MD4883C1 - Bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate, exhibiting bacteriostatic activity against Streptococcus pneumoniae bacteria species - Google Patents
Bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate, exhibiting bacteriostatic activity against Streptococcus pneumoniae bacteria speciesInfo
- Publication number
- MD4883C1 MD4883C1 MDA20220028A MD20220028A MD4883C1 MD 4883 C1 MD4883 C1 MD 4883C1 MD A20220028 A MDA20220028 A MD A20220028A MD 20220028 A MD20220028 A MD 20220028A MD 4883 C1 MD4883 C1 MD 4883C1
- Authority
- MD
- Moldova
- Prior art keywords
- pyridin
- streptococcus pneumoniae
- methylidene
- cyclohexyl
- carbamohydrazonthioato
- Prior art date
Links
- 241000193998 Streptococcus pneumoniae Species 0.000 title claims abstract description 16
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 title claims abstract description 15
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 title claims abstract description 14
- 230000003385 bacteriostatic effect Effects 0.000 title claims abstract description 8
- 230000001747 exhibiting effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 241000894006 Bacteria Species 0.000 claims description 7
- 239000003814 drug Substances 0.000 abstract description 16
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229910052759 nickel Inorganic materials 0.000 abstract description 3
- 230000035755 proliferation Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000004599 antimicrobial Substances 0.000 abstract description 2
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- 230000000845 anti-microbial effect Effects 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 6
- 229960000723 ampicillin Drugs 0.000 description 6
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- -1 aliphatic alcohols Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- OINIXPNQKAZCRL-UHFFFAOYSA-L nickel(2+);diacetate;tetrahydrate Chemical compound O.O.O.O.[Ni+2].CC([O-])=O.CC([O-])=O OINIXPNQKAZCRL-UHFFFAOYSA-L 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical group CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-M ampicillin(1-) Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-M 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OLQDGRQSFFQIIZ-UHFFFAOYSA-N copper;1h-imidazole Chemical compound [Cu].C1=CNC=N1 OLQDGRQSFFQIIZ-UHFFFAOYSA-N 0.000 description 1
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 229940042396 direct acting antivirals thiosemicarbazones Drugs 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 150000002815 nickel Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- GCSHUYKULREZSJ-UHFFFAOYSA-N phenyl(pyridin-2-yl)methanone Chemical compound C=1C=CC=NC=1C(=O)C1=CC=CC=C1 GCSHUYKULREZSJ-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N thiosemicarbazide group Chemical group NNC(=S)N BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- 150000003584 thiosemicarbazones Chemical class 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Invenţia se referă la chimie şi medicină şi anume, la un compus coordinativ de nichel biologic activ, din clasa tiosemicarbazonaţilor metalelor de tranziţie. Acest complex manifestă activitate bacteriostatică înaltă faţă de bacteriile din specia Streptococcus pneumoniae şi datorită acestor proprietăţi poate găsi aplicare în medicină şi veterinărie în calitate de preparat antimicrobian. The invention refers to chemistry and medicine, namely, to a coordinating compound of biologically active nickel, from the class of thiosemicarbazonates of transition metals. This complex exhibits high bacteriostatic activity against bacteria of the Streptococcus pneumoniae species and due to these properties it can find application in medicine and veterinary medicine as an antimicrobial preparation.
Streptococcus pneumoniae sunt bacterii gram-pozitive, care provoacă meningită, otită, sinuzită, pneumonii, endocardită, artrită septică, peritonită primară etc. În practica medicală şi veterinară pentru tratarea şi profilaxia bolilor provocate de microorganismul sus-numit se utilizează medicamentul Ampicilina [1] - antibiotic semisintetic cu formula: Streptococcus pneumoniae are gram-positive bacteria that cause meningitis, otitis, sinusitis, pneumonia, endocarditis, septic arthritis, primary peritonitis, etc. In medical and veterinary practice, for the treatment and prophylaxis of diseases caused by the above-mentioned microorganism, the drug Ampicillin [1] is used - a semi-synthetic antibiotic with the formula:
Acest medicament inhibă creşterea şi multiplicarea bacteriilor din specia Streptococcus pneumoniae la concentraţia 0,5 µg/mL, însă nu poate fi utilizat în cazurile, când este necesară o activitate antimicrobiană mai înaltă a preparatului faţă de acest microorganism. This medicine inhibits the growth and multiplication of Streptococcus pneumoniae bacteria at a concentration of 0.5 µg/mL, but it cannot be used in cases where a higher antimicrobial activity of the preparation against this microorganism is required.
Din toţi compuşii chimici descrişi în literatura de specialitate, care conţin în componenţa sa fragmentul tiosemicarbazidic şi care inhibă creşterea şi multiplicarea bacteriilor din specia Streptococcus pneumoniae, cel mai înalt efect antimicrobian a fost obţinut în cazul hidratului de nitrato-{N-(prop-2-en-1-il)-N'-[1-(piridin-2-il)-etiliden]carbamohidrazontioato}imidazolcupru [2] (analogul structural) cu formula: Of all the chemical compounds described in the specialized literature, which contain in their composition the thiosemicarbazide fragment and which inhibit the growth and multiplication of bacteria of the Streptococcus pneumoniae species, the highest antimicrobial effect was obtained in the case of nitrato-{N-(prop-2) hydrate -en-1-yl)-N'-[1-(pyridin-2-yl)-ethylidene]carbamohydrazonthioato}imidazole copper [2] (the structural analogue) with the formula:
Acest compus după activitatea bacteriostatică faţă de bacteriile din specia Streptococcus pneumoniae depăşeşte de 16,7 ori caracteristicile respective ale Ampicilinei, utilizate actualmente în medicină pentru tratarea şi profilaxia bolilor provocate de bacteria dată. This compound, after its bacteriostatic activity against bacteria of the Streptococcus pneumoniae species, exceeds 16.7 times the respective characteristics of Ampicillin, currently used in medicine for the treatment and prophylaxis of diseases caused by this bacterium.
Dezavantajul hidratului de nitrato-{N-(prop-2-en-1-il)-N'-[1-(piridin-2-il)-etiliden]carbamohidrazontioato}imidazolcupru constă în faptul, că el nu posedă o activitate antimicrobiană suficient de înaltă şi din această cauză nu a găsit o aplicare în medicină sau veterinărie. The disadvantage of copper nitrato-{N-(prop-2-en-1-yl)-N'-[1-(pyridin-2-yl)-ethylidene]carbamohydrazonthioato}imidazole hydrate is that it does not possess antimicrobial activity high enough and for this reason it did not find an application in medicine or veterinary medicine.
Problema pe care o rezolvă prezenta invenţie constă în extinderea arsenalului de inhibitori ai bacteriilor din specia Streptococcus pneumoniae cu activitate antimicrobiană înaltă. The problem that the present invention solves consists in expanding the arsenal of inhibitors of Streptococcus pneumoniae bacteria with high antimicrobial activity.
Esenţa invenţiei constă în sinteza şi utilizarea în calitate de inhibitor al proliferării bacteriilor din specia Streptococcus pneumoniae a hidratului de bis{N-ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazontioato}nichel cu formula: The essence of the invention consists in the synthesis and use as an inhibitor of the proliferation of Streptococcus pneumoniae bacteria of bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate with the formula:
Structura cristalină a complexului dat, proprietăţile lui şi metoda de sinteză nu sunt descrise în literatura de specialitate. The crystal structure of the given complex, its properties and the synthesis method are not described in the specialized literature.
Rezultatul tehnic al invenţiei constă în obţinerea compusului coordinativ, care manifestă activitate bacteriostatică faţă de bacteriile din specia Streptococcus pneumoniae, ce depăşeşte de 261,8 ori activitatea medicamentului Ampicilina utilizată în medicină şi de 15,7 ori depăşeşte activitatea antimicrobiană a analogului său structural. The technical result of the invention consists in obtaining the coordinating compound, which exhibits bacteriostatic activity against Streptococcus pneumoniae bacteria, which exceeds 261.8 times the activity of the drug Ampicillin used in medicine and 15.7 times the antimicrobial activity of its structural analogue.
Rezultatul tehnic obţinut se datorează faptului, că în compusul propus în invenţie se realizează o combinare nouă de legături chimice deja cunoscute. The technical result obtained is due to the fact that in the compound proposed in the invention a new combination of already known chemical bonds is achieved.
Hidratul de bis{N-ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazontioato}nichel revendicat se obţine la interacţiunea soluţiilor etanolice fierbinţi ale tetrahidratului diacetatului de nichel(II) şi N-ciclohexil-N'-[(piridin-2-il)-metiliden]carbamohidrazontioatului [N(4)-ciclohexiltiosemicarbazonei 2-formilpiridinei], luate în raport molar 1:2. Reacţia decurge în 3 ore la reflux, conform următoarei scheme de sinteză: The claimed bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate is obtained by the interaction of hot ethanolic solutions of nickel(II) diacetate tetrahydrate and N-cyclohexyl-N'-[( pyridin-2-yl)-methylidene]carbamohydrazonethioate [N(4)-cyclohexylthiosemicarbazone 2-formylpyridine], taken in a 1:2 molar ratio. The reaction proceeds in 3 hours at reflux, according to the following synthesis scheme:
Mecanismul reacţiei date constă în deprotonizarea grupei tiolice ale tiosemicarbazonei în prezenţa acetat-ionului, care joacă rolul de acceptor de protoni. Astfel fiind obţinuţi, doi anioni de N-ciclohexil-N'-[(piridin-2-il)-metiliden]carbamohidrazontioatului, coordinează la ionul de nichel(2+) ca liganzi N,N,S-tridentaţi monodeprotonaţi, formând complex de tip neelectrolit cu geometria atomului central octaedrică. The mechanism of the given reaction consists in the deprotonation of the thiol group of the thiosemicarbazone in the presence of the acetate ion, which plays the role of proton acceptor. Thus obtained, two anions of N-cyclohexyl-N'-[(pyridin-2-yl)-methylidene]carbamohydrazonethioate, coordinate to the nickel(2+) ion as monodeprotonated N,N,S-tridentate ligands, forming a complex of non-electrolyte type with octahedral central atom geometry.
Procedeul de obţinere al compusului declarat este simplu în executare, substanţele iniţiale sunt accesibile, randamentul constituie 76% faţă de cel teoretic calculat. N-Ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazontioatul (N(4)-ciclohexiltiosemicarbazona 2-formilpiridinei) se obţine după metodica descrisă în literatură (West D. X., Billeh I. S., Jasinski J. P., Jasinski J. M., Butcher R. J. Complexes of N(4)-cyclohexylsemicarbazones, N(4)-cyclohexylthiosemicarbazones derived 2-formyl-, 2-acetyl- and 2-benzoylpyridine. Transition Met. Chem., 1998, vol. 23, p. 209-214). Complexul sintetizat are culoarea verde-închisă, este stabil în contact cu aerul, puţin solubil în apă şi alcooli alifatici, solubil în N,N-dimetilformamidă şi dimetilsulfoxid, practic insolubil în eter. The procedure for obtaining the declared compound is simple in execution, the initial substances are accessible, the yield is 76% compared to the theoretically calculated one. N-Cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioate (N(4)-cyclohexylthiosemicarbazone 2-formylpyridine) is obtained according to the method described in the literature (West D. X., Billeh I. S., Jasinski J. P., Jasinski J. M., Butcher R. J. Complexes of N(4)-cyclohexylsemicarbazones, N(4)-cyclohexylthiosemicarbazones derived 2-formyl-, 2-acetyl- and 2-benzoylpyridine. Transition Met. Chem., 1998, vol. 209-214). The synthesized complex has a dark green color, is stable in contact with air, slightly soluble in water and aliphatic alcohols, soluble in N,N-dimethylformamide and dimethylsulfoxide, practically insoluble in ether.
Exemplu de obţinere a hidratului de bis{N-ciclohexil-N'-[(piridin-2-il)-metiliden]carbamohidrazontioato}nichel. Example of obtaining bis{N-cyclohexyl-N'-[(pyridin-2-yl)-methylidene]carbamohydrazonthioato}nickel hydrate.
Se amestecă 0,2488 g (1 mmol) de tetrahidrat al diacetatului de nichel(2+) cu 10 mL de soluţie etanolică, care conţine 0,5247 g (2 mmol) N-ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazonotioat (N(4)-ciclohexiltiosemicarbazona 2-formilpiridinei). Amestecul obţinut se omogenizează şi se refluxează 3 ore. La răcire din soluţie se depun cristale mărunte de culoare verde-închisă, care sunt filtrate prin filtru de sticlă, spălate cu etanol, eter şi uscate la aer. Se obţine 0,4552 g (η= 76%) de compus declarat. Solubilitatea complexului în etanol alcătuieşte 10 mg în 2 mL; în DMSO/DMF = 10 mg - 1 mL (25°C). Mix 0.2488 g (1 mmol) of nickel(2+) diacetate tetrahydrate with 10 mL of ethanolic solution, which contains 0.5247 g (2 mmol) of N-cyclohexyl-N'-[(pyridine-2- yl)methylidene]carbamohydrazonothioate (N(4)-cyclohexylthiosemicarbazone 2-formylpyridine). The obtained mixture is homogenized and refluxed for 3 hours. Upon cooling, small dark green crystals are deposited from the solution, which are filtered through a glass filter, washed with ethanol, ether and dried in air. 0.4552 g (η= 76%) of the declared compound is obtained. The solubility of the complex in ethanol is 10 mg in 2 mL; in DMSO/DMF = 10 mg - 1 mL (25°C).
Analiza elementală (%) pentru C26H36N8NiOS2 (calculat/determinat ): C -52,09 / 52,10%; H - 6,05 / 6,09%; N -18,69 / 18,71%; Ni -9,79 / 9,81%; S -10,70 / 10,72%. Conductivitatea specifică (σ în EtOH-H2O): 6,4 µS·cm-1. În baza analizei conductivităţii specifice putem concluziona că compusul obţinut este neelectrolit. Elemental analysis (%) for C26H36N8NiOS2 (calculated/determined): C -52.09 / 52.10%; H - 6.05 / 6.09%; N -18.69 / 18.71%; Ni -9.79 / 9.81%; S -10.70 / 10.72%. Specific conductivity (σ in EtOH-H2O): 6.4 µS·cm-1. Based on the specific conductivity analysis, we can conclude that the obtained compound is non-electrolyte.
FT-IR, (νmax, cm-1): 3203, m, lat, (N4-H); 3054, s, (C-H, Py); 2922, m, as, (C-H, din CH2 al Cy); 2849, m, si, (C-H, din CH2 al Cy); 1597, s, (C=N, azometin); 1492, m, lat, (δ, N-H); 1469, s; 1448, s; 1395, m, lat; 1366, s; 1336, s; 1270, s; 1250, s; 1237, s; 1211, m; 1186, s; 1147, m; 1129, m; 1104, s; 1083, m, (N-N); 973, s; 882, p; 768, m; 744, m; 675, m; 634, m; 568, s; 519, s; 457, s; 424. FT-IR, (νmax, cm-1): 3203, m, lat, (N4-H); 3054, s, (C-H, Py); 2922, m, as, (C-H, from CH2 of Cy); 2849, m, si, (C-H, from CH2 of Cy); 1597, s, (C=N, azomethine); 1492, m, wide, (δ, N-H); 1469, s; 1448, s; 1395, m, wide; 1366, s; 1336, s; 1270, s; 1250, s; 1237, s; 1211, m; 1186, s; 1147, m; 1129, m; 1104, s; 1083, m, (N-N); 973, s; 882, p; 768, m; 744, m; 675, m; 634, m; 568, s; 519, s; 457, s; 424.
La evaporarea filtratului la temperatura camerei au fost obţinute monocristale ale hidratului de bis{N-ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazontioato}nichel, structura cărora a fost stabilită cu ajutorul analizei cu raze X. Măsurătorile cristalografice au fost efectuate utilizând un difractometru de tip Xcalibur E CCD Oxford-Diffraction cu monocromator de grafit înzestrat cu sursă de raze X de tip Mo-Kα. Procedeele de determinare a parametrilor celulei elementare şi de integrare a datelor experimentale au fost efectuate cu ajutorul setului de programe “CrysAlis package Oxford Diffraction”. Pentru structura cercetată soluţia a fost determinată prin metoda directă cu ajutorul programului SHELXS-97 şi fitată prin metoda pătratelor minimale în cadrul programului SHELXL-97 în varianta anizotropică pentru toţi atomii cu masă molară mai mare decât a atomului de hidrogen. Atomii de hidrogen au fost introduşi în poziţii idealizate (dCH = 0,96 Å) utilizând modelul pivot cu fixarea parametrilor izotropici de deplasare la valoarea de 120% faţă de valorile respective ale atomilor de carbon cu care sunt legaţi. Formula empirică a compusului investigat este C26H36N8NiOS2, grupa spaţială P 21/n, parametrii celulei elementare, [Å]: a = 12,8803(10); b = 12,7180(14), c = 46,701(6); α = 90°, β = 96,881(9) °, γ = 90°; volumul celulei 7595,03 Å3. Upon evaporation of the filtrate at room temperature, single crystals of bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate were obtained, the structure of which was established with the help of X-ray analysis. Crystallographic measurements were performed using an Xcalibur E CCD Oxford-Diffraction diffractometer with a graphite monochromator equipped with a Mo-Kα X-ray source. The procedures for determining the parameters of the elementary cell and integrating the experimental data were carried out with the help of the "CrysAlis package Oxford Diffraction" program set. For the investigated structure, the solution was determined by the direct method using the SHELXS-97 program and fitted by the least squares method within the SHELXL-97 program in the anisotropic version for all atoms with a molar mass greater than that of the hydrogen atom. The hydrogen atoms were introduced in idealized positions (dCH = 0.96 Å) using the pivot model with the isotropic displacement parameters fixed at the value of 120% compared to the respective values of the carbon atoms with which they are linked. The empirical formula of the investigated compound is C26H36N8NiOS2, space group P 21/n, unit cell parameters, [Å]: a = 12.8803(10); b = 12.7180(14), c = 46.701(6); α = 90°, β = 96.881(9)°, γ = 90°; cell volume 7595.03 Å3.
A fost stabilit (figură - Structura cristalină a compusului revendicat cu notarea parţială a atomilor, atomii de hidrogen au fost omişi pentru claritate), că compusul investigat reprezintă un monomer, în care poliedrul coordinativ al generatorului de complex reprezintă o bipiramidă tetragonală distorsionată. În sfera internă a atomului central se află două molecule de tiosemicarbazone tridentate, care coordinează la atomul de nichel prin atomii de azot piridinici [d(Ni-N) = 2,053 şi 2,117 Å], azometinici [d(Ni-N) = 1,998 şi 2,003 Å] şi atomii de sulf în forma tiolică deprotonată [d(Ni - S) = 2,403 şi 2,407 Å], formând câte două metalocicluri din cinci atomi. Legătura dublă în molecula de izotiosemicarbazonă coordinată este localizată între atomii de carbon şi azot N4 [d(C - N4) = 1,304 şi 1,370 Å, iar d(C - N2) = 1,506 şi 1,374 Å]. Alte distanţe interatomice şi unghiuri de valenţă sunt standarde pentru compuşii din această clasă. În sfera externă a complexului se află o moleculă de apă de hidratare. Structura cristalului este stabilizată de numeroasele legături de hidrogen cu participarea acestei molecule de apă. It was established (figure - Crystal structure of the claimed compound with partial notation of atoms, hydrogen atoms omitted for clarity), that the investigated compound represents a monomer, in which the coordination polyhedron of the complex generator represents a distorted tetragonal bipyramid. In the inner sphere of the central atom there are two molecules of tridentate thiosemicarbazones, which coordinate to the nickel atom through the pyridinic nitrogen atoms [d(Ni-N) = 2.053 and 2.117 Å], azomethine [d(Ni-N) = 1.998 and 2.003 Å] and the sulfur atoms in the deprotonated thiol form [d(Ni - S) = 2.403 and 2.407 Å], forming two five-atom metallocycles. The double bond in the coordinated isothiosemicarbazone molecule is located between the carbon and nitrogen atoms N4 [d(C - N4) = 1.304 and 1.370 Å, and d(C - N2) = 1.506 and 1.374 Å]. Other interatomic distances and valence angles are standard for compounds in this class. In the outer sphere of the complex is a molecule of water of hydration. The crystal structure is stabilized by numerous hydrogen bonds with the participation of this water molecule.
Astfel, în baza rezultatelor analizei elementelor, cercetărilor fizico-chimice şi a analizei cu raze X a fost stabilită compoziţia şi structura compusului declarat. Thus, based on the results of element analysis, physico-chemical research and X-ray analysis, the composition and structure of the declared compound was established.
Cercetarea activităţii antimicrobiene a hidratului de bis{N-ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazontioato}nichel declarat a fost efectuată în mediu nutritiv lichid [bulion peptonat din carne de 2%, pH 7,0] prin metoda diluţiilor succesive. În calitate de cultură de referinţă în experimentul in vitro a fost folosită tulpina standard de Streptococcus pneumoniae ATCC 6305. Dizolvarea substanţei studiate în N,N-dimetilformamidă, cultivarea microorganismului, obţinerea suspensiei, determinarea concentraţiei minime de inhibare (CMI) a fost efectuată după metoda standard descrisă în literatură. Investigation of the antimicrobial activity of the declared bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate was performed in liquid nutrient medium [2% meat peptonate broth, pH 7.0] by the method of successive dilutions. As a reference culture in the in vitro experiment, the standard strain of Streptococcus pneumoniae ATCC 6305 was used. Dissolving the studied substance in N,N-dimethylformamide, cultivating the microorganism, obtaining the suspension, determining the minimum inhibition concentration (MIC) was performed according to the method standard described in the literature.
Rezultatele studiului activităţii antimicrobiene a hidratului de bis{N-ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazontioato}nichel declarat sunt prezentate în tabel, din care se observă, că compusul declarat posedă activitate bacteriostatică la concentraţia 0,00191 µg/mL. Pentru comparaţie, în acelaşi tabel, sunt prezentate rezultatele cercetării activităţii antimicrobiene caracteristice Ampicilinei şi nitrato-{N-(prop-2-en-1-il)-N'-[1-(piridin-2-il)-etiliden]carbamohidrazontioato}imidazolcupru - analogului structural al compusului declarat. Datele experimentale obţinute demonstrează, că hidratul de bis{N-ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazontioato}nichel în calitate de inhibitor al proliferării bacteriilor din specia Streptococcus pneumoniae, manifestă o activitate bacteriostatică faţă de aceste bacterii, ce depăşeşte de 261,8 ori activitatea medicamentului Ampicilina utilizată în medicină şi de 15,7 ori depăşeşte activitatea antimicrobiană a analogului său structural [2]. The results of the study of the antimicrobial activity of the declared bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate are presented in the table, from which it can be seen that the declared compound possesses bacteriostatic activity at a concentration of 0, 00191 µg/mL. For comparison, in the same table, the results of the research of the antimicrobial activity characteristic of Ampicillin and nitrato-{N-(prop-2-en-1-yl)-N'-[1-(pyridin-2-yl)-ethylidene]carbamohydrazonthioato are presented copper imidazole - the structural analogue of the declared compound. The obtained experimental data demonstrate that bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate as an inhibitor of the proliferation of Streptococcus pneumoniae bacteria, exhibits a bacteriostatic activity against these bacteria , which exceeds 261.8 times the activity of the drug Ampicillin used in medicine and 15.7 times the antimicrobial activity of its structural analogue [2].
Proprietăţile depistate ale compusului nominalizat prezintă interes din punct de vedere al extinderii arsenalului de remedii antimicrobiene şi poate fi utilizat în cazul rezistenţei bacteriilor din specia Streptococcus pneumoniae faţă de medicamentele tradiţionale. The detected properties of the nominated compound are of interest from the point of view of expanding the arsenal of antimicrobial remedies and can be used in the case of resistance of Streptococcus pneumoniae bacteria to traditional drugs.
Tabel Table
Concentraţia minimă de inhibare (CMI) a compusului declarat faţă de bacteriile din specia Streptococcus pneumoniae ATCC 6305 în comparaţie cu Ampicilina şi analogul structural, µg/mL The minimum inhibitory concentration (MIC) of the declared compound against the bacteria of the species Streptococcus pneumoniae ATCC 6305 in comparison with Ampicillin and the structural analogue, µg/mL
№ Compusul CMI 1 Compuşii iniţialia) ˃10 000,0 2 Ampicilina 0,5 3 Hidratul de nitrato-{N-(prop-2-en-1-il)-N'-[1-(piridin-2-il)-etiliden]carbamohidrazontioato}imidazolcupru (analogul structural) 0,03 4 Hidratul de bis{N-ciclohexil-N'-[(piridin-2-il)metiliden]carbamohidrazontioato}nichel 0,00191 № CMI compound 1 Initial compounds) ˃10 000.0 2 Ampicillin 0.5 3 Nitrato-{N-(prop-2-en-1-yl)-N'-[1-(pyridin-2-yl) hydrate -ethylidene]carbamohydrazonthioato}imidazolecopper (structural analogue) 0.03 4 Bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate 0.00191
*Notă: a) Compuşii iniţiali - Ni(CH3COO)2·4H2O. şi N-ciclohexil-N'-[(piridin-2-il)-metiliden]carbamohidrazontioat [N(4)-ciclohexiltiosemicarbazona 2-formilpiridinei]. *Note: a) Initial compounds - Ni(CH3COO)2·4H2O. and N-cyclohexyl-N'-[(pyridin-2-yl)-methylidene]carbamohydrazonethioate [2-formylpyridine N(4)-cyclohexylthiosemicarbazone].
1. Машковский М. Д. Лекарственные средства. М: Новая Волна, 2012, p. 772-773. 1. Mashkovsky M. D. Medicines. М: Новая Волна, 2012, p. 772-773.
2. MD 4621 B1 2019.02.28 2. MD 4621 B1 2019.02.28
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MDA20220028A MD4883C1 (en) | 2022-05-26 | 2022-05-26 | Bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate, exhibiting bacteriostatic activity against Streptococcus pneumoniae bacteria species |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MDA20220028A MD4883C1 (en) | 2022-05-26 | 2022-05-26 | Bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate, exhibiting bacteriostatic activity against Streptococcus pneumoniae bacteria species |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| MD20220028A2 MD20220028A2 (en) | 2023-11-30 |
| MD4883B1 MD4883B1 (en) | 2024-01-31 |
| MD4883C1 true MD4883C1 (en) | 2024-08-31 |
Family
ID=88969452
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MDA20220028A MD4883C1 (en) | 2022-05-26 | 2022-05-26 | Bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate, exhibiting bacteriostatic activity against Streptococcus pneumoniae bacteria species |
Country Status (1)
| Country | Link |
|---|---|
| MD (1) | MD4883C1 (en) |
-
2022
- 2022-05-26 MD MDA20220028A patent/MD4883C1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| MD20220028A2 (en) | 2023-11-30 |
| MD4883B1 (en) | 2024-01-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lopez-Sandoval et al. | Synthesis, structure and biological activities of cobalt (II) and zinc (II) coordination compounds with 2-benzimidazole derivatives | |
| Smoleński et al. | New water-soluble polypyridine silver (I) derivatives of 1, 3, 5-triaza-7-phosphaadamantane (PTA) with significant antimicrobial and antiproliferative activities | |
| Rodríguez-Argüelles et al. | Complexes of 2-thiophenecarbonyl and isonicotinoyl hydrazones of 3-(N-methyl) isatin.: A study of their antimicrobial activity | |
| Balan et al. | Novel 2‐formylpyridine 4‐allyl‐S‐methylisothiosemicarbazone and Zn (II), Cu (II), Ni (II) and Co (III) complexes: Synthesis, characterization, crystal structure, antioxidant, antimicrobial and antiproliferative activity | |
| Lapasam et al. | Antimicrobial selectivity of ruthenium, rhodium, and iridium half sandwich complexes containing phenyl hydrazone Schiff base ligands towards B. thuringiensis and P. aeruginosa bacteria | |
| Bharty et al. | Mn (II), Ni (II), Cu (II), Zn (II), Cd (II), Hg (II) and Co (II) complexes of 1-phenyl-1H-tetrazole-5-thiol: Synthesis, spectral, structural characterization and thermal studies | |
| Yuoh et al. | Synthesis, Crystal Structure, and Antimicrobial Properties of a Novel 1‐D Cobalt Coordination Polymer with Dicyanamide and 2‐Aminopyridine | |
| MD4133C1 (en) | [(2-Carbamotioylhydrazone)propionato(2-)]-(4-aminobenzenesulfonamide)copper, manifesting antimicrobial activity against bacteria of the genus Bacillus cereus | |
| Ye et al. | Syntheses, characterizations and biological activities of two Cu (II) complexes with acylhydrazone ligand bearing pyrrole unit | |
| Bazhina et al. | Zinc (II) and copper (II) complexes with N-substituted imines derived from 4-amino-1, 2, 4-triazole: Synthesis, crystal structure, and biological activity | |
| Li et al. | Design, synthesis, and biological evaluation of dinuclear bismuth (III) complexes with Isoniazid-derived Schiff bases | |
| Jaćimović et al. | Synthesis and characterization of copper, nickel, cobalt, zinc complexes with 4-nitro-3-pyrazolecarboxylic acid ligand | |
| Gulea et al. | Synthesis, structure and biological activity of coordination compounds of copper, nickel, cobalt, and iron with ethyl N'-(2-hydroxybenzylidene)-N-prop-2-en-1-ylcarbamohydrazonothioate | |
| Mahalingam et al. | New Ru (II)–DMSO complexes of ON/SN chelates: Synthesis, behavior of Schiff bases towards hydrolytic cleavage of CN bond, electrochemistry and biological activities | |
| Çakmakçı et al. | Cobalt (II), nickel (II), palladium (II) and zinc (II) metallothiosemicarbazones: Synthesis, characterization, X-ray structures and biological activity | |
| Gruia et al. | Synthesis, characterization and crystal structures of Cd (II) and Zn (II) complexes with 2, 2′-biimidazole | |
| Gulea et al. | Synthesis, Structure, and Biological Activity of Copper and Cobalt Coordination Compounds with Substituted 2-(2-Hydroxybenzylidene)-N-(prop-2-en-1-yl) hydrazinecarbothioamides | |
| MD4883C1 (en) | Bis{N-cyclohexyl-N'-[(pyridin-2-yl)methylidene]carbamohydrazonthioato}nickel hydrate, exhibiting bacteriostatic activity against Streptococcus pneumoniae bacteria species | |
| Luo et al. | Synthesis, characterization and bioactivity of four novel trinuclear copper (II) and nickel (II) complexes with pentadentate ligands derived from N-acylsalicylhydrazide | |
| MD4132C1 (en) | Di(µ-S)-bis{chloro-[phenyl(pyridine-2-yl)methanone-thiosemicarbazonato(1-)]-copper} manifesting the property of inhibiting the proliferation of mammary cancer T-47D cells | |
| Senthilkumar et al. | Monomeric mixed cadmium-2, 2′-dipyridylamine complex derived from ferrocenecarboxylic acid: Structural, electrochemical and biological studies | |
| MD4832C1 (en) | Bis{[(cyclohexylamino)phenyl(pyridin-2-yl)methylidenehydrazono]methanesulfinato-N,N',S}iron(III) nitrate, which exhibits antimicrobial activity against bacteria of the species Bacillus cereus | |
| MD4842C1 (en) | Nitrato-{N-(prop-2-en-1-yl)-N'-[1-(pyridin-2-yl)-ethylidene]carbamohydrazonothioato}copper, exhibiting antimicrobial activity against bacteria of Streptococcus pneumoniae species | |
| Altamimi et al. | Synthesis, Structure Analysis and Antibacterial Activity of Zn (II) and Co (III) Complexes | |
| MD4462C1 (en) | Chloro-{N-(3,4-dimethylphenyl)-2-[1-(2-hydroxyphenyl)ethylidene]-hydrazinecarbothioamido(1-)}nickel, exhibiting antimicrobial activity against Klebsiella pneumoniae and Pseudomonas aeruginosa bacterial species |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG4A | Patent for invention issued |