Synthesis and antibacterial activity of novel 4-chloro-2-mercaptobenzenesulfonamide derivatives

Figures & data

Scheme 1.  Synthesis of N-[4-chloro-5-R¹-2-(R²-methylthio)benzenesulfonyl]cyanamide potassium salts (12–15). Reagents, conditions and yields: (A) 25% NH₄OH / EtOH (1.1 molar equiv.) r.t. 44 h, 73%; (B) anhydrous K₂CO₃ (excess), dry THF, reflux 24 h, 68%–74%; (C) R²-CH₂-X (1.0–1.1 molar equiv.) (X = Br or Cl), water, r.t., 1-2 h, 80%–98%.

Scheme 2.  Synthesis of 2-benzylthio-4-chlorobenzenesulfonamide derivatives (16–28). Reagents and conditions: (A) appropriate hydrazinecarbodithioic acid esters or 1-substituted carbothioic acid hydrazides (1 molar equiv.), glacial acetic acid, reflux 8–40 h; (B) 16 (1 mmol), 2-(piperazin-1-yl)pyrimidine (4.5 mmol), dry toluene, reflux 56 h.

Scheme 3.  Synthesis of 4-chloro-2-mercaptobenzenesulfonamide derivatives (29–49). Reagents and conditions: (A) ortho-aminocarboxylate component (1.0–1.1 molar equiv.), glacial acetic acid, reflux 15 h and 12 h at r.t. or reflux 14–17 h; (B) 2-aminophenol or 2-aminothiophenol (1 molar equiv.), glacial acetic acid, reflux 6–7 h, then 12 h r.t.

Table 1.  Minimal inhibitory concentration (MIC µg/mL) of test compounds 16–24, 26, 28–33.

	M^†	16	17	18	19	20	21	22	23	24	26	28	29	30	31	32	33
Anaerobic bacteria
Gram-positive:
Peptostreptococcus anaerobius	≤ 0.4	NT	NT	50	25	≤ 6.2	50	≤ 6.2	≤ 6.2	50	25	≤ 6.2	25	50	≤ 6.2	≤ 6.2	≤ 6.2
Finegoldia magna	≤ 0.4	≤ 6.2	≤ 6.2	50	50	12.5	50	25	≤ 6.2	50	100	50	25	≤ 6.2	≤ 6.2	≤ 6.2	≤ 6.2
Micromonas micros	0.8	50	25	50	25	≤ 6.2	*	≤ 6.2	100	50	*	*	50	*	≤ 6.2	100	*
Actinomyces viscosus	6.2	NT	NT	50	*	12.5	*	≤ 6.2	*	50	25	50	50	≤ 6.2	≤ 6.2	12.5	≤ 6.2
Actinomyces odotolyticus	3.1	NT	NT	*	*	*	*	*	*	50	NT	NT	50	NT	NT	NT	NT
Actinomyces israelii	≥ 100	100	50	NT	NT	NT	NT	NT	NT	NT	NT	NT	NT	NT	NT	NT	NT
Propionibacterium acnes	≥ 100	100	*	*	*	25	*	≤ 6.2	*	*	*	*	50	*	*	100	*
Propionibacterium granulosum	≥ 100	NT	NT	*	*	*	*	*	*	50	NT	NT	50	NT	NT	NT	NT
Gram-negative:
Prevotella bivia	≤ 0.4	100	100	*	*	*	*	*	*	*	*	*	*	*	*	*	*
Prevotella buccalis	≤ 0.4	100	25	*	*	*	*	*	*	*	*	*	*	*	*	*	*
Prevotella intermedia	≤ 0.4	100	100	*	*	*	*	*	*	100	*	*	*	*	*	*	*
Prevotella loescheii	≤ 0.4	*	25	*	*	*	*	*	*	50	*	*	*	*	*	*	*
Porphyromonas asaccharolytica	≤ 0.4	100	25	*	*	*	*	*	*	50	*	*	*	*	*	*	*
Fusobacterium nucleatum	≤ 0.4	*	100	*	*	*	*	*	100	50	*	*	*	*	*	*	*
Fusobacterium necrophorum	≤1.6	100	*	*	*	*	*	*	100	100	*	*	*	*	*	*	*
Bacteroides fragilis	≤ 0.4	100	100	*	*	*	*	*	*	*	*	*	*	*	*	*	*
Bacteroides ureolyticus	≤6.2	100	50	*	*	*	*	*	100	*	*	*	50	*	*	*	*
Bacteroides vulgatus	≤ 0.4	NT	NT	*	*	*	*	*	*	*	*	*	*	*	*	*	*
Aerobic bacteria
Gram-positive:	A^‡
Staphylococcus aureus	6.2	*	*	50	≤ 6.2	12.5	≤ 6.2	≤ 6.2	12,5	25	*	*	*	*	100	*	*
Staphylococcus epidermidisot	6.2	NT	NT	*	*	*	*	*	*	100	*	*	*	*	*	100	*
Enterococcus faecalis	25	NT	NT	≤ 6.2	50	≤ 6.2	*	*	*	25	*	*	*	*	*	100	*
Corynebacterium spp.	50	*	*	25	*	*	25	*	≤ 6.2	*	*	*	*	*	*	≤ 6.2	*

†M − Metronidazole (Fluka); ‡A − Amikacin (Fluka); *MIC ≥ 200. NT, not tested.

Table 2.  Minimal inhibitory concentration (MIC µg/mL) of test compounds 38–40, 43–49.

	M^†	38	39	40	43	44	45	46	47	48	49
Anaerobic bacteria
Gram-positive
Peptostreptococcus anaerobius	≤ 0.4	100	≤ 6.2	50	25	≤ 6.2	≤ 6.2	50	*	≤ 6.2	≤ 6.2
Finegoldia magna	≤ 0.4	≤ 6.2	≤ 6.2	50	25	50	≤ 6.2	50	*	≤ 6.2	≤ 6.2
Micromonas micros	0.8	100	50	*	25	25	100	*	100	≤ 6.2	100
Actinomyces viscosus	6.2	100	12.5	*	50	≤ 6.2	50	12.5	50	≤ 6.2	≤ 6.2
Aerobic bacteria
Gram-positive	A^‡
Staphylococcus aureus	6.2	*	*	*	*	*	*	*	50	*	*
Corynebacterium spp.	50	*	*	*	*	*	*	*	*	50	*

^†M − Metronidazole (Fluka); ^‡A− Amikacin (Fluka); * MIC ≥ 200 NT, not tested.