Synthesis and Antimycobacterial Activity of Novel Mandelic Acid Derived Diamide

Introduction Increasing drug resistance and poor activity of existing therapies towards the latent stage of Mycobacterium tuberculosis infection has produced a clear need to develop novel therapeutics to treat tuberculosis [1]. Thus fast-acting drugs with novel mechanisms of action that are not cross resistant to existing drugs are being sought actively. Wilkinson and coworkers first reported the synthesis and activity of ethambutol (EMB) (Fig. 1. I) [2]. EMB was a useful addition to tuberculosis chemotherapy, despite a relatively modest MIC of 10 μM, in part because of very low toxicity and relatively few side-effects. Based on structure-activity relationship (SAR) studies it appeared that the distance between the two nitrogens, the presence of β-aminoalcohols, and the small side chains were critical for determining activity. The configuration of the molecule is decisively important for the activity, since EMB with (S,S) -configuration is approx. 200-500 fold more potent than its (R,R)-enantiomer. Removal or significant alteration of the basicity of either amino group resulted in a loss of potency, with the exception that the corresponding amides retained activity in some analogues (Fig. 1. II) [3]. Inspired by the two β-amino-alcohol fragments in the molecule of EMB we dedicated our studies towards the development of camphane based structures and evaluation of their antimycobacterial activity towards M. tuberculosis H37Rv. A series of β-amidoalcohol structures were synthesized using 3-exo-aminoisoborneol (Fig. 1. III) and isobornylamine (Fig. 1. IV) as key starting compounds [4]. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. Noteworthy, although that the carbon atom at the nitrogen in all camphane structures possesses (R)-configuration, most of the molecules are extremely active. This is opposite to the fact that (S,S)-EMB is approximately 500 fold more active than (R,R)-EMB. In the present study we describe the synthesis and antimycobacterial activity of a novel, mandelic acid derived diamido-diol containing (1R,2R)-1,2-diamidocyclohexane scaffold (Fig. 1. V). Thus, we had the opportunity to investigate both the effect of a second amide function and a different type of aliphatic skeleton. side-effects. Based on structure-activity relationship (SAR) studies it appeared that the