Anti-Tuberculosis Mur Inhibitors: Structural Insights and the Way Ahead for Development of Novel Agents

Abstract

Mur enzymes serve as critical molecular devices for the synthesis of UDP-MurNAc-pentapeptide, the main building block of bacterial peptidoglycan polymer. These enzymes have been extensively studied for bacterial pathogens such as Escherichia coli and Staphylococcus aureus. Various selective and mixed Mur inhibitors have been designed and synthesized in the past few years. However, this class of enzymes remains relatively unexplored for Mycobacterium tuberculosis (Mtb), and thus offers a promising approach for drug design to overcome the challenges of battling this global pandemic. This review aims to explore the potential of Mur enzymes of Mtb by systematically scrutinizing the structural aspects of various reported bacterial inhibitors and implications concerning their activity. Diverse chemical scaffolds such as thiazolidinones, pyrazole, thiazole, etc., as well as natural compounds and repurposed compounds, have been reviewed to understand their in silico interactions with the receptor or their enzyme inhibition potential. The structural diversity and wide array of substituents indicate the scope of the research into developing varied analogs and providing valuable information for the purpose of modifying reported inhibitors of other multidrug-resistant microorganisms. Therefore, this provides an opportunity to expand the arsenal against Mtb and overcome multidrug-resistant tuberculosis.

Keywords: MurB; MurE; Mycobacterium tuberculosis; inhibitors; molecular hybrids; thiazolidinones.

Figure 1

(a) Peptidoglycan biosynthesis pathway depicting various Mur enzyme families. (b) Crystal structure of E. Coli Mur B (1MBT) [25]. (c) Crystal structure of Mtb Mur E (2XJA) [27].

Figure 2

Structural classes of Mur B substrates. (1) Substituted-4-thiazolidinone; (2) imidazolinones; (3) 5-Benzylidene-2-thiazolyimino-4-thiazolidinones; (4) benzylidene benzothiazolo thiazolidinones derivative; (5) benzothiazole-based thiazolidinones; (6) triazole-based thiazolidinones; (7) 5-Indolylmethylen-4-oxo-2-thioxothiazolidines; (8) 5-Hydroxy-1H-pyrazol-3(2H)-one; (9) 5-Hydroxy-1H-pyrazol-3(2H)-one carboxamide derivatives; (10) 3,5-Dioxopyrazolidines; (11) 4-substituted 1,2-bis(4-chlorophenyl) pyrazolidine-3,5-diones; (12) bis(pyrazole-benzofuran) hybrids containing piperazine linker.

Figure 3

Modifications of the core scaffold of triazolyl pyrazole MurB inhibitors. (a) 3-(1-(2,3-dichloro-6-methyl-5-(trifluoromethyl)phenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-(3,5-dinitrophenyl)-1H-pyrazole-4-carbaldehyde. (b) 3-(1-(2,3-dichloro-6-methyl-5-(trifluoromethyl)phenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbaldehyde. (c) 3-(1-(2,3-dichloro-6-methyl-5-(trifluoromethyl)phenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-(phthalazin-1-yl)-1H-pyrazole-4-carbaldehyde. (d) 3-(5-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde. (e) 3-(5-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-1-(8-(trifluoromethyl)quinolin-4-yl)-1H-pyrazole-4-carbaldehyde. (f) 3-(5-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-1-(phthalazin-1-yl)-1H-pyrazole-4-carbaldehyde.

Figure 4

Chloropicolinate hybrids. (13a) Amide analogs derived from chloropicolinate. (13b) Urea and thiourea analogs derived from chloropicolinate. (13c) o-Dichloro benzamide derivative. (13d) p-Trifluoromethyl benzamide derivative. (13e) m-Fluroro benzamide derivative.

Figure 5

Classes of MurB inhibitors. (14) Purine-2,6-dione linked piperazine derivatives. (15) Triazolo-thiazole derivatives. (16) Sacubitril-based thiourea. (17) Tetrazolyl acetamides.

Figure 6

Coumarin triazoles and coumarin-furocoumarins as MurB inhibitors.

Figure 7

Structural scaffolds of mixed inhibitors. (21) Adamantan thiadiazole-based thiazolidinones. (22) Cyclohexylidene derivative of pulvinone. (23) Biphenyl derivative of pulvinone. (24) Benzylidene derivative of pulvinone. (25) 5′-deoxy-5′-(4-substituted-1,2,3-triazol-1-yl)-uridine amide. (26) Glucosamine derivative.

Figure 8

(27) N-methyl-2-alkenyl-4-quinolones, (28) 3-bromo-4,5-dihydroisoxazole, (29) phosphinates as Mur inhibitors.

Figure 9

Modifications of 5-benzylidenethiazolidine as Mur enzyme inhibitors.

Figure 10

Structural scaffolds of some MurE inhibitors. (30) D-glutamate-based 5-benzylidenethiazolidin-4-one. (31) Phosphorylated hydroxyethylamines. (32) Benzene-1,3-dicarboxylic acids containing thioxoxdihydropyrimidinedione. (33) Naphthyl tetronic acid derivatives. (34) Furan- and triazole-containing stilbene derivatives.