Investigation of the Mechanism of Action of Natural and Synthetic Monoterpenoids: For a New Route in Antimycotic Molecules

Monoterpenoids are well-recognized natural antimycotic agents, but their mechanism of action is still unclear. Interestingly, synthetic derivatives, such as 4-bromothymol (4-bromo-2-isopropyl-5-methylphenol), are emerging as promising alternatives to natural molecules, due to their even greater biological activity. Herein, the antimycotic efficacy of 4-bromothymol is evaluated: in vivo experiments on species of acclaimed resistance demonstrate that 4-bromothymol has a minimum inhibitory concentration up to 6 times lower than thymol. In silico investigations, sweeping from partition coefficient (LogP) determination through density functional theory and molecular dynamics simulations based on a minimum bias approach, support its improved antifungal activity with respect to thymol, carvacrol, and thymyl acetate. A structural insight of the mechanism of action is proposed. Even though all the analyzed compounds are able to penetrate the cellular membrane, 4-bromothymol shows a higher predicted affinity for the bilayer, and it causes a strong perturbation at the water/bilayer interface, altering the stability of the membrane, thus leading to cell death.