Discovery of Schaeffer’s Acid Analogues as Lead Structures of Mycobacterium tuberculosis Type II Dehydroquinase Using a Rational Drug Design Approach (original) (raw)

Although the causative agent of tuberculosis (TB), a lethal infection disease that attacks the lungs, Mycobacterium tuberculosis (MTB), was identified in 1882 by Robert Koch, [1a] TB is now more prevalent in the world due to emerging resistances, with 9.8 million new cases in 2011. [1b,c] New therapeutic strategies are urgently needed. It has been shown that the enzyme M. tuberculosis type II dehydroquinase (MtDHQase), which converts 3-dehydroquinate (1) to 3-dehydroshikmate (2) in the shikimate pathway (Scheme 1), is essential for MTB virulence. [2] Crystallographic studies on DHQase from M. tuberculosis and other bacteria have shown that the enzyme is a dodecamer. [3] In MtDHQase, two residues, Arg 19 and Tyr 24, are essential for the catalytic conversion of 1 to 2 (Scheme 1). [3a] Both residues are part of a flexible loop (residues 19-24) that acts as the closure head of the active site. Recently, structures showing that movement of Arg 19 creates an additional subpocket next to the active site have been reported (Figure 1). [3b-d] Simultaneously, elaborated dehydroquinate analogues have emerged as highly potent in vitro inhibitors (such as compound 4; Figure 1 b and 2 a). [4] These inhibitors target both the active site and the subpocket formed by the flexible loop. [3b-d] However, dehydroquinate analogues typically have no or low levels of activity in cell-based assays. [4c,d] This is likely due to their hydrophilic nature leading to poor cellular uptake. As such, drug-like small-molecule inhibitors with therapeutic potential are needed.

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