Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors: synthesis, structure-activity relationship analysis, and biological activity

Figures & data

Figure 1.  Conception of CAPE-like analogues IN inhibitors.

Scheme 1.  Reagents and conditions: (i) 4-acetamidobenzene-1-sulfonyl chloride, pyridine, 0°C− rt, 4 h; (ii) 5 M NaOH, MeOH, 70°C, 4 h; (iii) Ac₂O, pyridine, rt, 24 h; (iv) SOCl₂, 80°C, 5 h.

Scheme 2.  Reagents and conditions: (v) pyridine, acetone, 0°C− rt, 20 h; and (vi) MeOH, THF, HCl, 60°C, 1 h.

Scheme 3.  Reagents and conditions: (vii) pyridine, acetone, -5°C− rt, 16 h; and (viii) EtOH, THF, HCl, 65°C, 0.5 h.

Table 1.  Inhibition of HIV-1 integrase catalytic activities of compounds 9a-s.

Code	Inhibition of HIV-1 IN IC50 (μM)*		Code	Inhibition of HIV-1 IN IC50 (μM)*
	3′-P	ST		3′-P	ST
9a	7	0.9 ± 0.1	9k	8 ± 2	2.5 ± 0.5
9b	4 ± 2	1.5	9l	1.3	0.8 ± 0.21
9c	7 ± 2	3 ± 2	9m	7 ± 3	1.5 ± 0.1
9d	7 ± 3	2 ± 1	9n	6 ± 2	2 ± 1
9e	3 ± 2	0.7 ± 0.3	9o	5 ± 2	2 ± 1
9f	2 ± 1	0.7 ± 0.3	9p	8 ± 3	8 ± 1
9g	5 ± 3	1.4 ± 0.3	9q	5	4.5
9h	5 ± 1	1.7	9r	4 ± 2	3 ± 0.2
9i	3 ± 1	2.5 ± 0.5	9s	7 ± 3	2 ± 1
9j	6	1.3

*IC₅₀, Inhibitory concentration 50% (inhibition of purified integrase).

Table 2.  Inhibition of HIV-1 integrase catalytic activities of compounds 11a-m, t-x.

Code	Inhibition of HIV-1 IN IC50 (μM)*		Code	Inhibition of HIV-1 IN IC50 (μM)*
	3′-P	ST		3′-P	ST
11a	8 ± 3	5 ± 1	11j	35 ± 15	9 ± 1
11b	11 ± 1	6 ± 1	11k	5 ± 1	4 ± 1
11c	29 ± 9	11 ± 1	11l	22 ± 12	14 ± 6
11d	24 ± 8	9 ± 4	11m	16 ± 5	12 ± 4
11e	35 ± 15	8 ± 4	11t	14 ± 1	10 ± 1
11f	49 ± 23	22 ± 9	11u	8 ± 2	4 ± 1
11g	11 ± 1	9 ± 2	11v	8 ± 2	4 ± 2
11h	17 ± 9	6 ± 1	11w	100	50 ± 10
11i	25 ± 3	7 ± 3	11x	45 ± 7	15 ± 5

*IC₅₀, Inhibitory concentration 50% (inhibition of purified integrase).

Table 3.  Inhibition of HIV-1 integrase catalytic activities of compounds 8g, l, m, s and 10b, h, k, l.

Code	Inhibition of HIV-1 IN IC50 (μM)*		Code	Inhibition of HIV-1 IN IC50 (μM)*
	3′-P	ST		3′-P	ST
8g	12 ± 7	3 ± 1	10b	60 ± 0.01	11 ± 0.01
8l	5 ± 3	2 ± 0.4	10h	75 ± 35	7 ± 0.4
8m	8	1.6	10k	80 ± 28	16 ± 1
8s	>10	1.6	10l	50 ± 18	13 ± 7

*IC₅₀, Inhibitory concentration 50% (inhibition of purified integrase).

Table 4.  Anti-HIV activity and cytotoxicity of selected compounds in HIV-1 infected MT-4 cells.

Code	Anti-HIV-1 activity EC50 (μM) ^§	Cytotoxicity CC50 (μM)^¶ in MT-4	Code	Anti-HIV-1 activity EC50 (μM) ^§	Cytotoxicity CC50 (μM) ^¶ in MT-4
9g	>25	>25	11v	>14	14
9l	>25	>25	8g	>25	>25
11b	20	22	8l	>25	>25
11e	>15	15	10b	25	20
11g	13	49	10h	>20	20
11k	>12	12	10k	>13	13
11l	19	21	10l	>25	>25

^§EC₅₀ is the effective concentrations inhibiting 50% HIV replication.

^¶CC₅₀, cytotoxic concentration 50%.