PL214847B1 - New derivatives of 1-(1-arylimidazolidine-2-ylidene) 4-substituted thiosemicarbazide and process for preparation thereof - Google Patents
New derivatives of 1-(1-arylimidazolidine-2-ylidene) 4-substituted thiosemicarbazide and process for preparation thereofInfo
- Publication number
- PL214847B1 PL214847B1 PL391100A PL39110010A PL214847B1 PL 214847 B1 PL214847 B1 PL 214847B1 PL 391100 A PL391100 A PL 391100A PL 39110010 A PL39110010 A PL 39110010A PL 214847 B1 PL214847 B1 PL 214847B1
- Authority
- PL
- Poland
- Prior art keywords
- ylidene
- general formula
- atcc
- derivatives
- substituted
- Prior art date
Links
- -1 4-substituted thiosemicarbazide Chemical class 0.000 title claims description 23
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- MDKCFLQDBWCQCV-UHFFFAOYSA-N benzyl isothiocyanate Chemical compound S=C=NCC1=CC=CC=C1 MDKCFLQDBWCQCV-UHFFFAOYSA-N 0.000 claims description 6
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- QAADZYUXQLUXFX-UHFFFAOYSA-N N-phenylmethylthioformamide Natural products S=CNCC1=CC=CC=C1 QAADZYUXQLUXFX-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- WIPKZLIKOXLWCF-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-2-ylhydrazine Chemical class NNC1=NCCN1 WIPKZLIKOXLWCF-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 8
- 229920001817 Agar Polymers 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000008272 agar Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000304886 Bacilli Species 0.000 description 3
- 244000063299 Bacillus subtilis Species 0.000 description 3
- 235000014469 Bacillus subtilis Nutrition 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 241000193738 Bacillus anthracis Species 0.000 description 2
- 241000193755 Bacillus cereus Species 0.000 description 2
- 241001079698 Bacillus cereus ATCC 10876 Species 0.000 description 2
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 241001148470 aerobic bacillus Species 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- AWKZWYZUEGYQCY-UHFFFAOYSA-N C1=CC(C(=NNC(N)=S)C)=CC=C1S(=O)(=O)NC1=CC(C)=NN1C1=CC=CC=C1 Chemical group C1=CC(C(=NNC(N)=S)C)=CC=C1S(=O)(=O)NC1=CC(C)=NN1C1=CC=CC=C1 AWKZWYZUEGYQCY-UHFFFAOYSA-N 0.000 description 1
- 241001660259 Cereus <cactus> Species 0.000 description 1
- 206010016952 Food poisoning Diseases 0.000 description 1
- 208000019331 Foodborne disease Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241000191938 Micrococcus luteus Species 0.000 description 1
- 241000219470 Mirabilis Species 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010037888 Rash pustular Diseases 0.000 description 1
- 241000751182 Staphylococcus epidermidis ATCC 12228 Species 0.000 description 1
- BHIRTUJCQXDFRD-UHFFFAOYSA-N [Si].[P].[S] Chemical compound [Si].[P].[S] BHIRTUJCQXDFRD-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000000095 emetic effect Effects 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000029561 pustule Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Przedmiotem wynalazku są pochodne 1-(1-fenyloimidazolidyno-2-ylideno) 4-podstawione tiosemikarbazydu o wzorze ogólnym 1, gdzie R oznacza 2-metylofenyl, 2,3-dimetylofenyl, 4-metoksyfenyl, 4-chlorofenyl, 2,6-dichlorofenyl oraz sposób ich otrzymywania.The present invention relates to 1- (1-phenyimidazolidine-2-ylidene) 4-substituted thiosemicarbazide derivatives of the general formula I, where R is 2-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 2,6-dichlorophenyl and how to receive them.
W znanym stanie techniki, a w szczególności w publikacji Phosphorus Sulfur Silicon Relat. Elem. 2002, 177,195 występuje tiosemikarbazon 3-metylo-1-fenylo-5-(4-acetylobenzenosulfonamido)-pirazolu. Związek ten wykazuje aktywność przeciwbakteryjną.In the known art, and in particular in the publication Phosphorus Sulfur Silicon Relat. Elem. 2002,177,195 there is 3-methyl-1-phenyl-5- (4-acetylbenzenesulfonamido) -pyrazole thiosemicarbazone. This compound has antibacterial activity.
Będące przedmiotem wynalazku nowe pochodne stanowią związki 1-(1-fenyloimidazolidyno-2-ylideno)-4-benzylotiosemikarbazydy o wzorze ogólnym 1, gdzie R oznacza 2-metylofenyl, 2,3-dimetylofenyl, 4-metoksyfenyl, 4-chlorofenyl, 2,6-dichlorofenyl, wykazujące aktywność przeciwdrobnoustrojową a zwłaszcza wobec przetrwalnikujących warunkowo chorobotwórczych laseczek tlenowych Bacillus spp.The new derivatives of the invention are the compounds 1- (1-phenylimidazolidine-2-ylidene) -4-benzylthiosemicarbazides of the general formula I, where R is 2-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 2, 6-dichlorophenyl, showing antimicrobial activity, especially against spore-forming conditionally pathogenic aerobic bacillus spp.
Związki o wzorze ogólnym 1, gdzie R oznacza 2-metylofenyl, 2,3-dimetylofenyl, 4-metoksyfenyl, 4-chlorofenyl, 2,6-dichlorofenyl sposobem według wynalazku otrzymuje się w wyniku reakcji izotiocyjanianu benzylu, o wzorze ogólnym 3 z odpowiednio podstawionymi wolnymi pochodnymi 1-arylo-2-hydrazonoimidazolidyny o wzorze ogólnym 2, otrzymanymi z odpowiednio podstawionych jodowodorków o wzorze ogólnym 4. Reakcję prowadzi się w środowisku rozpuszczalnika organicznego, korzystnie dichlorometanu w łaźni wodno-lodowej przez okres co najmniej 5 godzin, stosując proporcje molowe 1:1. Po zakończeniu reakcji, rozpuszczalnik usuwa się przez destylację z łaźni wodnej. Wydzielony osad oczyszcza się przez krystalizację z rozpuszczalnika polarnego, korzystnie propan-2-olu.Compounds of general formula I, where R is 2-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 2,6-dichlorophenyl, are prepared by the process of the invention by reacting benzyl isothiocyanate of general formula III with appropriately substituted 1-aryl-2-hydrazonoimidazolidine free derivatives of general formula 2, obtained from appropriately substituted hydroiodides of general formula 4. The reaction is carried out in an organic solvent, preferably dichloromethane in an ice-water bath for a period of at least 5 hours using molar proportions 1 : 1. After completion of the reaction, the solvent is removed by distillation from the water bath. The separated precipitate is purified by crystallization from a polar solvent, preferably propan-2-ol.
Otrzymane według wynalazku pochodne mogą znaleźć zastosowanie do wytwarzania leków przeznaczonych do leczenia pacjentów z objawami zakażeń wywołanych warunkowo chorobotwórczymi (oportunistycznymi), przetrwalnikującymi laseczkami Gram-dodatnimi (np. Bacillus subtilis lub Bacillus cereus). Wśród tlenowych laseczek przetrwalnikujących, których przedstawicielem są wymienione gatunki, największe znaczenie mają bakterie z gatunku Bacillus anthracis, czynnik etiologiczny wąglika występującego w postaci schorzeń skórnych (czarna krosta), jelitowych i płucnych, o bardzo zróżnicowanym i trudnym do przewidzenia przebiegu. Bacillus cereus jest znanym od dawna czynnikiem etiologicznym zatruć pokarmowych, wytwarzającym entero toksyny o właściwościach wymiotnych. Laseczki tlenowe, występujące powszechnie w glebie, kurzu, wodzie lub pokarmach, które w stanie fizjologicznym są obojętne lub przyjazne dla zdrowego organizmu, mogą być w pewnych warunkach czynnikami etiologicznymi zakażeń, w tym również odzwierzęcych lub silnych toksykoinfekcjach, zwłaszcza u pacjentów z osłabioną odpornością lub z innymi chorobami układowymi. Mogą również powodować zakażenia lub zatrucia w niektórych grupach zawodowych (garbarze, hodowcy, weterynarze). Ponadto, drobnoustroje te, świadomie użyte, mogą służyć jako broń biologiczna.The derivatives obtained according to the invention may be used for the preparation of medicaments for the treatment of patients with symptoms of infections caused by conditionally pathogenic (opportunistic) spore Gram positive bacilli (e.g. Bacillus subtilis or Bacillus cereus). Among the aerobic spore-forming bacilli represented by the mentioned species, the most important are bacteria of the species Bacillus anthracis, the etiological factor of anthrax occurring in the form of skin (black pustule), intestinal and pulmonary diseases, with a very varied and unpredictable course. Bacillus cereus is a long known etiological agent of food poisoning, producing entero-toxins with emetic properties. Oxygen bacilli, commonly found in soil, dust, water or foods that are in their physiological state neutral or friendly to a healthy organism, may under certain conditions be etiological factors of infections, including zoonotic or severe toxic infections, especially in immunocompromised or weakened patients. with other systemic diseases. They can also cause infections or poisoning in certain professional groups (tanners, breeders, veterinarians). Moreover, these microorganisms, when consciously used, can serve as biological weapons.
P r z y k ł a d 1P r z k ł a d 1
1.59 g (0.005 mola) jodowodorku 1-(2-metylofenylo)-2-hydrazonoimidazolidyny rozpuszczono 33 w 50 cm3 wody destylowanej i dodano 0.4 g (0.01 mola) NaOH rozpuszczonego w 50 cm3 wody desty3 lowanej. Całość ekstrahowano trzema porcjami po 50 cm3 dichlorometanu. Następnie wysuszono bezwodnym K2CO3 i przesączono od środka suszącego. W kolbie stożkowej o pojemności 250 cm na mieszadle magnetycznym, w łaźni wodno-lodowej umieszczono wolną pochodną hydrazonową 3 w dichlorometanie i dodano roztwór 0.75 g (0.005 mola) izotiocyjanianu benzylu w 20 cm3 dichlorometanu. Całość mieszano 5 godzin. Na noc wstawiono do lodówki. Rozpuszczalnik oddestylowano na 3 wyparce rotacyjnej z łaźni wodnej, a do pozostałości dodano 20 cm3 propan-2-olu. Całość ogrzano do wrzenia. Po oziębieniu wypadł osad 1-[1-(2-metylofenylo)-imidazolidyno-2-ylideno]-4-benzylotiosemikarbazydu, wzór 1, który odsączono.1.59 g (0.005 mol) of 1- (2-methylphenyl) -2-hydrazonoimidazolidyny 33 was dissolved in 50 cm 3 of distilled water was added 0.4 g (0.01 mol) of NaOH dissolved in 50 cm 3 of water distillation 3 lated collector. It was extracted with three 50 cm 3 portions of dichloromethane. It was then dried over anhydrous K2CO3 and filtered off the drying agent. In a 250 cm conical flask with a magnetic stirrer, the free hydrazone derivative 3 in dichloromethane was placed in an ice-water bath and a solution of 0.75 g (0.005 mol) of benzyl isothiocyanate in 20 cm 3 of dichloromethane was added. The mixture was stirred for 5 hours. They were put in the refrigerator overnight. The solvent was distilled off on a 3 rotovap from a water bath, and 20 cm 3 of propan-2-ol was added to the residue. Everything was heated to boiling. On cooling, 1- [1- (2-methylphenyl) -imidazolidin-2-ylidene] -4-benzylthiosemicarbazide, Formula 1, precipitate which was filtered off.
Otrzymano 1.18 g (69.4%) osadu o t.t. 153-6°C.1.18 g (69.4%) of a solid with mp. 153-6 ° C.
Analiza elementarna dla wzoru C18H21N5S (m.cz. 339.47)Elemental analysis for the C18H21N5S formula (MW 339.47)
Obliczono: %C = 63.68 %H = 6.23 %N = 20.63 %S = 9.44Calculated:% C = 63.68% H = 6.23% N = 20.63% S = 9.44
Oznaczono: %C = 63.25 %H = 6.21 %N = 20.54 %S = 9.40Determined:% C = 63.25% H = 6.21% N = 20.54% S = 9.40
Widmo 1H NMR (D6-DMSO, δ, ppm, TMS) 1 H NMR spectrum (D6-DMSO, δ, ppm, TMS)?
9.36 (s, 1H, NH); 7.11-7.32 (m, 9H, 9CHarom); 7.04-7.07 (t, 1H, NH); 6.81- (s. 1H, 1NH); 4.62-4.63 (d, 2H, CH2aIif.); 3.63-3.67 (t, 2H, CH2imid.); 3.48-3.52 (t, 2H, CH2imid.); 2.16 (s,3H, CH3)9.36 (s, 1H, NH); 7.11-7.32 (m, 9H, 9CHarom); 7.04-7.07 (t, 1H, NH); 6.81- (s. 1H, 1NH); 4.62-4.63 (d, 2H, CH2aIif.); 3.63-3.67 (t, 2H, CH2imide); 3.48-3.52 (t, 2H, CH2imide); 2.16 (s, 3H, CH3)
Dane fizykochemiczne pozostałych pochodnych 1-(1-aryloimidazolidyno-2-ylideno)-4-benzylotiosemikarbazydu zamieszczono w Tabeli 1 w pozycjach od 1 do 4.The physicochemical data of the remaining 1- (1-arylimidazolidin-2-ylidene) -4-benzylthiosemicarbazide derivatives are presented in Table 1 in items 1 to 4.
PL 214 847 B1PL 214 847 B1
Wyniki badań aktywności mikrobiologicznej związków według wynalazku przeprowadzono na przykładzie 10 szczepów wzorcowych reprezentujących Gram- dodatnie i Gram- ujemne bakterie tlenowe. Wyniki te zamieszczono w Tabeli Nr 2. W badaniach wykorzystano 6 szczepów wzorcowych bakterii Gram-dodatnich (Sa6538-Staphylococcus aureus ATCC 6538, Sa25923-Staphylococcus aureus ATCC 25923, Se12228-Staphylococcus epidermidis ATCC 12228, Bs6638-Bacillus subtilis ATCC 6638, Bc10876-Bacillus cereus ATCC 10876, Ml10240-Micrococcus luteus ATCC 10240) oraz 4 szczepy wzorcowe bakterii Gram-ujemnych (Ec25922-Escherichia coli ATCC 25922, Kp13883Klebsiella pneumoniae ATCC 13883, Pm12453-Proteus mirabilis ATCC 12453, Pa9027Pseudomonas aeruginosa ATCC 9027). Dla każdego szczepu przygotowywano zawiesinę bakteryjną (inokulum) o gęstości wyjściowej 0.5 w skali McFarlanda - 150 x 106 CFU (Colony Forming Units)/mL w 0.85% NaCl.The results of investigating the microbial activity of the compounds according to the invention were carried out on the example of 10 reference strains representing gram-positive and gram-negative aerobic bacteria. These results are presented in Table No. 2. The study used 6 standard strains of Gram-positive bacteria (Sa6538-Staphylococcus aureus ATCC 6538, Sa25923-Staphylococcus aureus ATCC 25923, Se12228-Staphylococcus epidermidis ATCC 12228, Bs6638-Bacillus 6638-subtilis ATCC cereus ATCC 10876, Ml10240-Micrococcus luteus ATCC 10240) and 4 reference strains of gram-negative bacteria (Ec25922-Escherichia coli ATCC 25922, Kp13883Klebsiella pneumoniae ATCC 13883, Pm12453-Proteus mirabilis ATCC 12453, 90279027Pseudosa ATCC 12453, Pauginosa ATCC 12453, Pauginosa ATCC 12453. For each strain prepared bacterial suspension (inoculum) having a density output at 0.5 McFarland - 150 x 10 6 CFU (Colony Forming Units) / ml in 0.85% NaCl.
Przeciwdrobnoustrojową aktywność badanych związków oznaczano w oparciu o wartość MIC (minimal inhibitory concentration) metodą seryjnych rozcieńczeń w podłożu agarowym Mueller-Hinton II. Roztwory podstawowe badanych związków o stężeniu 50 mg/mL, przygotowane po rozpuszczeniu badanych substancji w DMSO (dimetylu sulfotlenek), dodawano w odpowiednich ilościach do upłynnionego podłoża agarowego, uzyskując podwójnie malejące stężenia końcowe badanych związków w zakresie wymaganym doświadczeniem (od 31,25 do 1000 μg/mL). Tak przygotowane płytki suszono w cieplarce w temperaturze 35 ± 2°C przez około 1 do 1,5 h, następnie dzielono na sektory i na każdy sektor nanoszono po 20 μΐ zawiesiny drobnoustrojów o gęstości 0,5 w skali McFarlanda. Płytki preinkubowano w temperaturze pokojowej przez 1,5 godziny celem wchłonięcia nadmiaru NaCl z zawiesin bakteryjnych, następnie inkubowano w temperaturze 35 ± 2°C przez 18 godzin. Po inkubacji oznaczano wartość MIC, definiowaną jako najniższe stężenie badanego związku w podłożu, przy którym wzrokowo nie obserwowano wzrostu bakterii w porównaniu z ich wzrostem na podłożu agarowym bez dodatku badanych substancji (płytka kontrolna). Nie wykazano wpływu DMSO dodanego do podłoża agarowego Mueller-Hinton II na namnażanie i wzrost badanych bakterii.The antimicrobial activity of the tested compounds was determined based on the minimal inhibitory concentration (MIC) value by serial dilution in Mueller-Hinton II agar medium. Stock solutions of the test compounds at a concentration of 50 mg / mL, prepared after dissolving the test substances in DMSO (dimethyl sulfoxide), were added in appropriate amounts to the liquefied agar medium, resulting in doubled final concentrations of the test compounds in the range required by the experiment (from 31.25 to 1000 μg / mL). The plates prepared in this way were dried in an oven at 35 ± 2 ° C for about 1 to 1.5 h, then divided into sectors and 20 µΐ of microorganism suspension with a density of 0.5 McFarland scale was applied to each sector. Plates were pre-incubated at room temperature for 1.5 hours to soak up excess NaCl from the bacterial suspensions, then incubated at 35 ± 2 ° C for 18 hours. After incubation, the MIC value was determined, defined as the lowest concentration of the test compound in the medium at which no bacterial growth was visually observed as compared to the growth on the agar medium without the addition of test substances (control plate). No effect of DMSO added to the Mueller-Hinton II agar medium on the multiplication and growth of the tested bacteria.
Zgodnie z uzyskanymi wynikami, nowo zsyntetyzowane substancje charakteryzowała zróżnicowana aktywność wobec większości bakterii Gram-dodatnich (MIC 125 do >1000 μg/mL). Wykazano potencjalną aktywność przeciwbakteryjną pochodnych 1-[1-(2,6-dichlorofenylo)-imidazolidyno-2-ylideno]-4-benzylotiosemikarbazydu, 1-[1-(2,3-dimetylofenylo)-imidazolidyno-2-ylideno]-4-benzylotiosemikarbazydu i 1-[1-(2-metylofenylo)-imidazolidyno-2-ylideno]-4-benzylotiosemikarbazydu (MIC=62,5-1000 μg/mL wobec Bacillus subtilis ATCC 6638 i Bacillus cereus ATCC 10876, co wskazuje, że badane substancje mogą być związkami wyjściowymi do syntezy pochodnych charakteryzujących się aktywnością wobec mikroorganizmów oportunistycznych. Uzyskane pochodne nie wykazywały aktywności wobec bakterii Gram- ujemnych - wartość MIC = 1000 pg/mL uzyskano tylko w przypadku związków 1-{[1-(2,3-dimetylofenyl)-oimidazolidyno-2-ylideno]-4-benzylotiosemikarbazydu i 1-[1-(2-metylofenylo)-imidazolidyno-2-ylideno]-4-benzylotiosemikarbazydu dla szczepu wzorcowego Escherichia coli ATCC 25922.According to the obtained results, the newly synthesized substances were characterized by different activity against the majority of gram-positive bacteria (MIC 125 to> 1000 μg / mL). Potential antibacterial activity of 1- [1- (2,6-dichlorophenyl) -imidazolidin-2-ylidene] -4-benzylthiosemicarbazide, 1- [1- (2,3-dimethylphenyl) -imidazolidin-2-ylidene] -4 derivatives has been demonstrated. -benzylthiosemicarbazide and 1- [1- (2-methylphenyl) -imidazolidin-2-ylidene] -4-benzylthiosemicarbazide (MIC = 62.5-1000 μg / mL against Bacillus subtilis ATCC 6638 and Bacillus cereus ATCC 10876, indicating that the tested substances may be the starting compounds for the synthesis of derivatives characterized by activity against opportunistic microorganisms.The obtained derivatives did not show activity against Gram-negative bacteria - the MIC value = 1000 pg / mL was obtained only for compounds 1 - {[1- (2,3- dimethylphenyl) -imidazolidin-2-ylidene] -4-benzylthiosemicarbazide and 1- [1- (2-methylphenyl) -imidazolidin-2-ylidene] -4-benzylthiosemicarbazide for the reference strain Escherichia coli ATCC 25922.
PL 214 847 B1PL 214 847 B1
T a b e l a 1T a b e l a 1
Dane fizykochemiczne pochodnych 1-(1-fenyloimidazolidyno-2-ylideno)-4-benzylotiosemikarbazyduPhysicochemical data of 1- (1-phenylimidazolidine-2-ylidene) -4-benzylthiosemicarbazide derivatives
T a b e l a 2T a b e l a 2
Aktywność przeciwbakteryjna pochodnych 1-(1-fenyloimidazolidyno-2-ylideno)-4-benzylotiosemikarbazydu oznaczona w oparciu o wartości MIC uzyskane metodą rozcieńczeń w podłożu agarowymAntimicrobial activity of 1- (1-phenylimidazolidin-2-ylidene) -4-benzylthiosemicarbazide derivatives based on MIC values obtained by dilution in agar medium
Skróty:Shortcuts:
Sa25923 - Staphylococcus aureus ATCC 25923Sa25923 - Staphylococcus aureus ATCC 25923
Sa6538 - Staphylococcus aureus ATCC 6538Sa6538 - Staphylococcus aureus ATCC 6538
Se12228 - Staphylococcus epidermidis ATCC 12228 Bs6638 - Bacillus subtilis ATCC 6638 Bc10876 - Bacillus cereus ATCC 10876Se12228 - Staphylococcus epidermidis ATCC 12228 Bs6638 - Bacillus subtilis ATCC 6638 Bc10876 - Bacillus cereus ATCC 10876
Ml10240 - Micrococcus luteus ATCC 10240Ml10240 - Micrococcus luteus ATCC 10240
Ec25922 - Escherichia coli ATCC 25922Ec25922 - Escherichia coli ATCC 25922
Kp13883 - Klebsiella pneumoniae ATCC 13883 Pm12453 - Proteus mirabilis ATCC 12453 Pa9027 - Pseudomonas aeruginosa ATCC 9027Kp13883 - Klebsiella pneumoniae ATCC 13883 Pm12453 - Proteus mirabilis ATCC 12453 Pa9027 - Pseudomonas aeruginosa ATCC 9027
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