Mycobacterium tuberculosis enoyl-acyl carrier protein reductase inhibitors as potential antituberculotics: development in the past decade

Figures & data

Figure 1. Structures of currently used front line antituberculotics and direct InhA inhibitor triclosan.

Figure 2. FAS II pathway; FabH: β-ketoacyl-ACP synthase; MabA: 3-ketoacyl-ACP reductase; InhA: Enoyl-ACP-reductase and KasA, KasB: β-ketoacyl-ACP synthase. KasA is specific for shorter chain substrates, KasB utitlizes longer chain substrates.

Table 1. Structures and in vitro results of notable InhA inhibitors.

Compound	InhA IC50 (µM)	Ki (µM)	MIC (µg/mL^−1/µM)	Reference/compound number
Isoniazide	0.1	0.075	0.4	4
Triclosan	2.8	0.2	12.5/43	26
	2		3.8/17.5	22/1
	0.08			22/2
	0.017	0.012	1.0/3.5	22/3
	0.011	0.009	2.1/7.8	22/4
	0.005	0.001	1.9/6.4	22/5
	0.15	0.03	175/460	22/6
	0.24		3.13/11.5	27/7
	0.16		3.13/11.5	27/8
	0.65		6.25/23.0	27/9
			100/301	27/10
	>100		75/275	27/11
	0.18 0.048 0.09		12.5/39.7 12.5/39.7 257/9,3	27/12,13,14
	0.062 1.1 0.055		3.13/11,0 100/350 12.5/43.8	27/15,16,17
	1.55 5.6 1.3		>200/>610 100/305 50/152	27/18,19,20
	2.36 0.58 1.93		100/280 130/363 >200/>560	27/20,21,22
	0.11 ± 0.031		9.4/27	21/23
	0.12 ± 0.019			21/24
	0.091 ± 0.015			21/25
	0.055 ± 0.02		9.4/30	21/26
	0.096 ± 0.046		19/60	21/27
	0.063 ± 0.009			21/28
	0.13 ± 0.056			21/29
	0.029 ± 0.011			21/30
	0.042 ± 0.001			21/31
	0.075 ± 0.016			21/32
	0.051 ± 0.006		9.4/27	21/33
	0.021 ± 0.008		19/52	21/34
	0.05 ± 0.014		4.7/13	21/35
	0.057 ± 0.004	0.000022	3.13/11.0	31^,33/36
	0.062 ± 0.005		3.13/11,0	33/37
	0.05 ± 0.002	0.00096	1.56/5.13	33/38
	0.01 ± 0.0008	0.0002	3.13/9.0	33/39
	0.03 ± 0.001		50/148	33/40
	0.045 ± 0.008	0.0037	25/63	33/41
	0.012 ± 0.005	0.00009	1.56/5.41	33/42
	0.048 ± 0.003	0.016	12.5/43.8	33/43
	0.24 ± 0.01	0.002	2.5/8.5	33/44
	0.16		>125/>318	34/45
	2.4		2.5/6.6	34/46
			0.5/1.6	35^,36/47
			2/5.3	36/48
			2/5.8	36/49
			2/5.4	36/50
			2/6.1	36/51
	0.89 ± 0.05			37/52
	0.97 ± 0.03			37/53
	0.39 ± 0.01			37/54
	0.85 ± 0.05			37/55
			16/39.7	38/56
			16/41.9	38/57
			16/41.1	38/58
			8/19.6	38/59
	3.07 ± 0.48			40/60
	0.99 ± 0.03			40/61
	1.85 ± 0.08			40/62
	0.40 ± 0.02			40/63
	0.09 ± 0.001			40/64
	1.89 ± 0.11			40/65
	2.04 ± 0.08			40/66
	24			41/67
	0.003		0.08/0.19	43/68
	0.004		0.2/0.5	43/69
	0.234		3.25/7.5	43/70
	0.03		<0.17/<0.4	43/71
	0.2		1.5/3.75	43/72
	<0.002		1.39/3.13	43/73
	<0.002		5.58/12.5	43/74
	0.97		>5.9/>12.5	43/75
	0.4		>45/>100	43/76

Figure 3. General structure of diphenyl ethers (1–6) published by Sullivan et al.; n = 1,3–5,7,13.

Figure 4. Structures of InhA inhibitors developed by Ende et al. R: NO₂, NH₂ and -NHCOCH₃.

Figure 5. Structures of triclosan analogues published by Freundlich et al.; R: aliphatic, aromatic or heteroaromatic substitution; R': Cl and CN.

Figure 6. Tight binding diphenyl ether InhA inhibitor PT70 (36).

Scheme 1. Alkyl substituted diphenylether inhibitor (5) binding mode (pdb no. 2B37).

Scheme 2. Triclosan binding mode, pdb no: 3FNF (24).

Scheme 3. PT70 (36) binding mode, pdb no. 2X23.

Scheme 4. Genz 10850 (45) binding mode, pdb no. 1P44.

Figure 7. General structures of compounds published by Pan and Tonge and colleagues in 2014; R: NO₂, NH₂, CH₃, Cl, Br, CF₃, I, F, OH and CN.

Figure 8. Structure of two inhibitors from Genzyme compound library.

Figure 9. General structure of two triazole derivatives classes. R: H and Cl; R’: Me, OMe and NO₂; R’’: phenyl, cyclohexyl and alkyl; n = 1–2.

Figure 10. General structure of triazole potential inhibitors derived from previously published class b compounds. R: halogen, Me and OMe and n: 5–11.

Figure 11. General structure of pyrrolidne carboxamide InhA inhibitors.

Scheme 5. Pyrrolidine carboxamide derivative binding mode, pdb no 2H7M.

Figure 12. General structure of pyrrolidine-2,5-diones. R: acyl group, akyl, aryl and β-amide.

Figure 13. General structures of arylamides R₁: small aliphatic or aromatic substituents and R₂: Cl, CF₃ and NO₂.

Figure 14. Compounds selected from Pharmacophore modeling study.

Figure 15. Compounds selected by exhaustive molecular docking published by Pauli et al.

Figure 16. Methyl-thiazole lead sructure and its derivatives published by Shirude et al.

Scheme 6. Arylamides binding mode.

Scheme 7. Methyl-thiazole “Tyr158 out” binding mode.

Rawat R, Whitty A, Tonge PJ. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc Natl Acad Sci USA 2003;100:13881–6

 PubMed Web of Science ®Google Scholar

Boyne ME, Sullivan TJ, am Ende CW, et al. Targeting fatty acid biosynthesis for the development of novel chemotherapeutics against Mycobacterium tuberculosis: evaluation of A-ring-modified diphenyl ethers as high-affinity InhA inhibitors. Antimicrob Agents Chemother 2007;51:3562–7

 PubMed Web of Science ®Google Scholar

Sullivan TJ, Truglio JJ, Boyne ME, et al. High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. ACS Chem Biol 2006;1:43–53

 PubMed Web of Science ®Google Scholar

am Ende CW, Knudson SE, Liu N, et al. Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors. Bioorg Med Chem Lett 2008;18:3029–33

 PubMed Web of Science ®Google Scholar

Freundlich JS, Wang F, Vilcheze C, et al. Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis. Chem Med Chem 2009;4:241–8

 Web of Science ®Google Scholar

Luckner SR, Liu N, am Ende CW, et al. A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. J Biol Chem 2010;285:14330–7

 PubMed Web of Science ®Google Scholar

Pan P, Knudson SE, Bommineni GR, et al. Time-dependent diaryl ether inhibitors of InhA: structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy. Chem Med Chem 2014;9:776–91

 Google Scholar

Kuo MR, Morbidoni HR, Alland D, et al. Targeting tuberculosis and malaria through inhibition of enoyl reductase. J Biol Chem 2003;278:20851–9

 PubMed Web of Science ®Google Scholar

Menendez C, Gau S, Lherbet C, et al. Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents. Eur J Med Chem 2011;46:5524–31

 PubMed Web of Science ®Google Scholar

Menendez C, Chollet A, Rodriguez F, et al. Chemical synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and antituberculosis agents. Eur J Med Chem 2012;52:275–83

 PubMed Web of Science ®Google Scholar

He X, Alian A, Stroud R, Ortiz de Montellano PR. Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J Med Chem 2006;49:6308–23

 PubMed Web of Science ®Google Scholar

Matviiuk T, Rodriguez F, Saffon N, et al. Design, chemical synthesis of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione derivatives and biological activity against enoyl-ACP reductase (InhA) and Mycobacterium tuberculosis. Eur J Med Chem 2013;70:37–48

 PubMed Web of Science ®Google Scholar

He X, Alian A, Ortiz de Montellano PR. Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorg Med Chem 2007;15:6649–58

 PubMed Web of Science ®Google Scholar

Pauli I, dos Santos RN, Rostirolla DC, et al. Discovery of new inhibitors of Mycobacterium tuberculosis InhA enzyme using virtual screening and a 3D-pharmacophore-based approach. J Chem Inf Model 2013;53:2390–401

 PubMed Web of Science ®Google Scholar

Shirude PS, Madhavapeddi P, Naik M, et al. Methyl-thiazoles: a novel mode of inhibition with the potential to develop novel inhibitors targeting InhA in Mycobacterium tuberculosis. J Med Chem 2013;56:8533–42

 PubMed Web of Science ®Google Scholar