Research Article Salicylanilide Diethyl Phosphates as Potential Inhibitors of Some Mycobacterial Enzymes Martin Krátký, 1 Eva Novotná, 2 Shalini Saxena, 3 Perumal Yogeeswari, 3 Dharmarajan Sriram, 3 Markéta Švarcová, 1 and Jarmila Vinšová 1 1 Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovsk´ eho 1203, 500 05 Hradec Kr´ alov´ e, Czech Republic 2 Department of Biochemical Sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovsk´ eho 1203, 500 05 Hradec Kr´ alov´ e, Czech Republic 3 Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Hyderabad 500078, India Correspondence should be addressed to Jarmila Vinˇ sov´ a; vinsova@faf.cuni.cz Received 24 July 2014; Accepted 26 September 2014; Published 4 November 2014 Academic Editor: Andrei Surguchov Copyright © 2014 Martin Kr´ atk´ y et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Antimycobacterially active salicylanilide diethyl phosphates were evaluated to identify their potential drug target(s) for the inhibi- tion of several mycobacterial enzymes, including isocitrate lyase, L-alanine dehydrogenase (MtAlaDH), lysine -aminotransferase, chorismate mutase, and pantothenate synthetase. he enzymes are related to the nongrowing state of Mycobacterium tuberculosis. Salicylanilide diethyl phosphates represent new candidates with signiicant inhibitory activity especially against L-alanine dehydrogenase. he most active MtAlaDH inhibitor, 5-chloro-2-[(3-chlorophenyl)carbamoyl]phenyl diethyl phosphate, has an IC 50 of 4.96 M and the best docking results. Other mycobacterial enzymes were mostly inhibited by some derivatives but at higher concentrations; isocitrate lyase showed the highest resistance to salicylanilide diethyl phosphates. 1. Introduction he increased number of drug-resistant tuberculosis (TB) cases worldwide and the evidence of recently reported totally drug-resistant strains demonstrate the urgent need for novel therapeutic interventions [1] including innovative antimy- cobacterial drugs with no cross-resistance to clinically used drugs. Recently, salicylanilide diethyl phosphates (diethyl [(2- phenylcarbamoyl)phenyl] phosphates 1; Figure 1) have been synthesized as potential antimycobacterial agents with activ- ity in the micromolar range (minimum inhibitory concen- trations (MICs) from 1 M). hey inhibit nontuberculous mycobacteria and both drug-susceptible and drug-resistant Mycobacterium tuberculosis () strains [2]. Previously, some salicylanilide-based derivatives were reported as mild inhibitors of mycobacterial isocitrate lyase (ICL) and methio- nine aminopeptidase [3]. he exact mechanism(s) of their action as antimicrobial agents has still not been fully eluci- dated. herefore, we screened the presented derivatives for new enzymatic targets of Mtb, especially those related to the nongrowing state. No inhibitor of the selected enzymes has been established for clinical practice to date. Mycobacterium tuberculosis exhibits a tendency to remain latent or persistent for decades before its activation into symptomatic disease. he bacterium has developed ingenious mechanisms to survive inside a hostile environment and to acquire essential nutrients. hese metabolic processes appear to provide potential targets for novel anti-TB agents [4]. Genetic analysis has revealed a set of new potential drug targets in Mtb. Isocitrate lyase (ICL; EC 4.1.3.1) is one of two enzymes comprising the glyoxylate shunt and splits isocitrate into succinate and glyoxylate; this metabolic pathway is absent in vertebrates. ICL is responsible for the persistence of Mtb and, additionally, disruption of the icl gene attenuated Hindawi Publishing Corporation e Scientific World Journal Volume 2014, Article ID 703053, 6 pages http://dx.doi.org/10.1155/2014/703053