Design, Synthesis, and Antibacterial Activity of Novel Pleuromutilin Derivatives Bearing an Amino Thiazolyl Ring

Abstract

A series of novel pleuromutilin derivatives containing the amino thiazolyl ring were designed, synthesized, and evaluated for their antibacterial activities in vitro against Gram-positive clinical bacteria. All the target compounds showed better aqueous solubility compared with the lead compound (10). Most compounds displayed strong antibacterial activities against both susceptible and resistant bacteria, particularly for the compound (12f) which showed extraordinary antibacterial properties superior to amoxicillin and tiamulin. Molecular docking studies revealed that the amino thiazolyl ring, the side chains of the pleuromutilin derivatives, can be adopted in the binding pocket of the 50S ribosomal subunit near the mutilin core. Therefore, our novel findings may provide new insights into the design of novel pleuromutilin derivatives and lay the basis for further studies on these promising antibiotics for human clinical use.

Synthesis and Biological Activities of Novel Pleuromutilin Derivatives with a Substituted Thiadiazole Moiety as Potent Drug-Resistant Bacteria Inhibitors

“…14-O-(Iodoacetyl)-mutilin (10). Compound 10 was prepared on the basis of a published method from a solution of compound 9 and KI, which was refluxed for 1 h. 30,31 The crude production was purified by recrystallization with acetone to give 81% compound 10 as a pale yellow powder; mp: 117−119 °C. 2H), 1.17 (s, 3H), 1.12 (d, J = 4.3 Hz, 1H), 0.87 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 6.9 Hz, 3H).…”

“…In this paper, we describe a different synthesis method using NaOH as a base, in which pleuromutilin is rapidly converted to 9 in excellent yield. Intermediate 10 was prepared in good yield under reflux for 3 h in acetone, as previously described. , Compound 11 was then obtained in good yield by the nucleophilic attack of 2-amino-5-mercapto-1, 3, 4-thiadiazole on intermediate 10 under alkaline conditions and without further separation by column chromatography. In addition to the above synthetic method, compound 11 can be synthesized directly from compound 9 in a strongly alkaline environment.…”

“…Compound 10 was prepared on the basis of a published method from a solution of compound 9 and KI, which was refluxed for 1 h. , The crude production was purified by recrystallization with acetone to give 81% compound 10 as a pale yellow powder; mp: 117–119 °C. IR (KBr): 3307, 2979, 2933, 1736, 1712, 1456, 1417, 1279, 1084, 1023, 985, 967 cm –1 .…”

Synthesis and Antibacterial Activity of Novel Pleuromutilin Derivatives

“…Compound 9d exhibited a docking mode better than that of tiamulin in general, which is inconsistent with MIC data, probably because tiamulin has a good lipid/water partition coefficient in vivo and better binding affinity in dynamic state of 50s ribosomal subunit. 28) …”

Chemical Synthesis and Biological Activities of Novel Pleuromutilin Derivatives with Substituted Amino Moiety

“…During the early 1980s, extensive effort was made to formulate azamulin ( Figure 1 ) for human use. Although azamulin showed good activity in vitro against many clinical isolates, it did not go into the stage for further clinic trial because of strongly inhibition of cytochrome P450 and terrible solubility in water [9] , [10] . Retapamulin ( Figure 1 ) became the first pleuromutilin approved for human use in 2007 by Food and Drug Administration (FDA) [11] , [12] .…”