title: 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.
authors.affiliation: Department of Experimental Pharmacology, Polish Academy of Sciences, Warsaw, Poland. zkazimierczuk@gmail.com
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Kazimierczuk
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Chalimoniuk
authors.forename: Agnieszka Ewa
authors.initials: AE
authors.lastname: Laudy
authors.forename: Rosa
authors.initials: R
authors.lastname: Moo-Puc
authors.forename: Roberto
authors.initials: R
authors.lastname: Cedillo-Rivera
authors.forename: Bohdan Jerzy
authors.initials: BJ
authors.lastname: Starosciak
authors.forename: Stanislaw J
authors.initials: SJ
authors.lastname: Chrapusta
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000201:enzymology; D015195:Drug Design; D004748:Entamoeba histolytica / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016829:Giardia lamblia / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009152:Mutagenicity Tests; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D021261:Parasitic Sensitivity Tests; D051381:Rats; D017208:Rats, Wistar; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D044366:Transition Temperature; D015003:Yeasts / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D013890:Thiourea