to acylwhich chloride, which reacted with the was converted with phosphorus trichloridetrichloride to acyl chloride, reacted with the appropriately appropriately substituted aniline to product give the desired
Summary
Inflammatory diseases of visceral organs, joints, bones, etc. can be based on an infectious or autoimmune basis, but the body always aims to eradicate noxious agents and restore tissue homeostasis [1]. Because the bacterial infection can trigger inflammation, which can cause subsequent damage of surrounding tissue [6], it seems advantageous to follow a multi-target approach in drug design and try to prepare molecules with dual antimicrobial and anti-inflammatory activity. Multi-target drug discovery represents an innovative approach of medicinal chemistry to overcome a crisis in drug design, reflected in the small number of newly approved drugs. This approach is based on the concepts of privileged scaffolds, polypharmacology, and multifactorial diseases [7,8,9,10,11,12]. From pharmacoeconomic and patients’ comfort point of view, it seems favorable to treat both a cause and a consequence (bacterial infection and inflammation) simultaneously with one active substance
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