Design and synthesis of some new benzoylthioureido phenyl derivatives targeting carbonic anhydrase enzymes

Figures & data

Figure 1. Chemical structure of some ureido and thioureido CAIs.

Table 1. Inhibition data (K_I, nM) of human CA isoforms hCA I, II, IX and XII with compounds 4a–d, 5a–d, 6a–d, 12a–c, 13a–c, and 14a–c against SLC-0111 and AAZ; by a stopped flow CO₂ hydrase assay.

				KI (nM)^a
Compound	R	R1	R2	hCA I	hCA II	hCA IX	hCA XII
4a	–	H	H	75.70	78.00	106.00	57.40
4b	–	Cl	H	58.50	58.10	115.40	>100,000
4c	–	Cl	Cl	40.40	90.00	>100,000	88.10
4d	–	Br	H	65.00	67.00	>100000	82.00
5a	–	H	H	1504.70	464.60	2932.00	>100,000
5b	–	Cl	H	8797.60	5535.80	>100,000	>100,000
5c	–	Cl	Cl	>100,000	6000.30	1741.00	>100,000
5d	–	Br	H	5556.20	>100,000	>100,000	>100,000
6a	–	H	H	>100,000	>100,000	1739.30	>100,000
6b	–	Cl	H	>100,000	>100,000	1403.60	>100,000
6c	–	Cl	Cl	809.10	>100,000	239.10	>100,000
6d	–	Br	H	85.38	31.00	>100,000	>100,000
12a	-CH3	–	–	67.60	15.50	32.20	83.00
12b	-CH(CH3)2	–	–	>100,000	2766.20	1784.30	>100,000
12c	-p-CH3-C6H4	–	–	91.00	94.20	144.00	225.70
13a	-CH3	–	–	1709.60	647.00	1092.60	>100,000
13b	-CH(CH3)2	–	–	>100,000	193.50	289.00	>100,000
13c	-p-CH3-C6H4	–	–	>100,000	504.00	802.10	>100,000
14a	-CH3	–	–	>100,000	>100,000	1146.20	>100,000
14b	-CH(CH3)2	–	–	>100,000	>100,000	1496.40	>100,000
14c	-p-CH3-C6H4	–	–	>100,000	2019.70	1367.30	>100,000
SLC-0111^23	–	–	–	5080.00	960.00	45.00	4.50
AAZ	–	–	–	250.00	12.1	25.70	5.70

^aMean from 3 different assays, by a stopped flow technique (errors were in the range of ± 5–10% of the reported values).

Figure 2. Design of the target compounds as analogues to SCL-0111.

Scheme 1. Reagents and reaction conditions: (i) SOCl_2, methylene chloride, reflux, 4–5 h, (ii) NH₄SCN, acetone, reflux, 1–3 h, (iii) sulphanilamide or 4-aminobenzoic acid or ethyl 4-aminobenzoate, acetone, reflux, 2–3 h.

Scheme 2. Reagents and reaction conditions: (i) KOH, acetonitrile, R.T, 1–2 h, (ii), SOCl₂, methylene chloride, reflux, 4–5 h, (iii) NH₄SCN, acetone, reflux, 1–3 h, (iv) sulphanilamide or 4-aminobenzoic acid or ethyl 4-aminobenzoate, acetone, reflux, 2–3 h.

Elbadawi MM, Eldehna WM, Nocentini A, Abo-Ashour MF, Elkaeed EB, Abdelgawad MA, Alharbi KS, Abdel-Aziz HA, Supuran CT, Gratteri P, et al. Identification of N-phenyl-2-(phenylsulfonyl)acetamides/propanamides as new SLC-0111 analogues: Synthesis and evaluation of the carbonic anhydrase inhibitory activities. Eur J Med Chem. 2021;218:113360.

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