Synthesis of carvacrol codrugs 1–4 and 9.

<p>Reagents and conditions: a) Ac₂O, AcOH, 4 h, rt for compounds <b>11–14</b>; KOH, Propargyl bromide, in dry MeOH, 1 h, 60°C (reflux) for compound <b>15</b>; b) DCC in DMF/DCM, 1 h, rt, then carvacrol, DMAP, 15 h, rt; c) TIPS, TFA in DCM, 48 h, rt under nitrogen atmosphere.</p

Physicochemical properties of carvacrol codrug 4.

<p>^aValues are means of three experiments, standard deviation is given in parentheses.</p><p>Physicochemical properties of carvacrol codrug 4.</p

Transmission electron microscopy demonstrating the effects of carvacrol codrug 4 on <i>S</i>. <i>aureus</i> ATCC 29213 (B), <i>E</i>. <i>coli</i> ATCC 8739 (D), <i>C</i>. <i>albicans</i> ATCC 10231 (F), and untreated cultures (control), respectively (A, C, and E).

<p>Microorganisms incubated for 3 h in media containing 12.5 mg/mL [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120937#pone.0120937.ref045" target="_blank">45</a>] of carvacrol codrug <b>4</b> (B, D, and F). Irregular features of septa in <i>S</i>. <i>aureus</i> ATCC 29213 (B: arrows); numerous electron-dense bubbles protrude from the cell surface (higher magnification b 140000x and c 110000x) in <i>E</i>. <i>coli</i> ATCC 8739 treated (D) and electron-dense granules of the substance internalized into the cytoplasm (d 110000x); integrity of the membrane (a 110000x) in the controls (C); disintegration of membrane in <i>C</i>. <i>albicans</i> ATCC 10231 (F).</p

PAMPA-GI permeability of carvacrol codrug 4 after 16 h of incubation.

<p>^a pH of both donor and acceptor compartment.</p><p>PAMPA-GI permeability of carvacrol codrug 4 after 16 h of incubation.</p

Kinetic data for hydrolysis of carvacrol codrug 4 at 37°C.^a

<p>^aValues are means of three experiments, standard deviation is given in parentheses.</p><p>^bAbbreviations: SGF, simulated gastric fluid; SIF, simulated intestinal fluid.</p><p>Kinetic data for hydrolysis of carvacrol codrug 4 at 37°C.<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120937#t004fn001" target="_blank">^a</a></p

Hemolytic activity of carvacrol codrugs 1–10, CAR, and NAC (A) and in a wider range of values for carvacrol codrug 4 (B).

<p>Hemolytic activity of carvacrol codrugs 1–10, CAR, and NAC (A) and in a wider range of values for carvacrol codrug 4 (B).</p