When Inhibitors Do Not Inhibit: Critical Evaluation of Rational Drug Design Targeting Chorismate Mutase from Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is a devastating disease that claims millions of lives every year. Hindered access or non-compliance to medication, especially in developing countries, led to drug resistance, further aggravating the situation. With current standard therapies in use for over 50 years and only few new candidates in clinical trials, there is an urgent call for new TB drugs. A powerful tool for the development of new medication is structure-guided design, combined with virtual screening or docking studies. Here, we report the results of a drug-design project, which we based on a publication that claimed the structure-guided discovery of several promising and highly active inhibitors targeting the secreted chorismate mutase (*MtCM) from Mycobacterium tuberculosis. We set out to further improve on these compounds and synthesized a series of new derivatives. Thorough evaluation of these molecules in enzymatic assays revealed, to our dismay, that neither the claimed lead compounds, nor any of the synthesized derivatives, show any inhibitory effects against *MtCM.

Unconventionally secreted effectors of two filamentous pathogens target plant salicylate biosynthesis

“…The findings suggest a promising strategy for disease control by inhibiting the activities of these enzymatic effectors or supplying the host with plant-defense activators to compensate for the SA shortage caused by pathogen effectors. For example, several highly active inhibitors targeting the secreted chorismate mutase from Mycobacterium tuberculosis have been designed and evaluated based on structure-guided approaches30. Our results suggest that secreted ISCs from phytopathogens could be suitable targets for disease control.…”

Stable and Easily Accessible Functional Dyes: Dihydrotetraazaanthracenes as Versatile Precursors for Higher Acenes

“…Diamines 10 can be obtained in four steps, starting with 4‐fluoro benzoic acid through nitration,19a followed by esterification,19b nucleophilic fluoride substitution and reduction (Scheme ) 20. The vicinal diamines 12 were prepared starting with 1,5‐dichloro‐2,4‐dinitrobenzene by aminolyses to give 8 21.…”

“…KNO 3 , H 2 SO 4 ;19a 2. SOCl 2 , MeOH;19b 3. R‐NH 2 : 36–99 %; b) H 2 ,Pd/C, EtOH; c) EtOH, R‐NH 2 : 40–97 %; d) Raney‐Nickel, 30 % NH 2 NH 2 , EtOH; e) Ph‐NH 2 , NaNO 2 , EtOH/H 2 O;22a f) NaS 2 O 4 , DMF 22b…”

Discovery and Structure Optimization of a Series of Isatin Derivatives as Mycobacterium tuberculosis Chorismate Mutase Inhibitors

“…Mycobacterium tuberculosis possess two chorismate mutases belonging to different subclasses , the secreted enzyme (*MtCM, γ ‐subclass) and the housekeeping enzyme (MtCM, δ ‐subclass), whereas the former is primarily involved in directing the protein from the cytoplasm to the pseudoperiplasmic space and may have some role in host–pathogen interaction. It is the secreted enzyme (usually referred to as *MtCM) that is likely related to pathogenicity and virulence of MTB . As vertebrates do not possess the shikimate pathway for the biosynthesis of aromatic compounds and lacks CM activity, this enzyme represents a prime target for the development of antibacterials.…”

“…The most promising analogue in the study (4‐(3,4‐dimethoxyphenethylamino)‐3‐nitro‐5‐sulfamoylbenzoic acid) exhibited a K i of 5.7 ± 1.2 μ m . But later an in vitro and in vivo evaluation of a library of molecules designed and synthesized based on Agrawal claims proved to be completely ineffective, with Munack et al . recently discrediting Agrawal's work in his study, as the reported lead molecules proved to be inactive.…”