Syntheses and In Vitro Biological Activity of Some Derivatives of C-9154 Antibiotic

In our continued attempts at designing new antibiotics based on the structure of the C-9154 antibiotic, to simultaneously improve activity and lower toxicity, an analogue to the C-9154 antibiotic and six derivatives of this analogue were synthesized. The approach was to significantly reduce the polarity of the synthesized analogue in the derivatives to achieve increased permeability across cell membranes by conversion of the highly polar carboxylic group to an ester functional group. The compounds were synthesized using a two-step reaction which involved an additional reaction between benzyl amine and maleic anhydride and then conversion of the terminal carboxylic acid functional group to an ester functional group using a thionyl chloride mediated esterification reaction. The compounds were fully characterized using Infrared, GC-MS, and 1D and 2D NMR experiments. The in vitro biological activity of the compounds showed that the derivatives were more active than the analogues as was anticipated with minimum inhibitory concentration in the range 0.625–5？μg/mL. The analogue had minimum inhibitory concentration in the range 2.5–10？μg/mL. These values are significantly better than that obtained for the original C-9154 antibiotic which had activity in the range 10–>100？μg/mL. 1. Introduction In 1889, Vuillemin, a French bacteriologist, suggested using the word “antiobiosis”, meaning “against life,” to describe the group of drugs that had action against microorganisms [1]. Selman Waksman, an American microbiologist and the discoverer of streptomycin, later changed this term to antibiotic in 1942 [2]. The term “antibiotic” as coined by Selman Waksman is used to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution (low concentration). This definition excluded substances that kill bacteria but are not produced by microorganisms such as gastric juices and hydrogen peroxide [3]. Antibiotics today, with advances in medicinal chemistry, are semisynthetic modifications of various natural compounds [4]. These include, for example, the beta-lactam antibiotics, which include the penicillins, the cephalosporins, and the carbapenems. Some antibiotic compounds are still isolated from living organisms like the aminoglycosides, whereas other antibiotics like the sulfonamides, the quinolones, and the oxazolidinones are produced solely by chemical synthesis [4]. This implies that synthesis of antibiotic compounds plays an important and vital role in the fight against disease-causing organisms. In light of