Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

Abstract

The reaction of substituted benzylhalides, or of halomethyl derivatives of thiophene or furane, with thiourea or its derivatives yielded the respective isothioureas as hydrohalide salts. The products (a total of 17, including 16 novel compounds) were tested for activity against five Gram-positive and nine Gram-negative bacterial strains, six yeast species and two protozoan species. The most active against Gram-positive bacteria were S-(2,4-dinitrobenzyl)isothiourea hydrochloride (MIC range for four out of five strains tested: 12.5-25 microg/mL) and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide (MIC range: 12.5-50 microg/mL). The lowest MICs of novel isothioureas for yeast and Gram-negative bacteria ranged between 50 and 100 microg/mL. Nine novel isothioureas showed appreciable genotoxicity in the Bacillus subtilis 'rec-assay' test, the most potent being S-2-(5-nitrofuran-2-ylmethyl)isothiourea and S-(2-nitrobenzyl) isothiourea. At 10 muM concentration, S-(3,4-dichlorobenzyl)isothiourea hydrochloride and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide inhibited Ca(2+)/calmodulin-dependent (non-inducible) nitric oxide synthase activity in normal rat brain homogenates stronger (p < 0.05) than the reference drug 7-nitroindazole (by 78, 76 and 60%, respectively); ten other new isothiourea derivatives significantly inhibited the activity to a lower extent (by 28-60%). These results extend the list of promising isothioureas with substantial activity in vitro and suggest that an in-depth study of toxicity, antimicrobial properties in vivo and nitric oxide synthase isoform selectivity of selected novel compounds is warranted.

Crystal structure of (Z)-3-(adamantan-1-yl)-1-(3-chlorophenyl)-S-benzylisothiourea, C24H27ClN2S

“…Several substituted isothiourea derivatives were reported to possess significant cardiovascular properties as nitric oxide synthase inhibitors [1][2][3][4][5], and calcium channel blockers [6]. Isothiourea derivatives were also reported to display potent antimicrobial [7,8], anticancer [9,10], and anti-anthelmintic [11] activities.…”

Endurance training upregulates the nitric oxide/soluble guanylyl cyclase/cyclic guanosine 3′,5′-monophosphate pathway in the striatum, midbrain and cerebellum of male rats

“…Nitric oxide synthases' activity was assayed as described earlier (Kazimierczuk et al, 2010). Briefly, for total NOS activity measurement, brain homogenates (0.2 mg protein/ sample) were incubated for 20 min at 37 o C, in a final volume of 300 ml, with 50 mM Tris-HCl buffer pH 7.4, 100 mM [ 14 C]Larginine (0.2 mCi), 2 mM CaCl 2 , 1 mM calmodulin (CaM), 15 mM FAD, 10 mM tetrahydrobiopterin, 1 mM NADPH, 1 mM EDTA, and 1 mM dithiotreitol.…”

Crystal structure of 4-bromobenzyl (Z)-N′-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidate, C28H34BrN3S

“…In addition, potent antimicrobial [14][15][16], anticancer [17,18], anti-in ammatory [19][20][21] and hypoglycemic [22] activities were reported for numerous adamantane-based derivatives. Isothiourea derivatives were also recognized as a structural motif of particular value in medicinal chemistry possessing diverse biological activities [23,24]. In the present study, we report the synthesis and the X-ray structure analysis of the title adamantane-isothiourea hybrid molecule as potential bioactive agent.…”