药学学报


6a	CD₃	H	6.38 ± 0.00	> 295.15
7a	CD₃	Cl	35.69 ± 0.03	41.29 ± 5.95
7b	CD₃	Br	20.62 ± 0.01	34.73 ± 7.46
7c	CD₃	I	70.73 ± 0.02	127.47 ± 5.77
8a	CD₃	4-Pyridyl	17.69 ± 0.01	49.79 ± 3.94
8b	CD₃	3-Pyridyl	19.61 ± 0.02	> 249.70
8c	CD₃	5-Pyrimidyl	23.77 ± 0.02	128.01 ± 2.65
8d	CD₃	3-Furyl	37.99 ± 0.01	51.24 ± 7.08
8e	CD₃	2-Furyl	62.36 ± 0.02	198.18 ± 12.46
8f	CD₃	2-Thienyl	67.41 ± 0.01	178.66 ± 9.98
8g	CD₃	3-Pyrazolyl	10.94 ± 0.00	38.64 ± 7.75
8h	CD₃	4-Pyrazolyl	22.26 ± 0.03	121.45 ± 11.26
8i	CD₃	5-Hydroxymethyl-2-thienyl	30.72 ± 0.02	149.40 ± 14.02
6b	CH₃	H	13.18 ± 0.01	> 297.27
7d	CH₃	Cl	13.35 ± 0.00	26.88 ± 8.71
7e	CH₃	Br	27.43 ± 0.03	18.02 ± 4.59
7f	CH₃	I	42.57 ± 0.03	44.47 ± 4.50
8j	CH₃	4-Pyridyl	9.88 ± 0.00	62.61 ± 5.26
8k	CH₃	3-Pyridyl	35.29 ± 0.03	> 251.22
8l	CH₃	5-Pyrimidyl	33.04 ± 0.02	118.09 ± 7.45
8m	CH₃	3-Furyl	39.55 ± 0.03	229.04 ± 7.62
8n	CH₃	2-Furyl	68.91 ± 0.05	> 256.91
8o	CH₃	3-Thienyl	256.35 ± 0.17	200.79 ± 2.60
8p	CH₃	2-Thienyl	66.11 ± 0.01	> 248.70
8q	CH₃	3-Pyrazolyl	12.91 ± 0.01	48.41 ± 22.30
8r	CH₃	4-Pyrazolyl	25.57 ± 0.03	66.67 ± 31.92
8s	CH₃	5-Hydroxymethyl-2-thienyl	8.88 ± 0.00	> 287.68
NVP			237.5 ± 0.18	> 15.021
EFV			4.58 ± 0.002	> 6.336
ETR			4.23 ± 0.002	> 4.595


6a	CD₃	H	6.38 ± 0.00	> 295.15
7a	CD₃	Cl	35.69 ± 0.03	41.29 ± 5.95
7b	CD₃	Br	20.62 ± 0.01	34.73 ± 7.46
7c	CD₃	I	70.73 ± 0.02	127.47 ± 5.77
8a	CD₃	4-Pyridyl	17.69 ± 0.01	49.79 ± 3.94
8b	CD₃	3-Pyridyl	19.61 ± 0.02	> 249.70
8c	CD₃	5-Pyrimidyl	23.77 ± 0.02	128.01 ± 2.65
8d	CD₃	3-Furyl	37.99 ± 0.01	51.24 ± 7.08
8e	CD₃	2-Furyl	62.36 ± 0.02	198.18 ± 12.46
8f	CD₃	2-Thienyl	67.41 ± 0.01	178.66 ± 9.98
8g	CD₃	3-Pyrazolyl	10.94 ± 0.00	38.64 ± 7.75
8h	CD₃	4-Pyrazolyl	22.26 ± 0.03	121.45 ± 11.26
8i	CD₃	5-Hydroxymethyl-2-thienyl	30.72 ± 0.02	149.40 ± 14.02
6b	CH₃	H	13.18 ± 0.01	> 297.27
7d	CH₃	Cl	13.35 ± 0.00	26.88 ± 8.71
7e	CH₃	Br	27.43 ± 0.03	18.02 ± 4.59
7f	CH₃	I	42.57 ± 0.03	44.47 ± 4.50
8j	CH₃	4-Pyridyl	9.88 ± 0.00	62.61 ± 5.26
8k	CH₃	3-Pyridyl	35.29 ± 0.03	> 251.22
8l	CH₃	5-Pyrimidyl	33.04 ± 0.02	118.09 ± 7.45
8m	CH₃	3-Furyl	39.55 ± 0.03	229.04 ± 7.62
8n	CH₃	2-Furyl	68.91 ± 0.05	> 256.91
8o	CH₃	3-Thienyl	256.35 ± 0.17	200.79 ± 2.60
8p	CH₃	2-Thienyl	66.11 ± 0.01	> 248.70
8q	CH₃	3-Pyrazolyl	12.91 ± 0.01	48.41 ± 22.30
8r	CH₃	4-Pyrazolyl	25.57 ± 0.03	66.67 ± 31.92
8s	CH₃	5-Hydroxymethyl-2-thienyl	8.88 ± 0.00	> 287.68
NVP			237.5 ± 0.18	> 15.021
EFV			4.58 ± 0.002	> 6.336
ETR			4.23 ± 0.002	> 4.595

Compd.	EC₅₀/nmol·L^-1
6a	9.27 ± 0.00	5.96 ± 0.00	29.04 ± 0.01	2 065.25 ± 0.81	24.56 ± 0.01
7a	38.60 ± 0.02	30.41 ± 0.02	65.13 ± 0.01	242.66 ± 0.05	59.56 ± 0.02
7b	21.35 ± 0.01	20.00 ± 0.01	39.51 ± 0.01	79.37 ± 0.02	46.18 ± 0.01
7c	30.94 ± 0.01	28.80 ± 0.02	67.94 ± 0.02	197.35 ± 0.16	53.01 ± 0.01
8a	37.36 ± 0.01	11.24 ± 0.00	61.98 ± 0.02	93.44 ± 0.06	42.55 ± 0.01
8b	16.58 ± 0.01	13.08 ± 0.01	44.50 ± 0.02	60.23 ± 0.01	31.36 ± 0.01
8c	31.90 ± 0.02	26.22 ± 0.02	83.09 ± 0.04	125.65 ± 0.07	44.61 ± 0.01
8d	25.18 ± 0.01	25.84 ± 0.00	86.20 ± 0.03	169.79 ± 0.03	41.87 ± 0.01
8e	62.04 ± 0.02	56.94 ± 0.01	290.00 ± 0.05	295.21 ± 0.06	279.38 ± 0.09
8f	51.22 ± 0.01	50.83 ± 0.01	172.90 ± 0.07	303.68 ± 0.08	93.70 ± 0.03
8g	21.29 ± 0.01	18.69 ± 0.01	45.91 ± 0.00	46.62 ± 0.01	32.27 ± 0.01
8h	11.54 ± 0.00	16.85 ± 0.01	40.55 ± 0.02	36.21 ± 0.02	26.76 ± 0.01
8i	20.12 ± 0.01	32.58 ± 0.02	52.46 ± 0.02	59.55 ± 0.01	35.33 ± 0.01
6b	19.56 ± 0.02	8.80 ± 0.00	63.26 ± 0.01	1 014.35 ± 0.52	68.97 ± 0.01
7d	17.04 ± 0.00	19.45 ± 0.02	60.72 ± 0.02	204.26 ± 0.11	51.66 ± 0.04
7e	12.52 ± 0.01	29.19 ± 0.02	55.07 ± 0.01	211.46 ± 0.07	54.42 ± 0.02
7f	31.30 ± 0.01	32.07 ± 0.01	42.92 ± 0.01	101.39 ± 0.05	47.49 ± 0.03
8j	14.97 ± 0.00	13.62 ± 0.00	41.95 ± 0.01	64.66 ± 0.03	20.00 ± 0.00
8k	76.12 ± 0.05	36.28 ± 0.01	161.53 ± 0.06	162.19 ± 0.07	147.26 ± 0.11
8l	61.88 ± 0.01	44.33 ± 0.03	187.29 ± 0.05	254.03 ± 0.04	71.51 ± 0.03
8m	39.36 ± 0.03	31.55 ± 0.01	94.49 ± 0.01	180.92 ± 0.05	49.79 ± 0.01
8n	94.75 ± 0.02	73.32 ± 0.05	187.13 ± 0.05	599.01 ± 0.34	144.23 ± 0.04
8o	273.77 ± 0.06	179.71 ± 0.05	655.38 ± 0.20	1 268.93 ± 0.33	352.61 ± 0.05
8p	33.13 ± 0.01	36.41 ± 0.01	127.04 ± 0.04	248.90 ± 0.07	134.00 ± 0.09
8q	28.05 ± 0.01	25.90 ± 0.01	50.77 ± 0.01	51.23 ± 0.01	56.78 ± 0.00
8r	22.97 ± 0.01	16.44 ± 0.00	42.60 ± 0.01	53.80 ± 0.02	62.43 ± 0.02
8s	7.54 ± 0.00	8.57 ± 0.00	24.28 ± 0.01	62.71 ± 0.02	14.38 ± 0.00
NVP	1 560.33 ± 1.56	3 740.14 ± 2.93	5 007.71 ± 2.09	7 524.92 ± 3.25	172.87 ± 0.12
EFV	28.53 ± 0.01	63.96 ± 0.02	5.83 ± 0.002	289.86 ± 0.12	5.97 ± 0.003
ETR	5.94 ± 0.002	2.95 ± 0.001	12.92 ± 0.01	19.9 ± 0.01	8.68 ± 0.01

Compd.	EC₅₀/nmol·L^-1
6a	9.27 ± 0.00	5.96 ± 0.00	29.04 ± 0.01	2 065.25 ± 0.81	24.56 ± 0.01
7a	38.60 ± 0.02	30.41 ± 0.02	65.13 ± 0.01	242.66 ± 0.05	59.56 ± 0.02
7b	21.35 ± 0.01	20.00 ± 0.01	39.51 ± 0.01	79.37 ± 0.02	46.18 ± 0.01
7c	30.94 ± 0.01	28.80 ± 0.02	67.94 ± 0.02	197.35 ± 0.16	53.01 ± 0.01
8a	37.36 ± 0.01	11.24 ± 0.00	61.98 ± 0.02	93.44 ± 0.06	42.55 ± 0.01
8b	16.58 ± 0.01	13.08 ± 0.01	44.50 ± 0.02	60.23 ± 0.01	31.36 ± 0.01
8c	31.90 ± 0.02	26.22 ± 0.02	83.09 ± 0.04	125.65 ± 0.07	44.61 ± 0.01
8d	25.18 ± 0.01	25.84 ± 0.00	86.20 ± 0.03	169.79 ± 0.03	41.87 ± 0.01
8e	62.04 ± 0.02	56.94 ± 0.01	290.00 ± 0.05	295.21 ± 0.06	279.38 ± 0.09
8f	51.22 ± 0.01	50.83 ± 0.01	172.90 ± 0.07	303.68 ± 0.08	93.70 ± 0.03
8g	21.29 ± 0.01	18.69 ± 0.01	45.91 ± 0.00	46.62 ± 0.01	32.27 ± 0.01
8h	11.54 ± 0.00	16.85 ± 0.01	40.55 ± 0.02	36.21 ± 0.02	26.76 ± 0.01
8i	20.12 ± 0.01	32.58 ± 0.02	52.46 ± 0.02	59.55 ± 0.01	35.33 ± 0.01
6b	19.56 ± 0.02	8.80 ± 0.00	63.26 ± 0.01	1 014.35 ± 0.52	68.97 ± 0.01
7d	17.04 ± 0.00	19.45 ± 0.02	60.72 ± 0.02	204.26 ± 0.11	51.66 ± 0.04
7e	12.52 ± 0.01	29.19 ± 0.02	55.07 ± 0.01	211.46 ± 0.07	54.42 ± 0.02
7f	31.30 ± 0.01	32.07 ± 0.01	42.92 ± 0.01	101.39 ± 0.05	47.49 ± 0.03
8j	14.97 ± 0.00	13.62 ± 0.00	41.95 ± 0.01	64.66 ± 0.03	20.00 ± 0.00
8k	76.12 ± 0.05	36.28 ± 0.01	161.53 ± 0.06	162.19 ± 0.07	147.26 ± 0.11
8l	61.88 ± 0.01	44.33 ± 0.03	187.29 ± 0.05	254.03 ± 0.04	71.51 ± 0.03
8m	39.36 ± 0.03	31.55 ± 0.01	94.49 ± 0.01	180.92 ± 0.05	49.79 ± 0.01
8n	94.75 ± 0.02	73.32 ± 0.05	187.13 ± 0.05	599.01 ± 0.34	144.23 ± 0.04
8o	273.77 ± 0.06	179.71 ± 0.05	655.38 ± 0.20	1 268.93 ± 0.33	352.61 ± 0.05
8p	33.13 ± 0.01	36.41 ± 0.01	127.04 ± 0.04	248.90 ± 0.07	134.00 ± 0.09
8q	28.05 ± 0.01	25.90 ± 0.01	50.77 ± 0.01	51.23 ± 0.01	56.78 ± 0.00
8r	22.97 ± 0.01	16.44 ± 0.00	42.60 ± 0.01	53.80 ± 0.02	62.43 ± 0.02
8s	7.54 ± 0.00	8.57 ± 0.00	24.28 ± 0.01	62.71 ± 0.02	14.38 ± 0.00
NVP	1 560.33 ± 1.56	3 740.14 ± 2.93	5 007.71 ± 2.09	7 524.92 ± 3.25	172.87 ± 0.12
EFV	28.53 ± 0.01	63.96 ± 0.02	5.83 ± 0.002	289.86 ± 0.12	5.97 ± 0.003
ETR	5.94 ± 0.002	2.95 ± 0.001	12.92 ± 0.01	19.9 ± 0.01	8.68 ± 0.01

Compd.	IC₅₀/μmol·L^-1		Compd.	IC₅₀/μmol·L^-1		Compd.	IC₅₀/μmol·L^-1
6a	0.057 ± 0.007		8g	0.091 ± 0.013		8m	0.061 ± 0.001
7a	0.062 ± 0.005	8h	0.045 ± 0.006	8n	0.086 ± 0.012
7b	0.066 ± 0.008	8i	0.093 ± 0.016	8o	0.144 ± 0.013
7c	0.049 ± 0.005	6b	0.043 ± 0.003	8p	0.081 ± 0.007
8a	0.109 ± 0.007	7d	0.059 ± 0.006	8q	0.082 ± 0.000
8b	0.100 ± 0.008	7e	0.057 ± 0.007	8r	0.074 ± 0.012
8c	0.110 ± 0.008	7f	0.096 ± 0.001	8s	0.052 ± 0.002
8d	0.092 ± 0.020	8j	0.106 ± 0.004	NVP	0.602 ± 0.066
8e	0.086 ± 0.029	8k	0.085 ± 0.018	EFV	0.014 ± 0.003
8f	0.080 ± 0.013	8l	0.078 ± 0.011	ETR	0.029 ± 0.005

Compd.	IC₅₀/μmol·L^-1		Compd.	IC₅₀/μmol·L^-1		Compd.	IC₅₀/μmol·L^-1
6a	0.057 ± 0.007		8g	0.091 ± 0.013		8m	0.061 ± 0.001
7a	0.062 ± 0.005	8h	0.045 ± 0.006	8n	0.086 ± 0.012
7b	0.066 ± 0.008	8i	0.093 ± 0.016	8o	0.144 ± 0.013
7c	0.049 ± 0.005	6b	0.043 ± 0.003	8p	0.081 ± 0.007
8a	0.109 ± 0.007	7d	0.059 ± 0.006	8q	0.082 ± 0.000
8b	0.100 ± 0.008	7e	0.057 ± 0.007	8r	0.074 ± 0.012
8c	0.110 ± 0.008	7f	0.096 ± 0.001	8s	0.052 ± 0.002
8d	0.092 ± 0.020	8j	0.106 ± 0.004	NVP	0.602 ± 0.066
8e	0.086 ± 0.029	8k	0.085 ± 0.018	EFV	0.014 ± 0.003
8f	0.080 ± 0.013	8l	0.078 ± 0.011	ETR	0.029 ± 0.005

氘代-联苯-DAPYs衍生物作为高效低毒非核苷类逆转录酶抑制剂的设计、合成及抗HIV-1病毒活性研究

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张坤 ¹^,² , 卜悦悦 ¹^,² , Christophe Pannecouque ³ , Erik De Clercq ³ , Enzo Tramontano ⁴ , Phuong-Thao Tran ⁵ , 王帅 ¹^,²^,^* , 陈芬儿 ¹^,²^,^*

药学学报 | 研究论文 2025,60(8): 2545-2554

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药学学报 |研究论文 2025 , 60 (8) : 2545 -2554

氘代-联苯-DAPYs衍生物作为高效低毒非核苷类逆转录酶抑制剂的设计、合成及抗HIV-1病毒活性研究

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张坤¹^,², 卜悦悦¹^,², Christophe Pannecouque³, Erik De Clercq³, Enzo Tramontano⁴, Phuong-Thao Tran⁵, 王帅¹^,²^,^*, 陈芬儿¹^,²^,^*

作者信息

¹复旦大学化学系手性分子催化与合成工程中心, 上海 200433

²郑州大学药物研究院, 河南郑州 450001

³Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium

⁴Dept Appl Sci Biosyst, University of Cagliari, Monserrato Ⅰ-09042, Italy

⁵Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 008404, Vietnam

通讯作者:

王帅, Tel: 86-21-65643811, E-mail: shuaiwang@fudan.edu.cn

陈芬儿, E-mail: rfchen@fudan.edu.cn

作者简介:

作者贡献:

张坤负责化合物的合成、表征、波谱数据解析; 卜悦悦负责化合物的合成及数据整理; Christophe Pannecouque、Erik De Clercq和Enzo Tramontano负责化合物的生物活性检测; Phuong-Thao Tran参与分子设计; 王帅负责课题规划及文章的撰写; 陈芬儿负责课题规划及论文的修改、校对。

Deuterated-biphenyl-DAPY derivatives as potent and low-cytotoxicity non-nucleoside reverse transcriptase inhibitors: design, synthesis and anti-HIV-1 evaluation

Kun ZHANG¹^,², Yue-yue BU¹^,², Christophe Pannecouque³, Erik De Clercq³, Enzo Tramontano⁴, Phuong-Thao Tran⁵, Shuai WANG¹^,²^,^*, Fen-er CHEN¹^,²^,^*

Affiliations

¹Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China

²Institute of Pharmaceutical Research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China

³Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium

⁴Dept Appl Sci Biosyst, University of Cagliari, Monserrato Ⅰ-09042, Italy

⁵Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 008404, Vietnam

出版时间: 2025-08-12 doi: 10.16438/j.0513-4870.2025-0653

文章导航

摘要

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非核苷类逆转录酶抑制剂(non-nucleoside reverse transcriptase inhibitors, NNRTIs) 在艾滋病的治疗中发挥重要作用。二芳基嘧啶类(diarylpyrimidines, DAPYs) 抑制剂是目前NNRTIs研究的热点。本研究以前期发现的氘代-联苯-DAPYs抑制剂ZK-4a为先导化合物, 针对其细胞毒性大的问题(CC₅₀ = 5.98 μmol·L^-1), 通过引入O原子取代NH基团, 并对嘧啶环C-5位进行修饰, 先后设计、合成了27个新型氘代-联苯-DAPYs。随后, 抗病毒活性研究发现, 新设计的氘代-联苯-DAPYs对HIV-1野生株和突变株具有广泛、高效的抑制活性, 同时显著降低了化合物对正常细胞的毒性(CC₅₀ = 18.02~ > 297.27 μmol·L^-1)。其中, 化合物8s对HIV-1野生株的EC₅₀值为8.88 nmol·L^-1, 对正常细胞的毒性较弱(CC₅₀ > 287.68 μmol·L^-1); 同时8s对L100I、K103N、Y181C、Y188L和E138K突变株表现出高效、广谱的抑制活性, EC₅₀值依次为7.54、8.57、24.28、62.71和14.38 nmol·L^-1。此外, RT酶抑制试验验证了氘代-联苯-DAPYs化合物可以有效抑制逆转录酶的DNA聚合酶活性。

关键词

艾滋病 / HIV-1 / 抗病毒 / 非核苷类逆转录酶抑制剂 / 氘代-联苯-DAPYs

Abstract

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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in AIDS treatment. Diarylpyrimidine derivatives (DAPYs) represent one of the most important classes of NNRTIs. The previously reported ZK-4a showed high cytotoxicity (CC₅₀ = 5.98 μmol·L^-1), significantly limiting its therapeutic potential. To resolve this issue, we adopted a two-pronged strategy: replacing the NH fragment with an O atom and modifying the C-5 position of the pyrimidine core. These modifications enabled the design and synthesis of 27 novel deuterated-biphenyl-DAPY analogues. Fortunately, all deuterated-biphenyl-DAPYs exhibited broad and highly efficient antiviral activity, as well as obviously decreased cytotoxicity (CC₅₀ = 18.02- > 297.27 μmol·L^-1). Among them, compound 8s achieved an EC₅₀ value of 8.88 nmol·L^-1 while showing negligible cytotoxicity (CC₅₀ > 287.68 μmol·L^-1). Compound 8s also displayed exceptional resistance profiles with EC₅₀ values of 7.54 nmol·L^-1 (L100I), 8.57 nmol·L^-1 (K103N), 24.28 nmol·L^-1 (Y181C), 62.71 nmol·L^-1 (Y188L) and 14.38 nmol·L^-1 (E138K). Additionally, the target of deuterated-biphenyl-DAPYs was verified by reverse transcriptase enzyme inhibition assays.

Key words

acquired immunodeficiency syndrome / human immunodeficiency virus-1 / antiviral / non-nucleoside reverse transcriptase inhibitor / deuterated-biphenyl-DAPY

引用本文

张坤, 卜悦悦, Christophe Pannecouque, Erik De Clercq, Enzo Tramontano, Phuong-Thao Tran, 王帅, 陈芬儿. 氘代-联苯-DAPYs衍生物作为高效低毒非核苷类逆转录酶抑制剂的设计、合成及抗HIV-1病毒活性研究. 药学学报, 2025 , 60 (8) : 2545 -2554 . DOI: 10.16438/j.0513-4870.2025-0653

Kun ZHANG, Yue-yue BU, Christophe Pannecouque, Erik De Clercq, Enzo Tramontano, Phuong-Thao Tran, Shuai WANG, Fen-er CHEN. Deuterated-biphenyl-DAPY derivatives as potent and low-cytotoxicity non-nucleoside reverse transcriptase inhibitors: design, synthesis and anti-HIV-1 evaluation[J]. Acta Pharmaceutica Sinica, 2025 , 60 (8) : 2545 -2554 . DOI: 10.16438/j.0513-4870.2025-0653

正文

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当前, 艾滋病(acquired immunodeficiency syndrome, AIDs) 仍是全球主要的流行性疾病之一^{[1, 2]}。研究表明, HIV (human immunodeficiency virus) 病毒感染是艾滋病病因^[3-5]。据报道, 2023年, 全球仍有约3 990万人感染HIV病毒, 约130万人为新增患者, 约63万人死于AIDs相关的疾病。然而, 现有医疗手段并不能彻底治愈AIDS, 患者一旦感染HIV病毒, 需终身服用抗病毒类药物^{[5, 6]}。但由于HIV病毒的高变异性, 长期单一药物的使用, 使得临床上不断出现新的耐药突变株, 导致现有药物的疗效下降^{[7, 8]}。因此, 研发新型抗病毒药物, 克服现有临床药物的缺陷, 是药物化学工作者迫在眉睫的任务。

非核苷类逆转录酶抑制剂(non-nucleoside reverse transcriptase inhibitors, NNRTIs) 是一种靶向HIV病毒逆转录酶(reverse transcriptase, RT) 变构结合位点的抑制剂^{[2, 9]}。自1996年第一款该类抑制剂奈韦拉平(nevirapine, NVP) 被批准上市以来, 全球已有多个该类药物先后被批准用于治疗AIDS, 包括最新一代的药物依曲韦林(etravirine, ETR) 和利匹韦林(rilpivirine, RPV)^{[10, 11]}。尽管ETR和RPV较第一代药物具有明显优势, 但也存在部分缺陷, 如: 细胞毒性高(CC₅₀ = ~4.61 μmol·L^-1)、CYP酶抑制以及其他毒副作用等^[12-14]。针对以上问题, 本课题组先后开发了多个联苯-二芳基嘧啶类(diarylpyrimidines, DAPYs) 化合物。其中, 化合物ZK-4a (1) 对HIV-1野生株(wild type, WT) 和突变株表现出高效的抑制活性, 但其细胞毒性较大(CC₅₀ = 5.98 μmol·L^-1), 限制了临床开发潜力^[9]。

调研文献发现, 将RPV左翼连接子的NH基团替换为O原子时, 化合物2的细胞毒性显著改善(图1A)^[15]。同时, 通过对ZK-4a的分子对接发现其嘧啶母核的C-5位指向入口通道区域, 存在较大的修饰空间(图1B)。因此, 本研究以ZK-4a为先导化合物, 将左侧连接子的NH基团替换为O原子, 同时对其入口通道区域进行修饰, 以期保持化合物抗病毒活性并改善其细胞毒性(图1C)。最终, 设计、合成了27个新型氘代-联苯-DAPYs抑制剂, 并进一步检测了其抗病毒活性和细胞毒性。

结果与讨论

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1　目标化合物的合成及结构表征

1.1　化合物的合成

目标化合物的合成路线如合成路线1所示。其中氘代片段3a、3b作为起始原料, 首先通过Suzuki偶联反应合成联苯片段4a、4b。随后, 4a、4b与化合物5进行芳香亲核取代得到化合物6a、6b。接着, 化合物6a、6b通过亲电反应在C-5位引入不同的卤素原子生成化合物7a~7f。最后, 化合物7c和7f通过与相应的硼酸反应得到化合物8a~8s。

1.2　化合物的表征

所有合成的氘代-联苯-DAPYs化合物经¹H NMR、¹³C NMR和HRMS确认(结果见实验方法部分)。

2　目标化合物对HIV-1野生株的抗病毒活性和细胞毒性

为评估目标化合物的抗病毒活性和细胞毒性, 采用MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) 法检测了化合物保护MT-4细胞免受HIV-1野生型病毒破坏的半数有效浓度(EC₅₀) 和化合物导致正常细胞死亡的半数致死浓度(CC₅₀)。上市药物NVP、依非韦仑(efavirenz, EFV) 和ETR被选做阳性对照, 所有实验均独立重复3次以上以计算有效的SD值。实验结果如表1所示。

所有化合物均表现出对HIV-1野生型毒株的有效抑制, 其EC₅₀值为6.38~256.35 nmol·L^-1。值得注意的是, 新设计的化合物对正常细胞的毒性与先导化合物相比显著下降, CC₅₀值为≥ 18.02 μmol·L^-1, 符合实验预期。其中, 化合物6a具有本系列最优的抗病毒活性, 其EC₅₀值达到了6.38 nmol·L^-1, 同时细胞毒性大于295.15 μmol·L^-1。与先导化合物ZK-4a相比, 化合物6a虽然在抗病毒活性方面略有下降(EC₅₀ = 1.83 vs. 6.38 nmol·L^-1), 但在细胞毒性方面显著改善, 较先导化合物改善了约49倍(CC₅₀ = 5.98 vs. > 295.15 μmol·L^-1)。此外, 单CD₃取代的化合物8s也表现出个位数纳摩尔浓度的抗病毒活性和极低的细胞毒性(EC₅₀ = 8.88 nmol·L^-1, CC₅₀ > 287.68 μmol·L^-1)。

初步的构效关系总结如下: 当R₁处取代基为CD₃时, R₂处无取代基表现出最佳的抗病毒抑制活性和最低的细胞毒性(6a); 当R₂处引入卤素(7a~7c) 或芳环(8a~8i) 时, 其抗病毒活性显著下降, 同时细胞毒性明显上升; 当芳环上的杂原子为N原子时, 化合物的抗病毒活性较其他杂原子时明显提升(8a~8c、8g、8h vs. 8d~8f、8i)。当R₁处取代基为甲基时, R₂处取代基为4-吡啶基(8j, EC₅₀ = 9.88 nmol·L-1) 和5-羟甲基-2-噻吩基(8s, EC₅₀ = 8.88 nmol·L-1) 时更有利于提升化合物的抗病毒活性。值得注意的是, 当在R₂处2-噻吩基上进行修饰时, 无论R₁处取代基为CD₃还是CH₃均能够有效的提升抗病毒活性(8f vs. 8i, 8p vs. 8s)。

3　目标化合物对HIV-1突变株的抗病毒活性

鉴于目标化合物对HIV-1野生株较好的抑制活性以及显著改善的细胞毒性, 进一步测试了目标化合物对5种常见临床单突变株(L100I、K103N、Y181C、Y188L和E138K) 的抑制活性, 以NVP、EFV和ETR为阳性对照。

氘代-联苯-DAPYs抑制剂对所选5种单突变株表现出个位数纳摩尔到微摩尔浓度之间的抑制活性。化合物6a对HIV-1野生株表现出最佳的抑制活性, 对L100I和K103N突变株也表现出个位数纳摩尔浓度的抑制活性(EC₅₀ = 9.27和5.96 nmol·L^-1), 对Y181C和E138K突变株表现出两位数纳摩尔浓度的抑制活性(EC₅₀ = 29.04和24.56 nmol·L^-1)。但化合物6a对Y188L突变株的抑制活性显著下降, EC₅₀值为2 065.25 nmol·L^-1, 在本系列化合物中对Y188L突变株抑制活性最差。值得注意的是, 本系列化合物通常对L100I和K103N突变株具有与WT株相似的EC₅₀值, 尤其是在K103N突变株中。但对Y188L突变株, 本系列化合物的抑制活性通常显著下降。不过, 当R₂处引入卤素或芳环取代时, 化合物对Y188L突变的抵抗更强, 如7b、8g~8j和8q~8s。这可能是由于R₂处引入取代基后, 化合物会通过与入口通道处氨基酸的相互作用, 抵消Y188L突变造成的影响。此外, 当R₁处取代基为CH₃, R₂取代基为5-羟甲基-2-噻吩基时, 化合物8s对突变株的抑制活性值得关注。其对5种突变株的的EC₅₀值依次为7.54、8.57、24.28、62.71、14.38 nmol·L^-1, 显著优于本系列其他化合物。

4　化合物对野生型逆转录酶的抑制活性

为了验证氘代-联苯-DAPYs抑制剂的作用靶点, 本研究检测了目标化合物对HIV-1野生型RT酶的抑制活性。上市药物NVP、EFV和ETR被选作阳性对照, 实验结果如表3所示。结果表明, 氘代-联苯-DAPYs可以有效的抑制RT酶的DNA聚合酶活性, 其IC₅₀值介于0.043~0.144 μmol·L^-1。其中, 化合物6b表现出最佳的RT酶抑制活性, IC₅₀值达到0.043 μmol·L^-1, 超过阳性对照NVP, 与上市药物EFV和ETR相当。

5　结论

本研究以课题组前期报道的化合物ZK-4a作为先导化合物, 通过引入O原子取代NH基团并对入口通道区域修饰, 先后设计并合成了27个氘代-联苯-DAPYs。随后, 对目标化合物的抗病毒活性实验中发现, 所设计的化合物在保持对HIV-1野生株抑制活性的同时, 对正常细胞的毒性显著降低, CC₅₀值改善3至49倍。其中, 化合物6a具有本系列最佳的抑制HIV-1野生株的活性和最低的细胞毒性(EC₅₀ = 6.38 nmol·L^-1, CC₅₀ > 295.15 μmol·L^-1)。随后的抗耐药性实验发现, 氘代-联苯-DAPYs对突变株具有广泛有效的抑制活性。其中, 对L100I和E138K突变株的抑制活性通常下降较少, 对Y188L突变株的抑制活性则显著降低。化合物8s表现出本系列最佳的抗耐药性, 对L100I、K103N、Y181C、Y188L和E138K突变株的EC₅₀值依次为7.54、8.57、24.28、62.71和14.38 nmol·L^-1。最后, 本研究通过RT酶抑制试验验证了氘代-联苯-DAPYs的作用靶点, 所测试化合物对RT酶普遍表现出纳摩尔到亚微摩尔水平的IC₅₀值。总之, 本研究发现氘代-联苯-DAPYs作为一种新型HIV-1非核苷类逆转录酶抑制剂, 可以高效、广泛的抑制HIV-1野生株和突变株, 同时展现出更低的细胞毒性, 具有进一步开发的潜力。

实验部分

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本实验所用原料均购自毕得医药、乐研试剂、麦克林试剂、阿拉丁试剂、安耐吉化学等商业化公司平台, 纯度为化学纯和分析纯, 无须纯化可直接使用。实验中所用部分仪器如下: 磁力搅拌器(RCT basic, 德国IKA公司), 旋转蒸发仪(IKA RV8, 德国IKA公司), 核磁共振仪(Bruker AV-400型, 美国布鲁克公司), 高分辨质谱仪(290Ⅱ-6545 Q-TOF, 美国安捷伦公司), 循环水式真空泵(A-1000S, 日本EYELA公司) 等。

1　化学合成

1.1　中间体4a~4b的合成

将化合物3a、3b^[9] (1.0 mmol, 1.0 equiv.)、对氰基苯硼酸(1.05 mmol, 1.05 equiv.)、碳酸铯(1.5 mmol, 1.5 equiv.) 和Pd(dppf)Cl₂ (0.05 mmol, 0.05 equiv.) 加入到25 mL的茄形瓶中。随后, 将6 mL的二氧六环∶水= 2∶1的混合溶液加入到反应瓶中, 并快速进行氮气置换。置换完毕, 将反应体系转至100 ℃加热反应12 h。TLC板监测反应进程。反应完毕后, 停止加热, 待体系冷却至室温后, 将反应液倒入50 mL水中, 用乙酸乙酯(50 mL × 3) 萃取3次。萃取完毕, 合并有机相, 饱和食盐水洗涤, 无水硫酸钠干燥, 过滤。将滤液浓缩后, 粗产品通过柱层析分离, 即得中间体4a、4b。

1.1.1　4′-羟基-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(4a)

白色固体, 产率: 31.6%。m.p.: 157.1~159.7 ℃。HRMS (ESI) m/z: Calcd. for C₁₅H₇D₆NO [M-H]^- 228.130 1, found 228.130 9。

1.1.2　4′-羟基-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(4b)

白色固体, 产率: 37.0%。m.p.: 155.7~156.5 ℃。HRMS (ESI) m/z: Calcd. for C₁₅H₁₀D₃NO [M-H]^- 225.111 3, found 225.112 1。

1.2　化合物6a、6b的合成

将中间体4a、4b (1.0 mmol, 1.0 equiv.)、中间体5^[9] (1.2 mmol, 1.2 equiv.) 和碳酸钾(1.5 mmol, 1.5 equiv.) 依次加入到25 mL的茄形瓶中, 随后加入5 mL N, N-二甲基甲酰胺(DMF)。将反应体系转至80 ℃下加热12 h, TLC板监测反应进程。反应完毕后, 停止加热, 待体系冷却至室温后, 将反应液倒入50 mL水中, 用乙酸乙酯(50 mL × 3) 萃取3次。萃取完毕, 合并有机相, 饱和食盐水洗涤, 无水硫酸钠干燥, 过滤。将滤液浓缩后, 粗产品通过柱层析分离, 即得化合物6a、6b。

1.2.1　4′-((2-((4-氰基苯基)氨基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(6a)

白色固体, 产率: 50.2%。m.p.: 265.6~268.3 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.16 (s, 1H), 8.49 (d, J = 5.7 Hz, 1H), 7.96 (s, 4H), 7.64 (d, J = 4.5 Hz, 4H), 7.44 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 5.6 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 168.91, 160.80, 159.68, 150.66, 145.04, 144.51, 136.14, 133.33, 133.02, 131.63, 128.00, 127.90, 119.80, 119.35, 118.74, 110.43, 102.90, 99.43, 15.89 (t, J = 19.6 Hz); HRMS (ESI) m/z: Calcd. for C₂₆H₁₃D₆N₅O [M+H]⁺ 424.203 9, found 424.203 4。

1.2.2　4′-((2-((4-氰基苯基)氨基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(6b)

白色固体, 产率: 57.5%。m.p.: 269.0~270.7 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.15 (s, 1H), 8.48 (d, J = 5.7 Hz, 1H), 7.95 (s, 4H), 7.64 (d, J = 3.0 Hz, 2H), 7.62 (s, 2H), 7.42 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 5.6 Hz, 1H), 2.16 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 168.91, 160.81, 159.68, 150.62, 145.04, 144.51, 136.14, 133.33, 133.02, 131.74, 131.65, 128.00, 127.98, 127.90, 119.80, 119.35, 118.75, 110.44, 102.91, 99.44, 16.66; HRMS (ESI) m/z: Calcd. for C₂₆H₁₆D₃N₅O [M+H]⁺ 421.185 1, found 421.184 0。

1.3　化合物7a~7f的合成

将化合物6a、6b (1.0 mmol, 1.0 equiv.) 和NXS (1.05 mmol, 1.05 equiv.) 加入到25 mL的茄形瓶中, 随后加入6 mL的乙腈溶解。室温搅拌状态下, 加入催化量的三氟乙酸。加入完毕, 室温搅拌4 h, TLC板监测反应进程。反应完毕后, 加入适量饱和氯化铵溶液淬灭反应。随后, 将反应液倒入50 mL水中, 用乙酸乙酯(50 mL × 3) 萃取3次。萃取完毕, 合并有机相, 饱和食盐水洗涤, 无水硫酸钠干燥, 过滤。将滤液浓缩后, 粗产品通过柱层析分离, 即得化合物7a~7f。

1.3.1　4′-((5-氯-2-((4-氰基苯基)氨基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(7a)

白色固体, 产率: 82.1%。m.p.: 274.1~276.3 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.29 (s, 1H), 8.62 (s, 1H), 7.96 (s, 4H), 7.67 (s, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 163.37, 158.74, 157.62, 150.59, 144.58, 144.39, 136.47, 133.35, 132.98, 131.46, 128.05, 127.93, 119.66, 119.32, 118.76, 110.53, 106.43, 103.30, 15.74; HRMS (ESI) m/z: Calcd. for C₂₆H₁₂D₆N₅OCl [M+Na]⁺ 480.146 9, found 480.148 3。

1.3.2　4′-((5-溴-2-((4-氰基苯基)氨基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(7b)

白色固体, 产率: 84.7%。m.p.: 291.8~293.2 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.28 (s, 1H), 8.67 (s, 1H), 7.96 (s, 4H), 7.66 (s, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 164.24, 161.22, 158.22, 150.77, 144.55, 144.40, 136.43, 133.35, 132.97, 131.43, 128.02, 127.92, 119.66, 119.33, 118.82, 110.51, 103.30, 94.24, 16.00~15.18 (m); HRMS (ESI) m/z: Calcd. for C₂₆H₁₂D₆N₅OBr [M+H]⁺ 502.114 4, found 502.113 8。

1.3.3　4′-((2-((4-氰基苯基)氨基)-5-碘嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(7c)

白色固体, 产率: 96.3%。m.p.: 284.2~286.1 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.24 (s, 1H), 8.74 (s, 1H), 7.96 (s, 4H), 7.66 (s, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 166.66, 166.43, 151.17, 144.60, 144.43, 136.30, 134.87, 133.35, 132.95, 131.40, 127.97, 127.91, 123.89, 119.68, 119.34, 118.86, 110.48, 103.18, 16.11~15.48 (m); HRMS (ESI) m/z: Calcd. for C₂₆H₁₂D₆N₅OI [M+H]⁺ 550.100 6, found 550.101 9。

1.3.4　4′-((5-氯-2-((4-氰基苯基)氨基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(7d)

白色固体, 产率: 94.4%。m.p.: 279.6~281.4 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.28 (s, 1H), 8.62 (s, 1H), 7.96 (s, 4H), 7.67 (s, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 163.36, 158.75, 157.63, 150.55, 144.58, 144.39, 136.48, 133.35, 132.98, 131.56, 131.47, 128.05, 127.93, 119.66, 119.32, 118.77, 110.53, 106.43, 103.31, 16.51; HRMS (ESI) m/z: Calcd. for C₂₆H₁₅D₃N₅OCl [M+H]⁺ 455.146 1, found 455.144 6。

1.3.5　4′-((5-溴-2-((4-氰基苯基)氨基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(7e)

白色固体, 产率: 65.9%。m.p.: 301.0~303.4 ℃。¹H NMR (400 MHz, DMSO-d₆, ) δ_H: 10.28 (s, 1H), 8.68 (s, 1H), 7.96 (s, 4H), 7.66 (s, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 2.16 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 164.23, 161.22, 158.23, 150.73, 144.56, 144.39, 136.43, 133.35, 132.97, 131.53, 131.44, 128.02, 127.92, 119.65, 119.32, 118.82, 110.52, 103.30, 94.24, 16.52; HRMS (ESI) m/z: Calcd. for C₂₆H₁₅D₃N₅OBr [M+Na]⁺ 521.077 5, found 521.075 3。

1.3.6　4′-((2-((4-氰基苯基)氨基)-5-碘嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(7f)

白色固体, 产率: 93.4%。m.p.: 304.0~305.0 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.23 (s, 1H), 8.75 (s, 1H), 7.97 (s, 4H), 7.68 (s, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 2.15 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 166.66, 166.45, 158.98, 151.14, 144.60, 144.44, 136.31, 133.37, 132.96, 131.51, 131.42, 127.98, 127.93, 119.68, 119.35, 118.87, 110.49, 103.18, 16.56; HRMS (ESI) m/z: Calcd. for C₂₆H₁₅D₃N₅OI [M+H]⁺: 547.081 7, found 547.080 3。

1.4　化合物8a~8s的合成

化合物8a~8s的合成方法类似于中间体4a~4b的合成, 将其中的Pd(dppf)Cl₂催化剂换成Pd(PPh₃)₄。

1.4.1　4′-((2-((4-氰基苯基)氨基)-5-(吡啶-4-基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8a)

白色固体, 产率: 59.2%。m.p.: 254.5~256.7 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.41 (s, 1H), 8.82 (s, 1H), 8.73~8.63 (m, 2H), 7.98 (s, 4H), 7.87~7.81 (m, 2H), 7.69 (s, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 165.56, 160.29, 159.09, 150.90, 150.46, 144.61, 144.46, 141.01, 136.24, 133.39, 132.95, 131.58, 128.02, 127.91, 123.24, 119.64, 119.36, 118.91, 110.48, 110.05, 103.31; HRMS (ESI) m/z: Calcd. for C₃₁H₁₆D₆N₆O [M+H]⁺ 501.230 5, found 501.230 6。

1.4.2　4′-((2-((4-氰基苯基)氨基)-5-(吡啶-3-基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8b)

白色固体, 产率: 73.2%。m.p.: 250.4~252.8 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.33 (s, 1H), 8.98 (s, 1H), 8.72 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.96 (s, 4H), 7.67 (s, 2H), 7.55 (dt, J = 9.7, 5.1 Hz, 3H), 7.34 (d, J = 8.4 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 165.54, 159.94, 158.82, 150.90, 149.41, 149.01, 144.78, 144.47, 136.48, 136.18, 133.37, 132.95, 131.59, 129.46, 127.99, 127.89, 124.16, 119.69, 119.35, 118.78, 110.46, 109.94, 103.10; HRMS (ESI) m/z: Calcd. for C₃₁H₁₆D₆N₆O [M+H]⁺ 501.230 5, found 501.229 4。

1.4.3　4′-((2-((4-氰基苯基)氨基)-[5, 5′-二吡啶]-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8c)

白色固体, 产率: 58.9%。m.p.: 298.2~299.6 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.41 (s, 1H), 9.23 (s, 3H), 8.82 (s, 1H), 7.97 (s, 4H), 7.67 (s, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 165.57, 160.11, 159.26, 157.63, 156.44, 150.73, 144.61, 144.45, 136.30, 133.37, 132.98, 131.63, 128.01, 127.91, 127.86, 119.65, 119.34, 118.94, 110.48, 106.75, 103.34; HRMS (ESI) m/z: Calcd. for C₃₀H₁₅D₆N₇O [M+H]⁺ 502.225 7, found 502.223 6。

1.4.4　4′-((2-((4-氰基苯基)氨基)-5-(呋喃-3-基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8d)

灰色固体, 产率: 22.0%。m.p.: 216.4~217.0 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.23 (s, 1H), 8.91 (s, 1H), 8.30~8.27 (m, 1H), 8.02~7.94 (m, 4H), 7.86 (t, J = 1.8 Hz, 1H), 7.69 (s, 2H), 7.54 (dd, J = 9.0, 3.3 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 1.9 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 164.64, 157.69, 157.58, 151.17, 144.96, 144.55, 144.29, 141.22, 136.16, 133.36, 132.91, 131.66, 127.92, 127.89, 119.77, 119.36, 118.50, 117.82, 110.44, 108.92, 105.15, 102.72; HRMS (ESI) m/z: Calcd. for C₃₀H₁₅D₆N₅O₂ [M+H]⁺ 490.214 5, found 490.215 0。

1.4.5　4′-((2-((4-氰基苯基)氨基)-5-(呋喃-2-基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8e)

白色固体, 产率: 45.8%。m.p.: 255.8~256.9 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.33 (s, 1H), 8.88 (s, 1H), 7.99 (d, J = 1.9 Hz, 4H), 7.86 (d, J = 1.8 Hz, 1H), 7.70 (s, 2H), 7.54 (dd, J = 8.6, 5.9 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 3.4 Hz, 1H), 6.69 (dd, J = 3.4, 1.9 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 163.36, 157.54, 155.55, 150.99, 146.42, 144.72, 144.51, 143.16, 136.26, 134.82, 133.37, 132.96, 131.61, 127.98, 127.91, 124.17, 118.69, 112.65, 110.47, 109.76, 104.59, 103.02; HRMS (ESI) m/z: Calcd. for C₃₀H₁₅D₆N₅O₂ [M+H]⁺ 490.214 5, found 490.214 8。

1.4.6　4′-((2-((4-氰基苯基)氨基)-5-(噻吩-2-基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8f)

白色固体, 产率: 47.5%。m.p.: 278.0~280.7 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.33 (s, 1H), 8.98 (s, 1H), 7.99 (d, J = 1.7 Hz, 4H), 7.78 (dd, J = 3.7, 1.2 Hz, 1H), 7.70 (s, 2H), 7.66 (dd, J = 5.1, 1.1 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.23 (dd, J = 5.1, 3.7 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 163.60, 157.79, 157.68, 150.90, 144.77, 144.50, 136.28, 134.36, 133.37, 132.95, 131.60, 128.06, 128.02, 127.92, 126.83, 125.22, 119.73, 119.35, 118.66, 110.48, 107.47, 102.98; HRMS (ESI) m/z: Calcd. for C₃₀H₁₅D₆N₅OS [M+H]⁺ 506.191 6, found 506.190 8。

1.4.7　4′-((2-((4-氰基苯基)氨基)-5-(1H-吡唑-3-基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8g)

白色固体, 产率: 42.0%。m.p.: 275.6~277.4 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 13.13 (s, 1H), 10.27 (s, 1H), 9.03 (s, 1H), 8.02~7.94 (m, 4H), 7.87 (d, J = 9.1 Hz, 1H), 7.69 (s, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 2.2 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 158.02, 157.75, 151.23, 144.90, 144.56, 136.09, 133.36, 132.92, 131.69, 130.02, 127.93, 127.89, 119.75, 119.36, 118.57, 110.44, 105.23, 102.82; HRMS (ESI) m/z: Calcd. for C₂₉H₁₅D₆N₇O [M+H]⁺ 490.225 7, found 490.223 9。

1.4.8　4′-((2-((4-氰基苯基)氨基)-5-(1H-吡唑-4-基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8h)

白色固体, 产率: 26.6%。m.p.: 263.7~265.6 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 13.12 (s, 1H), 10.14 (s, 1H), 8.91 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 8.02~7.91 (m, 4H), 7.68 (s, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 164.09, 157.12, 157.08, 151.31, 145.12, 144.58, 136.06, 133.36, 132.90, 131.71, 127.88, 119.82, 119.36, 118.33, 112.76, 110.43, 106.19, 102.47; HRMS (ESI) m/z: Calcd. for C₂₉H₁₅D₆N₇O [M+H]⁺ 490.225 7, found 490.224 4。

1.4.9　4′-((2-((4-氰基苯基)氨基)-5-(5-(羟甲基)噻吩-2-基)嘧啶-4-基)氧基)-3′, 5′-双(甲基-d₃)-[1, 1′-联苯]-4-腈(8i)

白色固体, 产率: 37.5%。m.p.: 255.0~256.7 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.29 (s, 1H), 8.92 (s, 1H), 8.01~7.92 (m, 4H), 7.69 (s, 2H), 7.59 (d, J = 3.7 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 3.7 Hz, 1H), 5.53 (t, J = 5.7 Hz, 1H), 4.69 (d, J = 3.9 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 163.56, 157.58, 157.51, 150.91, 147.13, 144.79, 144.50, 136.26, 133.36, 133.12, 132.94, 131.58, 128.00, 127.91, 124.91, 124.81, 119.73, 119.35, 118.65, 110.48, 107.73, 102.96, 58.84; HRMS (ESI) m/z: Calcd. for C₃₁H₁₇D₆N₅O₂S [M+H]⁺ 536.202 2, found 536.200 3。

1.4.10　4′-((2-((4-氰基苯基)氨基)-5-(吡啶-4-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8j)

白色固体, 产率: 83.3%。m.p.: 281.2~282.5 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.41 (s, 1H), 8.82 (s, 1H), 8.72~8.67 (m, 2H), 7.97 (d, J = 1.5 Hz, 4H), 7.88~7.81 (m, 2H), 7.68 (s, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 165.55, 160.27, 159.09, 150.86, 150.45, 144.60, 144.44, 141.01, 136.24, 133.36, 132.93, 131.67, 131.58, 127.99, 127.89, 123.23, 119.48 (d, J = 30.2 Hz), 118.91, 110.49, 110.05, 103.32, 16.80; HRMS (ESI) m/z: Calcd. for C₃₁H₁₉D₃N₆O [M+H]⁺ 498.211 6, found 498.212 1。

1.4.11　4′-((2-((4-氰基苯基)氨基)-5-(吡啶-3-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8k)

白色固体, 产率: 87.6%。m.p.: 290.5~291.7 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.33 (s, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.73 (s, 1H), 8.62 (dd, J = 4.9, 1.6 Hz, 1H), 8.20 (dt, J = 8.0, 2.0 Hz, 1H), 7.97 (s, 4H), 7.67 (s, 2H), 7.60~7.50 (m, 3H), 7.35 (d, J = 8.5 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 165.53, 159.94, 158.82, 150.86, 149.42, 149.01, 144.78, 144.46, 136.47, 136.18, 133.37, 132.95, 131.69, 131.60, 129.46, 127.98, 127.89, 124.16, 119.52 (d, J = 34.8 Hz), 118.78, 110.47, 109.94, 103.10, 16.82; HRMS (ESI) m/z: Calcd. for C₃₁H₁₉D₃N₆O [M+H]⁺ 498.211 6, found 498.210 5。

1.4.12　4′-((2-((4-氰基苯基)氨基)-[5, 5′-二吡啶]-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8l)

白色固体, 产率: 74.5%。m.p.: 303.4~305.0 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.41 (s, 1H), 9.23 (s, 2H), 9.23 (s, 1H), 8.83 (s, 1H), 7.97 (s, 4H), 7.67 (s, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 165.56, 160.11, 159.26, 157.63, 156.44, 150.69, 144.61, 144.44, 136.30, 133.37, 132.97, 131.72, 131.64, 128.00, 127.90, 127.86, 119.49 (d, J = 30.9 Hz), 118.93, 110.49, 106.74, 103.34, 16.82; HRMS (ESI) m/z: Calcd. for C₃₀H₁₈D₃N₇O [M+H]⁺ 499.206 9, found 499.204 8。

1.4.13　4′-((2-((4-氰基苯基)氨基)-5-(呋喃-3-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8m)

白色固体, 产率: 59.5%。m.p.: 284.6~286.6 ℃, HPLC purity: 95.12%; ¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.22 (s, 1H), 8.90 (s, 1H), 8.29~8.25 (m, 1H), 8.01~7.93 (m, 4H), 7.84 (t, J = 1.8 Hz, 1H), 7.68 (s, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 2.1 Hz, 1H), 2.15 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 164.63, 157.69, 157.58, 151.13, 144.96, 144.55, 144.29, 141.22, 136.16, 133.36, 132.91, 131.77, 131.68, 127.92, 127.89, 119.56 (d, J = 41.7 Hz), 118.51, 117.82, 110.45, 108.92, 105.16, 102.73, 16.66; HRMS (ESI) m/z: Calcd. for C₃₀H₁₈D₃N₅O₂ [M+H]⁺ 487.195 7, found 487.197 1。

1.4.14　4′-((2-((4-氰基苯基)氨基)-5-(呋喃-2-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8n)

白色固体, 产率: 80.9%。m.p.: 287.0~288.7 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.32 (s, 1H), 8.88 (s, 1H), 8.02~7.94 (m, 4H), 7.86 (dd, J = 1.9, 0.8 Hz, 1H), 7.69 (s, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 6.98 (dd, J = 3.4, 0.8 Hz, 1H), 6.68 (dd, J = 3.4, 1.9 Hz, 1H), 2.16 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 163.35, 157.53, 155.56, 150.95, 146.41, 144.71, 144.50, 143.16, 136.26, 133.38, 132.96, 131.72, 131.63, 127.98, 127.92, 119.54 (d, J = 36.6 Hz), 118.69, 112.66, 110.47, 109.77, 104.59, 103.03, 16.61; HRMS (ESI) m/z: Calcd. for C₃₀H₁₈D₃N₅O₂ [M+H]⁺ 487.195 7, found 487.193 9。

1.4.15　4′-((2-((4-氰基苯基)氨基)-5-(噻吩-3-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8o)

白色固体, 产率: 42.8%。m.p.: 296.6~298.4 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.24 (s, 1H), 8.91 (s, 1H), 8.06 (t, J = 1.9 Hz, 1H), 8.02~7.94 (m, 4H), 7.79~7.70 (m, 2H), 7.69 (s, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 164.79, 158.88, 157.67, 151.16, 144.91, 144.52, 136.11, 133.37, 133.09, 132.91, 131.75, 131.66, 127.95, 127.89, 127.35, 127.00, 123.55, 119.55 (d, J = 38.6 Hz), 118.54, 110.44, 108.52, 102.79, 16.76; HRMS (ESI) m/z: Calcd. for C₃₀H₁₈D₃N₅OS [M+H]⁺ 503.172 8, found 503.173 5。

1.4.16　4′-((2-((4-氰基苯基)氨基)-5-(噻吩-2-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8p)

白色固体, 产率: 68.5%。m.p.: 297.6~299.1 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.32 (s, 1H), 8.97 (s, 1H), 8.01~7.92 (m, 4H), 7.77 (dd, J = 3.7, 1.2 Hz, 1H), 7.68 (s, 2H), 7.64 (dd, J = 5.1, 1.2 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.22 (dd, J = 5.1, 3.7 Hz, 1H), 2.17 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 163.60, 157.79, 157.68, 150.87, 144.77, 144.50, 136.29, 134.37, 133.36, 132.94, 131.71, 131.62, 128.06, 128.00, 127.91, 126.81, 125.22, 119.53 (d, J = 38.1 Hz), 118.67, 110.49, 107.47, 103.00, 16.70; HRMS (ESI) m/z: Calcd. for C₃₀H₁₈D₃N₅OS [M+H]⁺ 503.172 8, found 503.171 4。

1.4.17　4′-((2-((4-氰基苯基)氨基)-5-(1H-吡唑-3-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8q)

白色固体, 产率: 48.3%。m.p.: 310.7~312.6 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 13.31~13.01 (m, 1H), 10.28 (s, 1H), 9.03 (s, 1H), 8.05~7.93 (m, 4H), 7.90~7.78 (m, 1H), 7.70 (s, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 2.2 Hz, 1H), 2.18 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 158.01, 157.74, 151.18, 144.90, 144.55, 136.09, 133.36, 132.92, 131.79, 131.70, 127.92, 127.89, 119.75, 119.36, 118.56, 110.44, 105.22, 102.81, 16.69; HRMS (ESI) m/z: Calcd. for C₂₉H₁₈D₃N₇O [M+H]⁺ 487.206 9, found 487.205 3。

1.4.18　4′-((2-((4-氰基苯基)氨基)-5-(1H-吡唑-4-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8r)

白色固体, 产率: 35.9%。m.p.: 292.4~294.4 ℃。¹H NMR (400 MHz, DMSO-d₆) δ_H: 13.13 (s, 1H), 10.15 (s, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 8.03~7.92 (m, 4H), 7.68 (s, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.36~7.28 (m, 2H), 2.16 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 164.08, 157.12, 157.08, 151.28, 145.12, 144.58, 136.07, 133.36, 132.90, 131.82, 131.73, 127.91, 127.88, 119.83, 119.36, 118.33, 112.77, 110.43, 106.18, 102.46, 16.71; HRMS (ESI) m/z: Calcd. for C₂₉H₁₈D₃N₇O [M+H]⁺ 487.206 9, found 487.206 0。

1.4.19　4′-((2-((4-氰基苯基)氨基)-5-(5-(羟甲基)噻吩-2-基)嘧啶-4-基)氧基)-3′-甲基-5′-(甲基-d₃)-[1, 1′-联苯]-4-腈(8s)

白色固体, 产率: 66.1%。m.p.: 258.9~261.0 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ_H: 10.31 (s, 1H), 8.93 (s, 1H), 8.03~7.94 (m, 4H), 7.70 (s, 2H), 7.59 (d, J = 3.7 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 3.7 Hz, 1H), 5.55 (t, J = 5.7 Hz, 1H), 4.69 (d, J = 5.7 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ_C: 163.54, 157.57, 157.52, 150.87, 147.14, 144.79, 144.49, 136.26, 133.38, 133.12, 132.95, 131.69, 131.60, 128.00, 127.92, 124.92, 124.80, 119.56 (d, J = 38.6 Hz), 118.64, 110.48, 107.72, 102.94, 58.84, 16.70; HRMS (ESI) m/z: Calcd. for C₃₁H₂₀D₃N₅O₂S [M+H]⁺ 533.183 4, found 533.181 9。

2　生物活性检测

本实验中所有化合物的生物活性检测, 包括抗病毒活性、细胞毒性、RT酶抑制活性均由比利时鲁汶大学Rega研究所进行^[10]。

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Kang DW, Sun YY, Feng D, et al. Development of novel dihydrofuro[3, 4-d]pyrimidine derivatives as HIV-1 NNRTIs to overcome the highly resistant mutant strains F227L/V106A and K103N/Y181C [J]. J Med Chem, 2022, 65: 2458-2470.

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2025年第60卷第8期

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doi: 10.16438/j.0513-4870.2025-0653

接收时间：2025-06-11
首发时间：2026-09-20
出版时间：2025-08-12

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收稿日期：2025-06-11
修回日期：2025-07-03

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¹复旦大学化学系手性分子催化与合成工程中心, 上海 200433

²郑州大学药物研究院, 河南郑州 450001

³Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium

⁴Dept Appl Sci Biosyst, University of Cagliari, Monserrato Ⅰ-09042, Italy

⁵Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 008404, Vietnam

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王帅, Tel: 86-21-65643811, E-mail: shuaiwang@fudan.edu.cn

陈芬儿, E-mail: rfchen@fudan.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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6a	CD₃	H	6.38 ± 0.00	> 295.15
7a	CD₃	Cl	35.69 ± 0.03	41.29 ± 5.95
7b	CD₃	Br	20.62 ± 0.01	34.73 ± 7.46
7c	CD₃	I	70.73 ± 0.02	127.47 ± 5.77
8a	CD₃	4-Pyridyl	17.69 ± 0.01	49.79 ± 3.94
8b	CD₃	3-Pyridyl	19.61 ± 0.02	> 249.70
8c	CD₃	5-Pyrimidyl	23.77 ± 0.02	128.01 ± 2.65
8d	CD₃	3-Furyl	37.99 ± 0.01	51.24 ± 7.08
8e	CD₃	2-Furyl	62.36 ± 0.02	198.18 ± 12.46
8f	CD₃	2-Thienyl	67.41 ± 0.01	178.66 ± 9.98
8g	CD₃	3-Pyrazolyl	10.94 ± 0.00	38.64 ± 7.75
8h	CD₃	4-Pyrazolyl	22.26 ± 0.03	121.45 ± 11.26
8i	CD₃	5-Hydroxymethyl-2-thienyl	30.72 ± 0.02	149.40 ± 14.02
6b	CH₃	H	13.18 ± 0.01	> 297.27
7d	CH₃	Cl	13.35 ± 0.00	26.88 ± 8.71
7e	CH₃	Br	27.43 ± 0.03	18.02 ± 4.59
7f	CH₃	I	42.57 ± 0.03	44.47 ± 4.50
8j	CH₃	4-Pyridyl	9.88 ± 0.00	62.61 ± 5.26
8k	CH₃	3-Pyridyl	35.29 ± 0.03	> 251.22
8l	CH₃	5-Pyrimidyl	33.04 ± 0.02	118.09 ± 7.45
8m	CH₃	3-Furyl	39.55 ± 0.03	229.04 ± 7.62
8n	CH₃	2-Furyl	68.91 ± 0.05	> 256.91
8o	CH₃	3-Thienyl	256.35 ± 0.17	200.79 ± 2.60
8p	CH₃	2-Thienyl	66.11 ± 0.01	> 248.70
8q	CH₃	3-Pyrazolyl	12.91 ± 0.01	48.41 ± 22.30
8r	CH₃	4-Pyrazolyl	25.57 ± 0.03	66.67 ± 31.92
8s	CH₃	5-Hydroxymethyl-2-thienyl	8.88 ± 0.00	> 287.68
NVP			237.5 ± 0.18	> 15.021
EFV			4.58 ± 0.002	> 6.336
ETR			4.23 ± 0.002	> 4.595

Compd.

R₁

R₂

EC₅₀/nmol·L^-1

CC₅₀/μmol·L^-1

CD₃

6.38 ± 0.00

> 295.15

CD₃

35.69 ± 0.03

41.29 ± 5.95

CD₃

20.62 ± 0.01

34.73 ± 7.46

CD₃

70.73 ± 0.02

127.47 ± 5.77

CD₃

4-Pyridyl

17.69 ± 0.01

49.79 ± 3.94

CD₃

3-Pyridyl

19.61 ± 0.02

> 249.70

CD₃

5-Pyrimidyl

23.77 ± 0.02

128.01 ± 2.65

CD₃

3-Furyl

37.99 ± 0.01

51.24 ± 7.08

CD₃

2-Furyl

62.36 ± 0.02

198.18 ± 12.46

CD₃

2-Thienyl

67.41 ± 0.01

178.66 ± 9.98

CD₃

3-Pyrazolyl

10.94 ± 0.00

38.64 ± 7.75

CD₃

4-Pyrazolyl

22.26 ± 0.03

121.45 ± 11.26

CD₃

5-Hydroxymethyl-2-thienyl

30.72 ± 0.02

149.40 ± 14.02

CH₃

13.18 ± 0.01

> 297.27

CH₃

13.35 ± 0.00

26.88 ± 8.71

CH₃

27.43 ± 0.03

18.02 ± 4.59

CH₃

42.57 ± 0.03

44.47 ± 4.50

CH₃

4-Pyridyl

9.88 ± 0.00

62.61 ± 5.26

CH₃

3-Pyridyl

35.29 ± 0.03

> 251.22

CH₃

5-Pyrimidyl

33.04 ± 0.02

118.09 ± 7.45

CH₃

3-Furyl

39.55 ± 0.03

229.04 ± 7.62

CH₃

2-Furyl

68.91 ± 0.05

> 256.91

CH₃

3-Thienyl

256.35 ± 0.17

200.79 ± 2.60

CH₃

2-Thienyl

66.11 ± 0.01

> 248.70

CH₃

3-Pyrazolyl

12.91 ± 0.01

48.41 ± 22.30

CH₃

4-Pyrazolyl

25.57 ± 0.03

66.67 ± 31.92

CH₃

5-Hydroxymethyl-2-thienyl

8.88 ± 0.00

> 287.68

NVP

237.5 ± 0.18

> 15.021

EFV

4.58 ± 0.002

> 6.336

ETR

4.23 ± 0.002

> 4.595

Compd.	EC₅₀/nmol·L^-1
6a	9.27 ± 0.00	5.96 ± 0.00	29.04 ± 0.01	2 065.25 ± 0.81	24.56 ± 0.01
7a	38.60 ± 0.02	30.41 ± 0.02	65.13 ± 0.01	242.66 ± 0.05	59.56 ± 0.02
7b	21.35 ± 0.01	20.00 ± 0.01	39.51 ± 0.01	79.37 ± 0.02	46.18 ± 0.01
7c	30.94 ± 0.01	28.80 ± 0.02	67.94 ± 0.02	197.35 ± 0.16	53.01 ± 0.01
8a	37.36 ± 0.01	11.24 ± 0.00	61.98 ± 0.02	93.44 ± 0.06	42.55 ± 0.01
8b	16.58 ± 0.01	13.08 ± 0.01	44.50 ± 0.02	60.23 ± 0.01	31.36 ± 0.01
8c	31.90 ± 0.02	26.22 ± 0.02	83.09 ± 0.04	125.65 ± 0.07	44.61 ± 0.01
8d	25.18 ± 0.01	25.84 ± 0.00	86.20 ± 0.03	169.79 ± 0.03	41.87 ± 0.01
8e	62.04 ± 0.02	56.94 ± 0.01	290.00 ± 0.05	295.21 ± 0.06	279.38 ± 0.09
8f	51.22 ± 0.01	50.83 ± 0.01	172.90 ± 0.07	303.68 ± 0.08	93.70 ± 0.03
8g	21.29 ± 0.01	18.69 ± 0.01	45.91 ± 0.00	46.62 ± 0.01	32.27 ± 0.01
8h	11.54 ± 0.00	16.85 ± 0.01	40.55 ± 0.02	36.21 ± 0.02	26.76 ± 0.01
8i	20.12 ± 0.01	32.58 ± 0.02	52.46 ± 0.02	59.55 ± 0.01	35.33 ± 0.01
6b	19.56 ± 0.02	8.80 ± 0.00	63.26 ± 0.01	1 014.35 ± 0.52	68.97 ± 0.01
7d	17.04 ± 0.00	19.45 ± 0.02	60.72 ± 0.02	204.26 ± 0.11	51.66 ± 0.04
7e	12.52 ± 0.01	29.19 ± 0.02	55.07 ± 0.01	211.46 ± 0.07	54.42 ± 0.02
7f	31.30 ± 0.01	32.07 ± 0.01	42.92 ± 0.01	101.39 ± 0.05	47.49 ± 0.03
8j	14.97 ± 0.00	13.62 ± 0.00	41.95 ± 0.01	64.66 ± 0.03	20.00 ± 0.00
8k	76.12 ± 0.05	36.28 ± 0.01	161.53 ± 0.06	162.19 ± 0.07	147.26 ± 0.11
8l	61.88 ± 0.01	44.33 ± 0.03	187.29 ± 0.05	254.03 ± 0.04	71.51 ± 0.03
8m	39.36 ± 0.03	31.55 ± 0.01	94.49 ± 0.01	180.92 ± 0.05	49.79 ± 0.01
8n	94.75 ± 0.02	73.32 ± 0.05	187.13 ± 0.05	599.01 ± 0.34	144.23 ± 0.04
8o	273.77 ± 0.06	179.71 ± 0.05	655.38 ± 0.20	1 268.93 ± 0.33	352.61 ± 0.05
8p	33.13 ± 0.01	36.41 ± 0.01	127.04 ± 0.04	248.90 ± 0.07	134.00 ± 0.09
8q	28.05 ± 0.01	25.90 ± 0.01	50.77 ± 0.01	51.23 ± 0.01	56.78 ± 0.00
8r	22.97 ± 0.01	16.44 ± 0.00	42.60 ± 0.01	53.80 ± 0.02	62.43 ± 0.02
8s	7.54 ± 0.00	8.57 ± 0.00	24.28 ± 0.01	62.71 ± 0.02	14.38 ± 0.00
NVP	1 560.33 ± 1.56	3 740.14 ± 2.93	5 007.71 ± 2.09	7 524.92 ± 3.25	172.87 ± 0.12
EFV	28.53 ± 0.01	63.96 ± 0.02	5.83 ± 0.002	289.86 ± 0.12	5.97 ± 0.003
ETR	5.94 ± 0.002	2.95 ± 0.001	12.92 ± 0.01	19.9 ± 0.01	8.68 ± 0.01

Compd.

EC₅₀/nmol·L^-1

L100I

K103N

Y181C

Y188L

E138K

9.27 ± 0.00

5.96 ± 0.00

29.04 ± 0.01

2 065.25 ± 0.81

24.56 ± 0.01

38.60 ± 0.02

30.41 ± 0.02

65.13 ± 0.01

242.66 ± 0.05

59.56 ± 0.02

21.35 ± 0.01

20.00 ± 0.01

39.51 ± 0.01

79.37 ± 0.02

46.18 ± 0.01

30.94 ± 0.01

28.80 ± 0.02

67.94 ± 0.02

197.35 ± 0.16

53.01 ± 0.01

37.36 ± 0.01

11.24 ± 0.00

61.98 ± 0.02

93.44 ± 0.06

42.55 ± 0.01

16.58 ± 0.01

13.08 ± 0.01

44.50 ± 0.02

60.23 ± 0.01

31.36 ± 0.01

31.90 ± 0.02

26.22 ± 0.02

83.09 ± 0.04

125.65 ± 0.07

44.61 ± 0.01

25.18 ± 0.01

25.84 ± 0.00

86.20 ± 0.03

169.79 ± 0.03

41.87 ± 0.01

62.04 ± 0.02

56.94 ± 0.01

290.00 ± 0.05

295.21 ± 0.06

279.38 ± 0.09

51.22 ± 0.01

50.83 ± 0.01

172.90 ± 0.07

303.68 ± 0.08

93.70 ± 0.03

21.29 ± 0.01

18.69 ± 0.01

45.91 ± 0.00

46.62 ± 0.01

32.27 ± 0.01

11.54 ± 0.00

16.85 ± 0.01

40.55 ± 0.02

36.21 ± 0.02

26.76 ± 0.01

20.12 ± 0.01

32.58 ± 0.02

52.46 ± 0.02

59.55 ± 0.01

35.33 ± 0.01

19.56 ± 0.02

8.80 ± 0.00

63.26 ± 0.01

1 014.35 ± 0.52

68.97 ± 0.01

17.04 ± 0.00

19.45 ± 0.02

60.72 ± 0.02

204.26 ± 0.11

51.66 ± 0.04

12.52 ± 0.01

29.19 ± 0.02

55.07 ± 0.01

211.46 ± 0.07

54.42 ± 0.02

31.30 ± 0.01

32.07 ± 0.01

42.92 ± 0.01

101.39 ± 0.05

47.49 ± 0.03

14.97 ± 0.00

13.62 ± 0.00

41.95 ± 0.01

64.66 ± 0.03

20.00 ± 0.00

76.12 ± 0.05

36.28 ± 0.01

161.53 ± 0.06

162.19 ± 0.07

147.26 ± 0.11

61.88 ± 0.01

44.33 ± 0.03

187.29 ± 0.05

254.03 ± 0.04

71.51 ± 0.03

39.36 ± 0.03

31.55 ± 0.01

94.49 ± 0.01

180.92 ± 0.05

49.79 ± 0.01

94.75 ± 0.02

73.32 ± 0.05

187.13 ± 0.05

599.01 ± 0.34

144.23 ± 0.04

273.77 ± 0.06

179.71 ± 0.05

655.38 ± 0.20

1 268.93 ± 0.33

352.61 ± 0.05

33.13 ± 0.01

36.41 ± 0.01

127.04 ± 0.04

248.90 ± 0.07

134.00 ± 0.09

28.05 ± 0.01

25.90 ± 0.01

50.77 ± 0.01

51.23 ± 0.01

56.78 ± 0.00

22.97 ± 0.01

16.44 ± 0.00

42.60 ± 0.01

53.80 ± 0.02

62.43 ± 0.02

7.54 ± 0.00

8.57 ± 0.00

24.28 ± 0.01

62.71 ± 0.02

14.38 ± 0.00

NVP

1 560.33 ± 1.56

3 740.14 ± 2.93

5 007.71 ± 2.09

7 524.92 ± 3.25

172.87 ± 0.12

EFV

28.53 ± 0.01

63.96 ± 0.02

5.83 ± 0.002

289.86 ± 0.12

5.97 ± 0.003

ETR

5.94 ± 0.002

2.95 ± 0.001

12.92 ± 0.01

19.9 ± 0.01

8.68 ± 0.01

Compd.	IC₅₀/μmol·L^-1		Compd.	IC₅₀/μmol·L^-1		Compd.	IC₅₀/μmol·L^-1
6a	0.057 ± 0.007		8g	0.091 ± 0.013		8m	0.061 ± 0.001
7a	0.062 ± 0.005	8h	0.045 ± 0.006	8n	0.086 ± 0.012
7b	0.066 ± 0.008	8i	0.093 ± 0.016	8o	0.144 ± 0.013
7c	0.049 ± 0.005	6b	0.043 ± 0.003	8p	0.081 ± 0.007
8a	0.109 ± 0.007	7d	0.059 ± 0.006	8q	0.082 ± 0.000
8b	0.100 ± 0.008	7e	0.057 ± 0.007	8r	0.074 ± 0.012
8c	0.110 ± 0.008	7f	0.096 ± 0.001	8s	0.052 ± 0.002
8d	0.092 ± 0.020	8j	0.106 ± 0.004	NVP	0.602 ± 0.066
8e	0.086 ± 0.029	8k	0.085 ± 0.018	EFV	0.014 ± 0.003
8f	0.080 ± 0.013	8l	0.078 ± 0.011	ETR	0.029 ± 0.005

Compd.

IC₅₀/μmol·L^-1

Compd.

IC₅₀/μmol·L^-1

Compd.

IC₅₀/μmol·L^-1

0.057 ± 0.007

0.091 ± 0.013

0.061 ± 0.001

0.062 ± 0.005

0.045 ± 0.006

0.086 ± 0.012

0.066 ± 0.008

0.093 ± 0.016

0.144 ± 0.013

0.049 ± 0.005

0.043 ± 0.003

0.081 ± 0.007

0.109 ± 0.007

0.059 ± 0.006

0.082 ± 0.000

0.100 ± 0.008

0.057 ± 0.007

0.074 ± 0.012

0.110 ± 0.008

0.096 ± 0.001

0.052 ± 0.002

0.092 ± 0.020

0.106 ± 0.004

NVP

0.602 ± 0.066

0.086 ± 0.029

0.085 ± 0.018

EFV

0.014 ± 0.003

0.080 ± 0.013

0.078 ± 0.011

ETR

0.029 ± 0.005