Searching for novel scaffold of triazole non-nucleoside inhibitors of HIV-1 reverse transcriptase

Figures & data

Figure 1. Three main groups of azole NNRTIs: aryl–CH₂–(–NH–, –O–) disubstituted azoles (a), azole-thioglycolanilide derivatives (b) and other (c).

Table 1. Considered R¹, R² and R³ substituents for triazole NNRTIs and selected results for Glide SP protocol in 2RKI receptor.

Compounds	R^1	R^2	R^3	Glide SP gscore	Glide SP emodel
1	Thiophen-2-yl	2,4-Dimethylphenyl	2-Nitrophenyl	−10.63	−70.33
2	Thiophen-2-yl	3-(Trifluoromethyl)phenyl	2-Nitrophenyl	−10.36	−85.13
3	4-Methyl-1,2,3-thiadiazol-5-yl	4-Methylphenyl	2-Nitrophenyl	−9.46	−85.28
4	Thiophen-2-yl	4-Methoxyphenyl	2-Chloro-4-sulfamoylphenyl	−10.46	−85.35
5	4-Methylimidazol-5-yl	2,4-Dichlorophenyl	2-Nitrophenyl	−9.56	−73.17
6	4-Methylimidazol-5-yl	3-(Trifluoromethyl)phenyl	2-Nitrophenyl	−10.46	−90.50
7	Thiophen-2-yl	4-Methoxyphenyl	2-Nitrophenyl	−8.63	−77.05
8	Thiophen-2-yl	4-Methylphenyl	2-Nitrophenyl	−9.94	−87.27
9	2-Methylfuran-3-yl	4-Methylphenyl	2-Nitrophenyl	−9.68	−84.16
Ref*				−10.75	−88.38

*4-Benzyl-3-(((2-chlorophenyl)methyl)sulfanyl)-5-(thiophen-2-yl)-4H-1,2,4-triazole – reference ligand from 2RKI crystallographic structure.

Table 2. Inhibitory activity (in µM) of triazoles 1–9 against HIV-1 RT (wild type, Innovagen kit).

	1	2	3	4	5	6	7	8	9	nvp*
IC50	6	9	7.5	15	43.5	>100	>100	>100	>100	<1

*Nevirapine.

Table 3. Structures of the 5-position substitution variants used for docking experiments and selected results for Glide SP protocol in 2RKI receptor.

Compounds	R1	R2	R3	X	Glide SP gscore	Glide SP emodel
10	Thiophen-2-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−11.75	−90.11
11	4-Methyl-1,2,3-thiadiazol-5-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−11.27	−92.65
12	4-Methylimidazol-5-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−11.00	−87.20
13	Pyrazin-2-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−10.76	−85.16
14	1,2,4-Triazol-3-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−10.66	−87.08
15	Pyrrol-2-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−10.55	−83.63
16	Piperidin-4-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−10.46	−82.02
17	t-Butyl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−10.01	−79.87
18	Pyrrol-2-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−9.97	−85.67
19	3-trifluoromethyl-phenyl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−9.96	−54.32
20	1,3-oxazol-2-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−9.71	−80.84
21	imidazol-2-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−9.57	−79.81
22	4-Trifluoromethyl-phenyl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−9.40	−69.44
23	4-Nitrophenyl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−9.14	−70.60
24	Isoquinolin-3-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−9.04	−48.88
25	Indol-2-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−8.92*	−47.14*
26	1H-Tetrazol-5-yl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−8.86	−78.10
27	Thiophen-2-yl	2,4-Dimethylphenyl	4-Carboxy-2-chlorophenyl	-CH2CONH-	−10.04	−86.64
28	4-Methyl-1,2,3-thiadiazol-5-yl	2,4-Dimethylphenyl	4-Carboxy-2-chlorophenyl	-CH2CONH-	−10.15	−79.34
29	Methyl	2,4-Dimethylphenyl	2-Chloro-4-sulfamoylphenyl	-CH2CONH-	−10.84	−89.58
30	Methyl	2,4-Dimethylphenyl	4-Carboxy-2-chlorophenyl	-CH2CONH-	−10.20	−82.71
31	Thiophen-2-yl	Benzyl	4-Carboxy-2-chlorophenyl	-CH2CONH-	−10.23	−89.02
32	Methyl	Benzyl	4-Carboxy-2-chlorophenyl	-CH2CONH-	−10.41	−84.90
33	Methyl	Benzyl	Phenyl	-CH2-	−10.38	−82.37
34	Methyl	2,4-Dimethylphenyl	Phenyl	-CH2-	−9.48	−59.62

*No valid poses consistent with other compounds found.

Scheme 1. General synthetic route and structures of examined compounds^a. R¹, R² and R³ substituents are presented in Tables 1 and 3. ^aReagents and conditions: (a) diethyl ether, 48 h, rt. (b) 2% NaOH, reflux, 2h. (c) 3M HCl, rt. (d) BrCH₂COBr, K₂CO₃, acetonitrile, 0 °C. (e) K₂CO₃, KI, methanol, 1–2 h, rt. (f) PhCH₂Br, K₂CO₃, KI, methanol, 1–2 h, rt.

Table 4. Inhibitory activity (in µM) of triazoles 10–12, 28–34 against HIV-1 RT (wild type, Roche kit).

Compound	3	10	11	12	28	29	30	31	32	33	34	nvp*
IC50	46	76 ± 3.5	53 ± 5.1	>100	45.8 ± 22.1	0.7 ± 0.5	0.3 ± 0.1	18.5 ± 7.5	7.1 ± 5.5	3.3 ± 0.6	∼100	0.7 ± 0.3

*Nevirapine.

Figure 2. ¹H-NMR spectra (250 MHz) showing the splitting of the signal of methylene protons resulting from constraining the phenyl group rotation by the 2-methyl substituent.

Table 5. Kinetic constants for the interaction between HIV-1 RT and triazoles 10, 28 and 32.

Compounds	Best model	Kinetic parameters
10	1	k1 = 1.14e4, k−1 = 4.75e-2, KD = 4.15e-6
28	1	k1 = 1.47e3, k−1 = 4.37e-2, KD = 2.97e-5
32	1	k1 = 2.85e3, k−1 = 2.11e-2, KD = 7.39e-6
Nevirapine	1	k1 = 2.03e3, k−1 = 5.61e-3, KD = 2.76e-6