Mycobacterial Targets for Thiourea Derivatives: Opportunities for
Virtual Screening in Tuberculosis Drug Discovery

Vinicius      de Melo Milani; Mariana   Luiza   Silva; Priscila   Goes   Camargo; Marcelle      de Lima Ferreira Bispo
doi:10.2174/0109298673276076231124104513
Abstract

Tuberculosis (TB) remains a primary global health concern, necessitating the discovery and development of new anti-TB drugs, mainly to combat drug-resistant strains. In this context, thiourea derivatives have emerged as promising candidates in TB drug discovery due to their diverse chemical structures and pharmacological properties. This review aimed to explore this potential, identifying and exploring molecular targets for thiourea derivatives in Mycobacterium tuberculosis (Mtb) and the potential application of virtual screening techniques in drug discovery. We have compiled a comprehensive list of possible molecular targets of thiourea derivatives in Mtb. The enzymes are primarily involved in the biosynthesis of various cell wall components, including mycolic acids, peptidoglycans, and arabinans, or targets in the branched-chain amino acid biosynthesis (BCAA) pathway and detoxification mechanisms. We discuss the potential of these targets as critical constituents for the design of novel anti-TB drugs. Besides, we highlight the opportunities that virtual screening methodologies present in identifying potential thiourea derivatives that can interact with these molecular targets. The presented findings contribute to the ongoing efforts in TB drug discovery and lay the foundation for further research in designing and developing more effective treatments against this devastating disease.
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[1]

Global tuberculosis report; World Health Organization (WHO), 2022. 

[2]

WHO consolidated guidelines on tuberculosis; World Health Organization (WHO), 2022. 

[3]
Espinosa-Pereiro, J.; Sánchez-Montalvá, A.; Aznar, M.L.; Espiau, M. MDR tuberculosis treatment. Medicina,  2022, 58(2), 188.
 [http://dx.doi.org/10.3390/medicina58020188] [PMID:  35208510]

[4]
Rendon, A.; Tiberi, S.; Scardigli, A.; D’Ambrosio, L.; Centis, R.; Caminero, J.A.; Migliori, G.B. Classification of drugs to treat multidrug-resistant tuberculosis (MDR-TB): Evidence and perspectives. J. Thorac. Dis.,  2016, 8(10), 2666-2671.
 [http://dx.doi.org/10.21037/jtd.2016.10.14] [PMID:  27867538]

[5]
Khan, E.; Khan, S.; Gul, Z.; Muhammad, M. Medicinal importance, coordination chemistry with selected metals (Cu, Ag, Au) and chemosensing of thiourea derivatives. A review. Crit. Rev. Anal. Chem.,  2020, 1-23.
 [http://dx.doi.org/10.1080/10408347.2020.1777523] [PMID:  32571090]

[6]
Ronchetti, R.; Moroni, G.; Carotti, A.; Gioiello, A.; Camaioni, E. Recent advances in urea- and thiourea-containing compounds: focus on innovative approaches in medicinal chemistry and organic synthesis. RSC Medicinal Chemistry,  2021, 12(7), 1046-1064.
 [http://dx.doi.org/10.1039/D1MD00058F] [PMID:  34355177]

[7]
Pereira, P.M.L.; Camargo, P.G.; Fernandes, B.T.; Flores-Junior, L.A.P.; Dias, L.R.S.; Lima, C.H.S.; Pinge-Filho, P.; Lioni, L.M.Y.; Yamada-Ogatta, S.F.; Bispo, M.L.F.; Macedo, F., Jr. In vitro evaluation of antitrypanosomal activity and molecular docking of benzoylthioureas. Parasitol. Int.,  2021, 80, 102225.
 [http://dx.doi.org/10.1016/j.parint.2020.102225] [PMID:  33160050]

[8]
Biasi-Garbin, R.P.; Fabris, M.; Morguette, A.E.B.; Andriani, G.M.; Cabral, W.R.C.; Pereira, P.M.L.; Brito, T.O.; Macedo, F., Jr; Da Silva Lima, C.H.; Lancheros, C.A.C.; Nakamura, C.V.; Pinge-Filho, P.; Tavares, E.R.; Yamauchi, L.M.; Bispo, M.L.F.; Yamada-Ogatta, S.F. In vitro antimicrobial screening of benzoylthioureas: Synthesis, antibacterial activity toward streptococcus agalactiae and molecular docking study. ChemistrySelect,  2022, 7(34), e202202117.
 [http://dx.doi.org/10.1002/slct.202202117]

[9]
Korkmaz, N.; Obaidi, O.A.; Senturk, M.; Astley, D.; Ekinci, D.; Supuran, C.T. Synthesis and biological activity of novel thiourea derivatives as carbonic anhydrase inhibitors. J. Enzyme Inhib. Med. Chem.,  2015, 30(1), 75-80.
 [http://dx.doi.org/10.3109/14756366.2013.879656] [PMID:  24666304]

[10]
Brito, T.O.; Abreu, L.O.; Gomes, K.M.; Lourenço, M.C.S.; Pereira, P.M.L.; Yamada-Ogatta, S.F.; de Fàtima, Â.; Tisher, C.A.; Jr, F.M.; Bispo, M.L.F. Benzoylthioureas: Design, synthesis and antimycobacterial evaluation. Med. Chem.,  2020, 16(1), 93-103.
 [http://dx.doi.org/10.2174/1573406415666181208110753] [PMID:  30526466]

[11]
Ertano, B.Y.; Demir, Y.; Nural, Y.; Erdoğan, O. Investigation of the effect of acylthiourea derivatives on diabetes‐associated enzymes. ChemistrySelect,  2022, 7(46), e202204149.
 [http://dx.doi.org/10.1002/slct.202204149]

[12]
Demir, Y.; Türkeş, C.; Küfrevioğlu, Ö.İ.; Beydemir, Ş. Molecular docking studies and the effect of fluorophenylthiourea derivatives on glutathione‐dependent enzymes. Chem. Biodivers.,  2023, 20(1), e202200656.
 [http://dx.doi.org/10.1002/cbdv.202200656] [PMID:  36538730]

[13]
Tugrak, M.; Gul, H.I.; Demir, Y.; Gulcin, I. Synthesis of benzamide derivatives with thiourea‐substituted benzenesulfonamides as carbonic anhydrase inhibitors. Arch. Pharm.,  2021, 354(2), 2000230.
 [http://dx.doi.org/10.1002/ardp.202000230] [PMID:  33043495]

[14]
Yıldız, M.L.; Demir, Y.; Küfrevioğlu, Ö.I. Screening of in vitro and in silico effect of Fluorophenylthiourea compounds on glucose 6‐phosphate dehydrogenase and 6‐phosphogluconate dehydrogenase enzymes. J. Mol. Recognit.,  2022, 35(12), e2987.
 [http://dx.doi.org/10.1002/jmr.2987] [PMID:  36326002]

[15]
Gallen, C.S. Isoxyl: A review of the results of its use over a five-year period in the tuberculosis field service of a large urban area. Antibiot Chemother,  1970, 16, 139-148.
 [http://dx.doi.org/10.1159/000386815]

[16]
Doğan, Ş.D.; Gündüz, M.G.; Doğan, H.; Krishna, V.S.; Lherbet, C.; Sriram, D. Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors. Eur. J. Med. Chem.,  2020, 199, 112402.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112402] [PMID:  32417538]

[17]
Tapera, M.; Kekeçmuhammed, H.; Sahin, K.; Krishna, V.S.; Lherbet, C.; Homberset, H.; Chebaiki, M.; Tønjum, T.; Mourey, L.; Zorlu, Y.; Durdagi, S.; Sarıpınar, E. Synthesis, characterization, anti-tuberculosis activity and molecular modeling studies of thiourea derivatives bearing aminoguanidine moiety. J. Mol. Struct.,  2022, 1270, 133899.
 [http://dx.doi.org/10.1016/j.molstruc.2022.133899]

[18]
Calixto, S.D.; Simão, T.L.B.V.; Palmeira-Mello, M.V.; Viana, G.M.; Assumpção, P.W.M.C.; Rezende, M.G.; do Espirito Santo, C.C.; de Oliveira Mussi, V.; Rodrigues, C.R.; Lasunskaia, E.; de Souza, A.M.T.; Cabral, L.M.; Muzitano, M.F. Antimycobacterial and anti-inflammatory activities of thiourea derivatives focusing on treatment approaches for severe pulmonary tuberculosis. Bioorg. Med. Chem.,  2022, 53, 116506.
 [http://dx.doi.org/10.1016/j.bmc.2021.116506] [PMID:  34890996]

[19]
Laborde, J.; Deraeve, C.; Bernardes-Génisson, V. Update of antitubercular prodrugs from a molecular perspective: Mechanisms of action, bioactivation pathways, and associated resistance. ChemMedChem,  2017, 12(20), 1657-1676.
 [http://dx.doi.org/10.1002/cmdc.201700424] [PMID:  28921911]

[20]
Lambelin, G. Pharmacology and toxicology of isoxyl. Antibiot Chemother.,  1970, 16, 84-95.
 [http://dx.doi.org/10.1159/000386807]

[21]
Urbancik, B. Clinical experience with thiocarlide (Isoxyl). Antibiot Chemother,  1970, 16, 117-123.

[22]
Wang, C.; Garcia-Contreras, L.; Muttil, P.; Hickey, A.J. Isoxyl assays in plasma. J. Pharm. Biomed. Anal.,  2012, 60, 1-6.
 [http://dx.doi.org/10.1016/j.jpba.2011.10.029] [PMID:  22119164]

[23]
de Freitas Paulo, T.; Duhayon, C.; de França Lopes, L.G.; Silva Sousa, E.H.; Chauvin, R.; Bernardes-Génisson, V. Further insights into the oxidative pathway of thiocarbonyl-type antitubercular prodrugs: Ethionamide, thioacetazone, and isoxyl. Chem. Res. Toxicol.,  2021, 34(8), 1879-1889.
 [http://dx.doi.org/10.1021/acs.chemrestox.1c00164] [PMID:  34319702]

[24]
Phetsuksiri, B.; Jackson, M.; Scherman, H.; McNeil, M.; Besra, G.S.; Baulard, A.R.; Slayden, R.A.; DeBarber, A.E.; Barry, C.E., III; Baird, M.S.; Crick, D.C.; Brennan, P.J. Unique mechanism of action of the thiourea drug isoxyl on Mycobacterium tuberculosis. J. Biol. Chem.,  2003, 278(52), 53123-53130.
 [http://dx.doi.org/10.1074/jbc.M311209200] [PMID:  14559907]

[25]
Akamatsu, Y.; Law, J.H. Enzymatic alkylenation of phospholipid fatty acid chains by extracts of Mycobacterium phlei. J. Biol. Chem.,  1970, 245(4), 701-708.
 [http://dx.doi.org/10.1016/S0021-9258(18)63319-8] [PMID:  4313604]

[26]
Lennarz, W.J.; Scheuerbrandt, G.; Bloch, K. The biosynthesis of oleic and 10-methylstearic acids in Mycobacterium phlei. J. Biol. Chem.,  1962, 237(3), 664-671.
 [http://dx.doi.org/10.1016/S0021-9258(18)60352-7] [PMID:  14463993]

[27]
Grzegorzewicz, A.E.; Korduláková, J.; Jones, V.; Born, S.E.M.; Belardinelli, J.M.; Vaquié, A.; Gundi, V.A.K.B.; Madacki, J.; Slama, N.; Laval, F.; Vaubourgeix, J.; Crew, R.M.; Gicquel, B.; Daffé, M.; Morbidoni, H.R.; Brennan, P.J.; Quémard, A.; McNeil, M.R.; Jackson, M. A common mechanism of inhibition of the Mycobacterium tuberculosis mycolic acid biosynthetic pathway by isoxyl and thiacetazone. J. Biol. Chem.,  2012, 287(46), 38434-38441.
 [http://dx.doi.org/10.1074/jbc.M112.400994] [PMID:  23002234]

[28]
Korduláková, J.; Janin, Y.L.; Liav, A.; Barilone, N.; Dos Vultos, T.; Rauzier, J.; Brennan, P.J.; Gicquel, B.; Jackson, M. Isoxyl activation is required for bacteriostatic activity against Mycobacterium tuberculosis. Antimicrob. Agents Chemother.,  2007, 51(11), 3824-3829.
 [http://dx.doi.org/10.1128/AAC.00433-07] [PMID:  17785510]

[29]
Grzegorzewicz, A.E.; Eynard, N.; Quémard, A.; North, E.J.; Margolis, A.; Lindenberger, J.J.; Jones, V.; Korduláková, J.; Brennan, P.J.; Lee, R.E.; Ronning, D.R.; McNeil, M.R.; Jackson, M. Covalent modification of the Mycobacterium tuberculosis FAS-II dehydratase by Isoxyl and Thiacetazone. ACS Infect. Dis.,  2015, 1(2), 91-97.
 [http://dx.doi.org/10.1021/id500032q] [PMID:  25897434]

[30]
Maitra, A.; Munshi, T.; Healy, J.; Martin, L.T.; Vollmer, W.; Keep, N.H.; Bhakta, S. Cell wall peptidoglycan in Mycobacterium tuberculosis: An Achilles’ heel for the TB-causing pathogen. FEMS Microbiol. Rev.,  2019, 43(5), 548-575.
 [http://dx.doi.org/10.1093/femsre/fuz016] [PMID:  31183501]

[31]
Dong, Y.; Qiu, X.; Shaw, N.; Xu, Y.; Sun, Y.; Li, X.; Li, J.; Rao, Z. Molecular basis for the inhibition of β-hydroxyacyl-ACP dehydratase HadAB complex from Mycobacterium tuberculosis by flavonoid inhibitors. Protein Cell,  2015, 6(7), 504-517.
 [http://dx.doi.org/10.1007/s13238-015-0181-1] [PMID:  26081470]

[32]
Dong, Y.; Li, J.; Qiu, X.; Yan, C.; Li, X. Expression, purification and crystallization of the (3R)-hydroxyacyl-ACP dehydratase HadAB complex from Mycobacterium tuberculosis. Protein Expr. Purif.,  2015, 114, 115-120.
 [http://dx.doi.org/10.1016/j.pep.2015.06.007] [PMID:  26118698]

[33]
Bibens, L.; Becker, J.P.; Dassonville-Klimpt, A.; Sonnet, P. A review of fatty acid biosynthesis enzyme inhibitors as promising antimicrobial drugs. Pharmaceuticals,  2023, 16(3), 425.
 [http://dx.doi.org/10.3390/ph16030425] [PMID:  36986522]

[34]
Singh, B.K.; Biswas, R.; Bhattacharyya, S.; Basak, A.; Das, A.K. The C‐terminal end of mycobacterial HadBC regulates AcpM interaction during the FAS‐II pathway: a structural perspective. FEBS J.,  2022, 289(16), 4963-4980.
 [http://dx.doi.org/10.1111/febs.16405] [PMID:  35175661]

[35]
Zhang, H.; Machutta, C.A.; Tonge, P.J. Fatty acid biosynthesis and oxidation. In:  Comprehensive Natural Products II; Elsevier, 2010; pp. 231-275.
 [http://dx.doi.org/10.1016/B978-008045382-8.00668-7]

[36]
Carel, C.; Nukdee, K.; Cantaloube, S.; Bonne, M.; Diagne, C.T.; Laval, F.; Daffé, M.; Zerbib, D. Mycobacterium tuberculosis proteins involved in mycolic acid synthesis and transport localize dynamically to the old growing pole and septum. PLoS One,  2014, 9(5), e97148.
 [http://dx.doi.org/10.1371/journal.pone.0097148] [PMID:  24817274]

[37]
Machaba, K.E.; Mhlongo, N.N.; Dokurugu, Y.M.; Soliman, M.E.S. Tailored-pharmacophore model to enhance virtual screening and drug discovery: A case study on the identification of potential inhibitors against drug-resistant Mycobacterium tuberculosis (3R)-hydroxyacyl-ACP dehydratases. Future Med. Chem.,  2017, 9(10), 1055-1071.
 [http://dx.doi.org/10.4155/fmc-2017-0020] [PMID:  28632406]

[38]
Grzegorzewicz, A.E.; Gee, C.; Das, S.; Liu, J.; Belardinelli, J.M.; Jones, V.; McNeil, M.R.; Lee, R.E.; Jackson, M. Mechanisms of resistance associated with the inhibition of the dehydration step of type II fatty acid synthase in mycobacterium tuberculosis. ACS Infect. Dis.,  2020, 6(2), 195-204.
 [http://dx.doi.org/10.1021/acsinfecdis.9b00162] [PMID:  31775512]

[39]
Li, M.; Huang, Q.; Zhang, W.; Cao, Y.; Wang, Z.; Zhao, Z.; Zhang, X.; Zhang, J. A novel acyl-acpm-binding protein confers intrinsic sensitivity to fatty acid synthase type II inhibitors in mycobacterium smegmatis. Front. Microbiol.,  2022, 13, 846722.
 [http://dx.doi.org/10.3389/fmicb.2022.846722] [PMID:  35444621]

[40]
Quémard, A.; Sacchettini, J.C.; Dessen, A.; Vilcheze, C.; Bittman, R.; Jacobs, W.R., Jr; Blanchard, J.S. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry,  1995, 34(26), 8235-8241.
 [http://dx.doi.org/10.1021/bi00026a004] [PMID:  7599116]

[41]
Khan, S.; Nagarajan, S.N.; Parikh, A.; Samantaray, S.; Singh, A.; Kumar, D.; Roy, R.P.; Bhatt, A.; Nandicoori, V.K. Phosphorylation of enoyl-acyl carrier protein reductase InhA impacts mycobacterial growth and survival. J. Biol. Chem.,  2010, 285(48), 37860-37871.
 [http://dx.doi.org/10.1074/jbc.M110.143131] [PMID:  20864541]

[42]
Prasad, M.S.; Bhole, R.P.; Khedekar, P.B.; Chikhale, R.V. Mycobacterium enoyl acyl carrier protein reductase (InhA): A key target for antitubercular drug discovery. Bioorg. Chem.,  2021, 115, 105242.
 [http://dx.doi.org/10.1016/j.bioorg.2021.105242] [PMID:  34392175]

[43]
Prati, F.; Zuccotto, F.; Fletcher, D.; Convery, M.A.; Fernandez-Menendez, R.; Bates, R.; Encinas, L.; Zeng, J.; Chung, C.; De Dios Anton, P.; Mendoza-Losana, A.; Mackenzie, C.; Green, S.R.; Huggett, M.; Barros, D.; Wyatt, P.G.; Ray, P.C. Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA. ChemMedChem,  2018, 13(7), 672-677.
 [http://dx.doi.org/10.1002/cmdc.201700774] [PMID:  29399991]

[44]
Pym, A.S.; Saint-Joanis, B.; Cole, S.T. Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect. Immun.,  2002, 70(9), 4955-4960.
 [http://dx.doi.org/10.1128/IAI.70.9.4955-4960.2002] [PMID:  12183541]

[45]
Wahab, H.A.; Choong, Y.S.; Ibrahim, P.; Sadikun, A.; Scior, T. Elucidating isoniazid resistance using molecular modeling. J. Chem. Inf. Model.,  2009, 49(1), 97-107.
 [http://dx.doi.org/10.1021/ci8001342] [PMID:  19067649]

[46]
Yan, W.; Zheng, Y.; Dou, C.; Zhang, G.; Arnaout, T.; Cheng, W. The pathogenic mechanism of Mycobacterium tuberculosis: Implication for new drug development. Molecular Biomedicine,  2022, 3(1), 48.
 [http://dx.doi.org/10.1186/s43556-022-00106-y] [PMID:  36547804]

[47]
Vilchèze, C.; Jacobs, W.R., Jr. Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis: Genes, mutations, and causalities. Microbiol. Spectr.,  2014, 2(4), 2.4.01.
 [http://dx.doi.org/10.1128/microbiolspec.MGM2-0014-2013] [PMID: 26104204]

[48]
Ghorab, M.M.; El-Gaby, M.S.A.; Soliman, A.M.; Alsaid, M.S.; Abdel-Aziz, M.M.; Elaasser, M.M. Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety. Chem. Cent. J.,  2017, 11(1), 42.
 [http://dx.doi.org/10.1186/s13065-017-0271-7] [PMID:  29086825]

[49]
Benson, T.E.; Marquardt, J.L.; Marquardt, A.C.; Etzkorn, F.A.; Walsh, C.T. Overexpression, purification, and mechanistic study of UDP-N-acetylenolpyruvylglucosamine reductase. Biochemistry,  1993, 32(8), 2024-2030.
 [http://dx.doi.org/10.1021/bi00059a019] [PMID:  8448160]

[50]
Barreteau, H.; Kovač, A.; Boniface, A.; Sova, M.; Gobec, S.; Blanot, D. Cytoplasmic steps of peptidoglycan biosynthesis. FEMS Microbiol. Rev.,  2008, 32(2), 168-207.
 [http://dx.doi.org/10.1111/j.1574-6976.2008.00104.x] [PMID:  18266853]

[51]
Eniyan, K.; Dharavath, S.; Vijayan, R.; Bajpai, U.; Gourinath, S. Crystal structure of UDP-N-acetylglucosamine-enolpyruvate reductase (MurB) from Mycobacterium tuberculosis. Biochim. Biophys. Acta. Proteins Proteomics,  2018, 1866(3), 397-406.
 [http://dx.doi.org/10.1016/j.bbapap.2017.11.013] [PMID:  29203374]

[52]
Konduri, S.; Pogaku, V.; Prashanth, J.; Siva Krishna, V.; Sriram, D.; Basavoju, S.; Behera, J.N.; Prabhakara Rao, K. Sacubitril‐based urea and thiourea derivatives as novel inhibitors for anti‐tubercular against dormant tuberculosis. ChemistrySelect,  2021, 6(16), 3869-3874.
 [http://dx.doi.org/10.1002/slct.202004724]

[53]
Epp, J.B.; Alexander, A.L.; Balko, T.W.; Buysse, A.M.; Brewster, W.K.; Bryan, K.; Daeuble, J.F.; Fields, S.C.; Gast, R.E.; Green, R.A.; Irvine, N.M.; Lo, W.C.; Lowe, C.T.; Renga, J.M.; Richburg, J.S.; Ruiz, J.M.; Satchivi, N.M.; Schmitzer, P.R.; Siddall, T.L.; Webster, J.D.; Weimer, M.R.; Whiteker, G.T.; Yerkes, C.N. The discovery of Arylex™ active and Rinskor™ active: Two novel auxin herbicides. Bioorg. Med. Chem.,  2016, 24(3), 362-371.
 [http://dx.doi.org/10.1016/j.bmc.2015.08.011] [PMID:  26321602]

[54]
Konduri, S.; Bhargavi, D.; Prashanth, J.; Krishna, V.S.; Sriram, D.; Rao, K.P. Design and synthesis of “chloropicolinate amides and urea derivatives” as novel inhibitors for Mycobacterium tuberculosis. ACS Omega,  2021, 6(2), 1657-1667.
 [http://dx.doi.org/10.1021/acsomega.0c05690] [PMID:  33490825]

[55]
Poen, S.; Nakatani, Y.; Opel-Reading, H.K.; Lassé, M.; Dobson, R.C.J.; Krause, K.L. Exploring the structure of glutamate racemase from Mycobacterium tuberculosis as a template for anti-mycobacterial drug discovery. Biochem. J.,  2016, 473(9), 1267-1280.
 [http://dx.doi.org/10.1042/BCJ20160186] [PMID:  26964898]

[56]
Glavas, S.; Tanner, M.E. Catalytic acid/base residues of glutamate racemase. Biochemistry,  1999, 38(13), 4106-4113.
 [http://dx.doi.org/10.1021/bi982663n] [PMID:  10194325]

[57]
Tanner, M.E.; Gallo, K.A.; Knowles, J.R. Isotope effects and the identification of catalytic residues in the reaction catalyzed by glutamate racemase. Biochemistry,  1993, 32(15), 3998-4006.
 [http://dx.doi.org/10.1021/bi00066a021] [PMID:  8097110]

[58]
May, M.; Mehboob, S.; Mulhearn, D.C.; Wang, Z.; Yu, H.; Thatcher, G.R.J.; Santarsiero, B.D.; Johnson, M.E.; Mesecar, A.D. Structural and functional analysis of two glutamate racemase isozymes from Bacillus anthracis and implications for inhibitor design. J. Mol. Biol.,  2007, 371(5), 1219-1237.
 [http://dx.doi.org/10.1016/j.jmb.2007.05.093] [PMID:  17610893]

[59]
Ruzheinikov, S.N.; Taal, M.A.; Sedelnikova, S.E.; Baker, P.J.; Rice, D.W. Substrate-induced conformational changes in Bacillus subtilis glutamate racemase and their implications for drug discovery. Structure,  2005, 13(11), 1707-1713.
 [http://dx.doi.org/10.1016/j.str.2005.07.024] [PMID:  16271894]

[60]
Glavas, S.; Tanner, M.E. Active site residues of glutamate racemase. Biochemistry,  2001, 40(21), 6199-6204.
 [http://dx.doi.org/10.1021/bi002703z] [PMID:  11371180]

[61]
Fisher, S.L. Glutamate racemase as a target for drug discovery. Microb. Biotechnol.,  2008, 1(5), 345-360.
 [http://dx.doi.org/10.1111/j.1751-7915.2008.00031.x] [PMID:  21261855]

[62]
Malapati, P.; Siva Krishna, V.; Nallangi, R.; Meda, N.; Reshma Srilakshmi, R.; Sriram, D. Lead identification and optimization of bacterial glutamate racemase inhibitors. Bioorg. Med. Chem.,  2018, 26(1), 177-190.
 [http://dx.doi.org/10.1016/j.bmc.2017.11.031] [PMID:  29239770]

[63]
Malapati, P.; Krishna, V.S.; Nallangi, R.; Srilakshmi, R.R.; Sriram, D. Identification and development of benzoxazole derivatives as novel bacterial glutamate racemase inhibitors. Eur. J. Med. Chem.,  2018, 145, 23-34.
 [http://dx.doi.org/10.1016/j.ejmech.2017.12.088] [PMID:  29310027]

[64]
Kalaiyarasi, A.; Haribabu, J.; Gayathri, D.; Gomathi, K.; Bhuvanesh, N.S.P.; Karvembu, R.; Biju, V.M. Chemosensing, molecular docking and antioxidant studies of 8-aminoquinoline appended acylthiourea derivatives. J. Mol. Struct.,  2019, 1185, 450-460.
 [http://dx.doi.org/10.1016/j.molstruc.2019.02.098]

[65]
Batt, S.M.; Jabeen, T.; Bhowruth, V.; Quill, L.; Lund, P.A.; Eggeling, L.; Alderwick, L.J.; Fütterer, K.; Besra, G.S. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc. Natl. Acad. Sci.,  2012, 109(28), 11354-11359.
 [http://dx.doi.org/10.1073/pnas.1205735109] [PMID:  22733761]

[66]
Piton, J.; Foo, C.S.Y.; Cole, S.T. Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors. Drug Discov. Today,  2017, 22(3), 526-533.
 [http://dx.doi.org/10.1016/j.drudis.2016.09.014] [PMID:  27666194]

[67]
Brecik, M.; Centárová, I.; Mukherjee, R.; Kolly, G.S.; Huszár, S.; Bobovská, A.; Kilacsková, E.; Mokošová, V.; Svetlíková, Z.; Šarkan, M.; Neres, J.; Korduláková, J.; Cole, S.T.; Mikušová, K. DprE1 is a vulnerable tuberculosis drug target due to its cell wall localization. ACS Chem. Biol.,  2015, 10(7), 1631-1636.
 [http://dx.doi.org/10.1021/acschembio.5b00237] [PMID:  25906160]

[68]
Mikušová, K.; Huang, H.; Yagi, T.; Holsters, M.; Vereecke, D.; D’Haeze, W.; Scherman, M.S.; Brennan, P.J.; McNeil, M.R.; Crick, D.C. Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl residues of Mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J. Bacteriol.,  2005, 187(23), 8020-8025.
 [http://dx.doi.org/10.1128/JB.187.23.8020-8025.2005] [PMID:  16291675]

[69]
Manina, G.; Pasca, R. Decaprenylphosphoryl-&#946;-D-ribose 2-epimerase from Mycobacterium tuberculosis is a magic drug target. Curr. Med. Chem.,  2010, 17, 3099-3108.
 [http://dx.doi.org/10.2174/092986710791959693] [PMID:  20629622]

[70]
Gawad, J.; Bonde, C. Decaprenyl-phosphoryl-ribose 2′-epimerase (DprE1): challenging target for antitubercular drug discovery. Chem. Cent. J.,  2018, 12(1), 72.
 [http://dx.doi.org/10.1186/s13065-018-0441-2] [PMID:  29936616]

[71]
Krishna, V.S.; Zheng, S.; Rekha, E.M.; Nallangi, R.; Sai Prasad, D.V.; George, S.E.; Guddat, L.W.; Sriram, D. Design and development of ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues as Mycobacterium tuberculosis ketol-acid reductoisomerase inhibitors. Eur. J. Med. Chem.,  2020, 193, 112178.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112178] [PMID:  32171154]

[72]
Tadrowski, S.; Pedroso, M.M.; Sieber, V.; Larrabee, J.A.; Guddat, L.W.; Schenk, G. Metal ions play an essential catalytic role in the mechanism of ketol-acid reductoisomerase. Chemistry,  2016, 22(22), 7427-7436.
 [http://dx.doi.org/10.1002/chem.201600620] [PMID:  27136273]

[73]
Lv, Y.; Kandale, A.; Wun, S.J.; McGeary, R.P.; Williams, S.J.; Kobe, B.; Sieber, V.; Schembri, M.A.; Schenk, G.; Guddat, L.W. Crystal structure of Mycobacterium tuberculosis ketol‐acid reductoisomerase at 1.0 Å resolution - a potential target for anti‐tuberculosis drug discovery. FEBS J.,  2016, 283(7), 1184-1196.
 [http://dx.doi.org/10.1111/febs.13672] [PMID:  26876563]

[74]
Krishna, V.S.; Zheng, S.; Rekha, E.M.; Guddat, L.W.; Sriram, D. Discovery and evaluation of novel Mycobacterium tuberculosis ketol-acid reductoisomerase inhibitors as therapeutic drug leads. J. Comput. Aided Mol. Des.,  2019, 33(3), 357-366.
 [http://dx.doi.org/10.1007/s10822-019-00184-1] [PMID:  30666485]

[75]
Gautheron, J.; Jéru, I. The multifaceted role of epoxide hydrolases in human health and disease. Int. J. Mol. Sci.,  2020, 22(1), 13.
 [http://dx.doi.org/10.3390/ijms22010013] [PMID:  33374956]

[76]
Johansson, P.; Unge, T.; Cronin, A.; Arand, M.; Bergfors, T.; Jones, T.A.; Mowbray, S.L. Structure of an atypical epoxide hydrolase from Mycobacterium tuberculosis gives insights into its function. J. Mol. Biol.,  2005, 351(5), 1048-1056.
 [http://dx.doi.org/10.1016/j.jmb.2005.06.055] [PMID:  16051262]

[77]
Schulz, E.C.; Henderson, S.R.; Illarionov, B.; Crosskey, T.; Southall, S.M.; Krichel, B.; Uetrecht, C.; Fischer, M.; Wilmanns, M. The crystal structure of mycobacterial epoxide hydrolase A. Sci. Rep.,  2020, 10(1), 16539.
 [http://dx.doi.org/10.1038/s41598-020-73452-y] [PMID:  33024154]

[78]
Madacki, J.; Kopál, M.; Jackson, M.; Korduláková, J. Mycobacterial epoxide hydrolase EphD is inhibited by urea and thiourea derivatives. Int. J. Mol. Sci.,  2021, 22(6), 2884.
 [http://dx.doi.org/10.3390/ijms22062884] [PMID:  33809178]

[79]
DeJesus, M.A.; Gerrick, E.R.; Xu, W.; Park, S.W.; Long, J.E.; Boutte, C.C.; Rubin, E.J.; Schnappinger, D.; Ehrt, S.; Fortune, S.M.; Sassetti, C.M.; Ioerger, T.R. Comprehensive essentiality analysis of the Mycobacterium tuberculosis genome via saturating transposon mutagenesis. MBio,  2017, 8(1), e02133-e16.
 [http://dx.doi.org/10.1128/mBio.02133-16] [PMID:  28096490]

[80]
Rengarajan, J.; Bloom, B.R.; Rubin, E.J. Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proc. Natl. Acad. Sci.,  2005, 102(23), 8327-8332.
 [http://dx.doi.org/10.1073/pnas.0503272102] [PMID:  15928073]

[81]
Dubnau, E.; Chan, J.; Raynaud, C.; Mohan, V.P.; Lanéelle, M.A.; Yu, K.; Quémard, A.; Smith, I.; Daffé, M. Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol. Microbiol.,  2000, 36(3), 630-637.
 [http://dx.doi.org/10.1046/j.1365-2958.2000.01882.x] [PMID:  10844652]
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DOI https://dx.doi.org/10.2174/0109298673276076231124104513	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery

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