Rational design and synthesis of novel diphenyl ether derivatives as antitubercular agents

Figures & data

Figure 1 Design of triclosan (1) mimic diphenyl ether derivatives (5a–f and 10a–c).

Figure 2 The general synthetic route for the synthesis of compounds 5a–f.

Notes: Reagents and conditions: (a) PhB(OH)₂, Cu(OAc)₂, C₅H₅N, CH₂Cl₂, 25°C–27°C, 72 hours, 48%; (b) ArCHO, KOH, EtOH, 25°C–27°C, 24 hours, 67%–78%; (c) cyanohydrin acetone, Bu₃(Me)N⁺OH⁻, K₂CO₃, Me₂CO, H₂O, 55°C–27°C, 14 hours, 80%–93%; and (d) H₂O₂, K₂CO₃, DMSO, from 5°C to 25°C–27°C, 2 hours, 70%–77%.
Abbreviation: DMSO, dimethyl sulfoxide.

Figure 3 The general synthetic route for the synthesis of compounds 10a–c.

Notes: Reagents and conditions: (a) PhB(OH)₂, Cu(OAc)₂, C₅H₅N, CH₂Cl₂, 25°C–27°C, 72 hours, 94%; (b) BBr₃ (1 M, CH₂Cl₂), CH₂Cl₂, from −78°C to 25°C–27°C, 3 hours, 96%; (c) ArCHO, KOH, EtOH, 25°C–27°C, 24 hours, 55%–72%; (d) cyanohydrin acetone, Bu₃(Me)N⁺OH⁻, K₂CO₃, Me₂CO, H₂O, 55°C–57°C, 14 hours, 80%–83%; and (e) H₂O₂, K₂CO₃, DMSO, from 0°C to 25°C–27°C, 5 hours, 81%–86%.
Abbreviation: DMSO, dimethyl sulfoxide.

Table 1 In vitro antitubercular activity (MIC), cytotoxicity (CC₅₀), SI, Clog P, and PSA of compounds 5a–f and 10a–c

Compound	R	MICa (µg/mL)	CC50b (µg/mL)		SIc	Clog Pd	PSAe (Å^Citation2)
			Vero	HepG2
5a	−H	>100	>300	>300	–	4.01	69.39
5b	4-Me	>100	>300	>300	–	4.51	69.39
5c	4-OMe	>100	>300	>300	–	3.93	78.62
5d	2-OMe	50	>300	>300	–	3.93	78.62
5e	4-F	50	>300	>300	–	4.16	69.39
5f	4-Cl	>100	>300	>300	–	4.73	69.39
10a	−H	20	>300	>300	>10	3.64	89.62
10b	4-Me	12.5	>300	>300	>10	4.14	89.62
10c	4-OMe	25	>300	260.6	>10	3.56	98.85
Triclosan	–	12.5	>300	>300	>10	5.52	29.46
Isoniazid	–	0.125	–	–	–	–	–

Notes:

a MIC, minimal drug concentration required to stop the growth of Mycobacterium tuberculosis H37Rv;

b CC₅₀, minimal drug concentration required for 50% death of viable cells;

c SI, CC₅₀/MIC;

d Clog P predicted from ChemDraw Ultra-2008;

e PSA predicted from ChemDraw Ultra-2008.

Abbreviations: CC₅₀, half-maximal cytotoxicity concentration; MIC, minimum inhibitory concentration; PSA, polar surface area; SI, selectivity index.

Table 2 Molecular docking results of compounds 5a–f and 10a–c

Compound	Docking score	Hydrophobic surface (1.4 Å)	Hydrogen bonding		Distance (Å)
			NAD-300	Tyr-158	NAD-300	Tyr-158
5a	−9.64	186.74	√	X	1.75	2.74
5b	−8.05	182.64	X	X	2.14	2.41
5c	−5.83	163.99	√	X	1.42	2.57
5d	−7.39	179.07	√	X	1.91	2.60
5e	−6.51	172.84	√	X	1.51	2.24
5f	−6.41	164.43	√	X	1.43	2.58
10a	−8.53	180.91	√	X	2.03	1.99
10b	−8.65	174.96	√	X	1.93	2.03
10c	−7.64	156.04	√	X	1.82	2.52
Triclosan	−8.48	117.36	√	√	1.63	1.76

Notes: √, presence of interaction; X, absence of interaction.

Abbreviations: NAD, nicotinamide adenine dinucleotide; Tyr, tyrosine.

Figure 4 Molecular docking interaction of compound 10b (green) with Mtb ENR (PDB 1P45).

Note: Dotted yellow line shows the hydrogen bonding interaction.
Abbreviations: Mtb ENR, enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis; NAD, nicotinamide adenine dinucleotide.

Table 3 Evaluation of druglikeness of compound 10b

log Pa	pKaa	% protein bindinga
4.059	7.59	90.5

Note:

a log P, pKa, and % protein binding were estimated from reverse-phase HPLC experiment.

Abbreviation: HPLC, high-performance liquid chromatography.

Table 4 Human microsome stability study of compound 10b

Percentage remaininga
15 minutes	30 minutes	1 hour	2 hours
70.18	57.49	50.68	40.35

Note:

a Percentage of compound that remained at different time points during incubation with HLM.

Abbreviation: HLM, human liver microsomes.

GreenKDGarneau-TsodikovaSResistance in tuberculosis: what do we know and where can we go?Front Microbiol2013420823888158

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