Cinnamaldehyde-Containing Combinations Demonstrate Favourable Cytotoxicity and Nitric Oxide Inhibitory Profiles In Vitro

Skin inflammation is a common dermatological concern that arises from infections. Essential oil compounds (EOCs) have garnered interest due to their potent anti-inflammatory properties. Preliminary studies have shown antimicrobial synergistic interactions between EOCs and conventional antimicrobials. The current study investigated the cytotoxicity and the ability to inhibit LPS-induced nitric oxide production of six EOCs (α-pinene, γ-terpinene, linalool, eugenol, carvacrol, and cinnamaldehyde) in combination with eight conventional antimicrobials using the MTT assay (HaCAT keratinocytes) and lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The cytotoxicity of the EOCs on HaCAT keratinocytes was dose-dependent, with IC50 values ranging from 274.0 µg/mL (linalool, least cytotoxic) to 28.6 µg/mL (cinnamaldehyde, most cytotoxic). Among the conventional antimicrobials, only miconazole demonstrated noteworthy toxicity against HaCAT cells. Among the combinations tested, amoxicillin–carvacrol (92.09%) and miconazole–carvacrol (91.82%) demonstrated the highest cell viabilities, while miconazole–cinnamaldehyde (78.53%) and erythromycin–cinnamaldehyde (78.42%) produced the greatest reductions in nitric oxide production. Ciprofloxacin–cinnamaldehyde demonstrated one of the most favourable overall profiles, combining substantial nitric oxide inhibition (77.66%) with the lowest cytotoxicity interaction index (CI = 0.12). All combinations involving cinnamaldehyde were interpreted as synergistic with respect to both reduced cytotoxicity and inhibition of LPS-induced nitric oxide production under the conditions tested. Among the combinations evaluated, ciprofloxacin–cinnamaldehyde demonstrated the most favourable overall profile in the in vitro screening models, with reduced cytotoxicity and inhibition of LPS-induced nitric oxide production. These findings support further investigation of this combination in additional experimental models; however, the present results should be interpreted as preliminary and are not sufficient to establish therapeutic efficacy in skin infections. These findings were obtained using in vitro screening models and require validation in additional skin-relevant cellular and in vivo models before therapeutic relevance can be established.