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Synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yakagadzirwa uye yakashandiswa kugadzira mhando dzakasiyana dzemakemikari anoshanda zvakanyanya eheterocyclic kuburikidza nekuita kwayo ne nitrogen nucleophiles dzakasiyana-siyana. Maumbirwo emusanganiswa wega wega weheterocyclic wakagadzirwa akanyatsotsanangurwa uchishandisa spectroscopic uye elemental analysis. Gumi pamakemikari matsva gumi nematatu eheterocyclic akaratidza kushanda kwakanaka kurwisa mabhakitiriya asingapindi mishonga yakawanda (MRSA). Pakati pawo, makemikari 6, 7, 10, 13b, uye 14 akaratidza kushanda kwakanyanya kwebhakitiriya nekudzivirira nzvimbo dziri pedyo ne4 cm. Zvisinei, zvidzidzo zve molecular docking zvakaratidza kuti makemikari aya aive nehukama hwakasiyana hwekubatanidza ne penicillin-binding protein 2a (PBP2a), chinangwa chikuru chekudzivirira MRSA. Mamwe makemikari akadai se7, 10 uye 14 akaratidza hukama hwakakwira hwekubatanidza uye kugadzikana kwekubatana panzvimbo inoshanda yePBP2a zvichienzaniswa ne co-crystallized quinazolinone ligand. Kusiyana neizvi, macompounds 6 ne13b aive nemazinga akaderera edocking asi achiri kuratidza kushanda kwakakura kweantibacterial, nepo compound 6 iine MIC yakaderera (9.7 μg/100 μL) uye MBC (78.125 μg/100 μL). Kuongororwa kwedocking kwakaratidza kudyidzana kwakakosha kunosanganisira hydrogen bonding uye π-stacking, kunyanya nema residues akadai saLys 273, Lys 316 naArg 298, ayo akaonekwa seanoshanda ne co-crystallized ligand mu crystal structure yePBP2a. Aya ma residues akakosha kune enzymatic activity yePBP2a. Mhedzisiro iyi inoratidza kuti macompounds akagadzirwa anogona kushanda semishonga inorwisa MRSA, zvichiratidza kukosha kwekubatanidza mamolecular docking ne bioassays kuti uone nzira dzinoshanda dzekurapa.
Mumakore mashoma ekutanga ezana rino remakore, kuedza kutsvagisa kwaive kwakatarisana nekugadzira nzira itsva uye dziri nyore dzekugadzira masisitimu matsva e heterocyclic ane basa rekuuraya utachiona uchishandisa zvinhu zvekutanga zviripo zviri nyore.
Acrylonitrile moieties inoonekwa sezvinhu zvakakosha zvekutanga pakugadzira masisitimu mazhinji anoshamisa eheterocyclic nekuti imakemikari anobatsira zvikuru. Uyezve, 2-cyanoacryloyl chloride derivatives yakashandiswa zvakanyanya mumakore achangopfuura mukugadzira nekugadzirisa zvigadzirwa zvakakosha mumunda wekushandiswa kwemishonga, zvakaita semishonga yepakati1,2,3, precursors ye anti-HIV, antiviral, anticancer, antibacterial, antidepressant uye antioxidant agents4,5,6,7,8,9,10. Munguva pfupi yapfuura, kushanda zvakanaka kweanthracene nemidziyo yayo, kusanganisira antibiotic yavo, anticancer11,12, antibacterial13,14,15 uye zvipembenene16,17, kwakakwezva kutariswa kukuru18,19,20,21. Mishonga inorwisa mabhakitiriya ine acrylonitrile neanthracene moieties inoratidzwa muMifananidzo 1 ne2.
Sekureva kweWorld Health Organization (WHO) (2021), kusakwanisa kurwisa mabhakitiriya (AMR) idambudziko guru pasi rose kuhutano nebudiriro22,23,24,25. Varwere havagone kurapwa, zvichikonzera kugara kwenguva refu muchipatara uye kudiwa kwemishonga inodhura, pamwe nekuwedzera kwekufa nekuremara. Kushaikwa kwemishonga inoshanda inorwisa mabhakitiriya kunowanzoita kuti hutachiona hwakasiyana-siyana husashande zvakanaka, kunyanya panguva yekurapa nechemotherapy nekuvhiyiwa kukuru kukundikane.
Sekureva kwemushumo weWorld Health Organisation 2024, methicillin-resistant Staphylococcus aureus (MRSA) neE. coli zvinosanganisirwa mune zvinotapukira zvinokosheswa. Mabhakitiriya ese ari maviri haadi mishonga inorwisa mabhakitiriya yakawanda, saka anomiririra hutachiona hwakaoma kurapa nekudzora, uye pane chikonzero chekukurumidzira chekugadzira mishonga mitsva uye inoshanda inorwisa mabhakitiriya kugadzirisa dambudziko iri. Anthracene nezvinobuda mairi mishonga inorwisa mabhakitiriya inozivikanwa zvikuru inogona kushanda pabhakitiriya yeGram-positive neGram-negative. Chinangwa chechidzidzo ichi ndechekugadzira mishonga mitsva inogona kurwisa mabhakitiriya aya ane njodzi kuhutano.
Sangano reWorld Health Organization (WHO) rinoti utachiona hwakawanda hwemabhakitiriya hahuna simba rekurwisa mishonga yakawanda inorwisa mabhakitiriya, kusanganisira methicillin-resistant Staphylococcus aureus (MRSA), iyo inowanzo kukonzera hutachiona munharaunda nenzvimbo dzehutano. Varwere vane hutachiona hweMRSA vanonzi vane huwandu hwerufu hwakakwira ne64% kupfuura avo vane hutachiona hunogona kubatwa nemishonga. Pamusoro pezvo, E. coli ine njodzi pasi rose nekuti nzira yekupedzisira yekudzivirira kubva kuEnterobacteriaceae inodzivirira carbapenem (kureva, E. coli) icolistin, asi mabhakitiriya anodzivirira colistin achangobva kutaurwa munyika dzinoverengeka. 22,23,24,25
Saka, maererano neWorld Health Organization Global Action Plan on Antimicrobial Resistance26, pane chikonzero chikuru chekuwanikwa nekuumbwa kwemishonga mitsva inorwisa utachiona. Kugona kukuru kweanthracene neacrylonitrile semishonga inorwisa utachiona27, antifungal28, anticancer29 uye antioxidant30 kwakaratidzwa mumapepa akawanda akabudiswa. Panyaya iyi, zvinogona kutaurwa kuti mishonga iyi inogona kushandiswa kurwisa methicillin-resistant Staphylococcus aureus (MRSA).
Ongororo dzekare dzemabhuku dzakatikurudzira kugadzira mishonga mitsva mumapoka aya. Nokudaro, chidzidzo ichi chaive nechinangwa chekugadzira masisitimu matsva eheterocyclic ane anthracene uye acrylonitrile, kuongorora kushanda kwawo kweantimicrobial uye antibacterial, uye kuongorora kugona kwawo kubatana nepenicillin-binding protein 2a (PBP2a) nekushandisa molecular docking. Zvichivakira pane zvidzidzo zvekare, chidzidzo ichi chakaenderera mberi nekugadzira, kuongorora biological, uye kuongorora komputa masisitimu eheterocyclic kuti vaone mishonga inorwisa antimethicillin-resistant Staphylococcus aureus (MRSA) ine simba rekudzivirira PBP2a31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Ongororo yedu yazvino inotarisa pakugadzirwa uye kuongororwa kwemakemikari matsva eheterocyclic ane anthracene uye acrylonitrile. 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yakagadzirwa uye yakashandiswa sechivharo chekuvaka masisitimu matsva eheterocyclic.
Maumbirwo ecompound 4 akaongororwa uchishandisa data respectral. 1H-NMR spectrum yakaratidza kuvapo kweCH= pa9.26 ppm, IR spectrum yakaratidza kuvapo kweboka recarbonyl pa1737 cm−1 uye boka recyano pa2224 cm−1, uye 13CNMR spectrum yakasimbisawo maumbirwo akarongwa (ona chikamu cheExperimental).
Kugadzirwa kwe3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kwakaitwa ne hydrolysis yemapoka e aromatic 250, 41, 42, 53 ne ethanolic sodium hydroxide solution (10%) kuti ipe acids 354, 45, 56, iyo yakazopihwa thionyl chloride mumvura yekugezera kuti acryloyl chloride derivative 4 ive negoho guru (88.5%), sezvakaratidzwa muMufananidzo 3.
Kuti pagadzirwe mishonga mitsva ye heterocyclic ine simba rekurwisa mabhakitiriya rinotarisirwa, acyl chloride 4 ine ma dinucleophile akasiyana-siyana yakaitwa.
Asidhi chloride 4 yakarapwa nehydrazine hydrate pa0° kweawa imwe chete. Zvinosuwisa kuti pyrazolone 5 haina kuwanikwa. Chigadzirwa chacho chaive acrylamide derivative ine chimiro chakasimbiswa ne spectral data. IR spectrum yayo yakaratidza mabhendi ekunyudzwa eC=O pa1720 cm−1, C≡N pa2228 cm−1 uye NH pa3424 cm−1. 1H-NMR spectrum yakaratidza chiratidzo chekuchinjana kwe singlet yema olefin protons nema NH protons pa9.3 ppm (ona Chikamu cheKuedza).
Mamoles maviri eacid chloride 4 akagadzirwa nemoles imwe yephenylhydrazine kuti awane N-phenylacryloylhydrazine derivative 7 mugoho rakanaka (77%) (Mufananidzo 5). Maumbirwo e7 akasimbiswa ne infrared spectroscopy data, iyo yakaratidza kunyudzwa kwemapoka maviri eC=O pa1691 ne1671 cm−1, kunyudzwa kweboka reCN pa2222 cm−1 uye kunyudzwa kweboka reNH pa3245 cm−1, uye 1H-NMR spectrum yayo yakaratidza boka reCH pa9.15 ne8.81 ppm uye NH proton pa10.88 ppm (ona chikamu cheExperimental).
Muchidzidzo ichi, maitiro eacyl chloride 4 ne1,3-dinucleophiles akaongororwa. Kurapa acyl chloride 4 ne2-aminopyridine mu1,4-dioxane neTEA sebase patembiricha yemukamuri kwakapa acrylamide derivative 8 (Mufananidzo 5), iyo chimiro chayo chakaonekwa uchishandisa data respectral. IR spectra yakaratidza mabhendi ekunyudzwa kwecyano akatambanudzwa pa2222 cm−1, NH pa3148 cm−1, uye carbonyl pa1665 cm−1; 1H NMR spectra yakasimbisa kuvapo kweolefin protons pa9.14 ppm (ona Chikamu Chekuyedza).
Compound 4 inopindirana nethiourea kuti ipe pyrimidinethione 9; compound 4 inopindirana nethiosemicarbazide kuti ipe thiopyrazole derivative 10 (Mufananidzo 5). Maumbirwo emakomboni 9 ne10 akasimbiswa nekuongorora kwespectral uye elemental (ona chikamu cheExperimental).
Tetrazine-3-thiol 11 yakagadzirwa nekuita kwe compound 4 ne thiocarbazide se 1,4-dinucleophile (Mufananidzo 5), uye chimiro chayo chakasimbiswa ne spectroscopy uye elemental analysis. Mu infrared spectrum, C=N bond yakaonekwa pa 1619 cm−1. Panguva imwe chete, 1H-NMR spectrum yayo yakachengeta ma multiplate signals ema aromatic protons pa 7.78–8.66 ppm uye SH protons pa 3.31 ppm (ona Chikamu cheKuedza).
Acryloyl chloride 4 inopindirana ne 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, uye ethanolamine se 1,4-dinucleophiles kuti igadzire masisitimu matsva e heterocyclic (13–16).
Maumbirwo emakomponi aya matsva akasimbiswa nekuongorora kwespectral neelemental (ona chikamu cheExperimental). 2-Hydroxyphenylacrylamide derivative 17 yakawanikwa nekuita ne2-aminophenol se dinucleophile (Mufananidzo 6), uye maumbirwo ayo akasimbiswa nekuongorora kwespectral neelemental. Iyo infrared spectrum yekomponi 17 yakaratidza kuti masaini eC=O neC≡N akaonekwa pa1681 ne2226 cm−1, zvichiteerana. Panguva iyi, spectrum yayo ye1H-NMR yakachengeta chiratidzo chesinglet cheolefin proton pa9.19 ppm, uye OH proton yakaonekwa pa9.82 ppm (ona chikamu cheExperimental).
Kuita kweacid chloride 4 ne nucleophile imwe (semuenzaniso, ethylamine, 4-toluidine, uye 4-methoxyaniline) mu dioxane se solvent uye TEA se catalyst patembiricha yemukamuri kwakapa green crystalline acrylamide derivatives 18, 19a, uye 19b. Ruzivo rwe elemental uye spectral rwemakomputa 18, 19a, uye 19b rwakasimbisa maumbirwo ema derivatives aya (ona Chikamu Chekuyedza) (Mufananidzo 7).
Mushure mekuongorora mashandiro emishonga inorwisa utachiona yemakemikari akasiyana-siyana ekugadzira, mhedzisiro dzakasiyana dzakawanikwa sezvakaratidzwa muTafura 1 neMufananidzo 8 (ona faira remufananidzo). Mishonga yese yakaedzwa yakaratidza mwero wakasiyana wekudzivirira kurwisa bhakitiriya yeGram-positive MRSA, nepo bhakitiriya yeGram-negative Escherichia coli yakaratidza kusakwanisa zvachose makemikari ese. Mishonga yakaedzwa inogona kukamurwa muzvikamu zvitatu zvichienderana nedhayamita yenzvimbo yekudzivirira kurwisa MRSA. Chikamu chekutanga chaive chinonyanya kushanda uye chaive nemakemikari mashanu (6, 7, 10, 13b na 14). Dhayamita yenzvimbo yekudzivirira yemakemikari aya yaive pedyo ne4 cm; mishonga inonyanya kushanda muchikamu ichi yaive makemikari 6 na 13b. Chikamu chechipiri chaive nekushanda zvine mwero uye chaive nemamwe makemikari mashanu (11, 13a, 15, 18 na 19a). Nzvimbo yekudzivirira yemakemikari aya yaive kubva pa3.3 kusvika 3.65 cm, nepo bhakitiriya 11 ichiratidza nzvimbo huru yekudzivirira ye3.65 ± 0.1 cm. Kune rumwe rutivi, boka rekupedzisira raiva nemakomichi matatu (8, 17 na19b) ane basa shoma rekuuraya utachiona (pasi pe3 cm). Mufananidzo 9 unoratidza kupararira kwenzvimbo dzakasiyana dzekudzivirira utachiona.
Kuenderera mberi nekuferefetwa kwebasa remishonga inorwisa utachiona yemishonga yakaedzwa kwaisanganisira kuona MIC neMBC yemushonga wega wega. Mhedzisiro yacho yakasiyana zvishoma (sezvinoratidzwa muTafura 2, 3 neMufananidzo 10 (ona faira remufananidzo)), nemakemikari 7, 11, 13a ne15 zvichiratidzika kunge zviri muchikamu chemishonga chakanakisa. Aive neMIC neMBC values ​​​​dzakaderera zvakafanana (39.06 μg/100 μL). Kunyangwe makemikari 7 ne8 aive neMIC values ​​​​dzakaderera (9.7 μg/100 μL), MBC values ​​​​dzavo dzaive dzakakwira (78.125 μg/100 μL). Nokudaro, vaionekwa sevasina simba pane makemikari ambotaurwa. Zvisinei, makemikari matanhatu aya ndiwo ainyanya kushanda pane akaedzwa, sezvo MBC values ​​dzavo dzaive pasi pe100 μg/100 μL.
Makombiyuta (10, 14, 18 na19b) akanga asina simba rakawanda kana tichienzanisa nemamwe makombiyuta akaedzwa sezvo kukosha kwawo kweMBC kwaibva pa156 kusvika 312 μg/100 μL. Kune rumwe rutivi, makombiyuta (8, 17 na19a) akanga asina simba rakawanda sezvo aiva neMBC yepamusoro (625, 625 na1250 μg/100 μL, zvichiteerana).
Chekupedzisira, zvichienderana nemazinga ekushivirira anoratidzwa muTafura 3, mishonga yakaedzwa inogona kukamurwa kuita mapoka maviri zvichienderana nemaitiro ayo: mishonga ine simba rekuuraya mabhakitiriya (7, 8, 10, 11, 13a, 15, 18, 19b) uye mishonga ine simba rekurwisa mabhakitiriya (6, 13b, 14, 17, 19a). Pakati payo, mishonga 7, 11, 13a uye 15 ndiyo inofarirwa, iyo inoratidza basa rekuuraya pahuwandu hwakaderera zvikuru (39.06 μg/100 μL).
Makemikoro gumi pagumi nematatu akaedzwa akaratidza kuti anogona kurwisa methicillin-resistant Staphylococcus aureus (MRSA) isingaurayiwi nemishonga inorwisa mabhakitiriya. Nokudaro, kuongororwa kwakawanda kwezvirwere zvisingaurayiwi nemishonga inorwisa mabhakitiriya (kunyanya zvipembenene zvemunharaunda zvinofukidza mabhakitiriya eGram-positive neGram-negative) uye mbiriso inokurudzirwa, pamwe nekuongororwa kwemakemikari ega ega kuti vaone kuchengetedzeka kwawo.
Zvidzidzo zveMolecular docking zvakaitwa kuti zviongorore kugona kwemakomichi akagadzirwa seanodzivirira penicillin-binding protein 2a (PBP2a) mu methicillin-resistant Staphylococcus aureus (MRSA). PBP2a ienzyme inokosha inobatanidzwa mukugadzirwa kwemadziro emasero ebhakitiriya, uye kudziviswa kweiyi enzyme kunokanganisa kuumbwa kwemadziro emasero, zvichizoguma nekukanganiswa kwebhakitiriya uye kufa kwemasero1. Mhedzisiro yedocking yakanyorwa muTafura 4 uye inotsanangurwa zvakadzama mufaira rekuwedzera redata, uye mhedzisiro inoratidza kuti makomichi akati wandei akaratidza hukama hwakasimba hwePBP2a, kunyanya ma residues akakosha anoshanda seLys 273, Lys 316, uye Arg 298. Kudyidzana, kusanganisira hydrogen bonding uye π-stacking, kwakafanana zvikuru nekwe co-crystallized quinazolinone ligand (CCL), zvichiratidza kugona kwemakomichi aya seanodzivirira zvine simba.
Data remamorekuru rekuisa mamorekuru, pamwe chete nedzimwe nzira dzekuverenga, rakaratidza zvakasimba kuti PBP2a inhibition ndiyo yaive nzira huru yekuonekwa kwemabasa ekurwisa mabhakitiriya emakomputa aya. Madocking scores uye root mean square deviation (RMSD) values ​​​​zvakaratidza hukama hwakanaka hwekubatanidza uye kugadzikana, zvichitsigira pfungwa iyi. Sezvakaratidzwa muTafura 4, nepo makomputa akati wandei akaratidza hukama hwakanaka hwekubatanidza, mamwe makomputa (semuenzaniso, 7, 9, 10, uye 14) aive nemadocking scores akakwira kupfuura co-crystallized ligand, zvichiratidza kuti anogona kunge aine hukama hwakasimba nemaresidues ePBP2a anoshanda. Zvisinei, makomputa anonyanya kushanda 6 na13b akaratidza madocking scores akaderera zvishoma (-5.98 na -5.63, zvichiteerana) zvichienzaniswa nemamwe ma ligands. Izvi zvinoratidza kuti kunyangwe madocking scores achigona kushandiswa kufanotaura hukama hwekubatanidza, zvimwe zvinhu (semuenzaniso, kugadzikana kwe ligand uye hukama hwemamorekuru munzvimbo yehupenyu) zvinoitawo basa guru mukuona basa rekurwisa mabhakitiriya. Zvinonyanya kukosha kuti RMSD values ​​​​yemakomputa ese akagadzirwa aive pasi pe2 Å, zvichiratidza kuti ma docking poses avo anoenderana nechimiro chekubatanidza kwe co-crystallized ligand, zvichiwedzera kutsigira kugona kwavo sevanodzivisa PBP2a vane simba.
Kunyangwe madokisheni ekuisa masero uye RMS values ​​​​zvichipa fungidziro dzinokosha, hukama huripo pakati pemhedzisiro iyi yedokisheni uye mashandiro ekuuraya utachiona hausi pachena nguva dzose pakutanga. Kunyangwe kudzivirira kwePBP2a kuchitsigirwa zvakanyanya sechinhu chakakosha chinokanganisa mashandiro ekurwisa utachiona, misiyano yakati wandei inoratidza kuti zvimwe zvinhu zvehupenyu zvinoitawo basa rakakosha. Macompounds 6 na13b akaratidza mashandiro epamusoro ekurwisa utachiona, aine dhayamita yenzvimbo yekudzivirira ye4 cm uye MIC yakaderera (9.7 μg/100 μL) uye MBC (78.125 μg/100 μL), kunyangwe ari mashoma edokisheni zvichienzaniswa nemakemikari 7, 9, 10 na14. Izvi zvinoratidza kuti kunyangwe kudzivirira kwePBP2a kuchibatsira mukuita kwemishonga inorwisa utachiona, zvinhu zvakaita sekunyungudika, bioavailability uye interaction dynamics munzvimbo yebhakitiriya zvinopesvedzerawo mashandiro ese. Mufananidzo 11 unoratidza maitiro avo edokisheni, zvichiratidza kuti makemikari ese ari maviri, kunyangwe aine mabonding scores akaderera, achiri kukwanisa kusangana nema residues akakosha ePBP2a, zvichigona kudzikamisa inhibition complex. Izvi zvinoratidza kuti kunyangwe kuvharwa kwemamorekuru kuchipa ruzivo rwakakosha mukudzivirira kwePBP2a, zvimwe zvinhu zvehupenyu zvinofanirwa kutariswa kuti zvinzwisise zvizere mhedzisiro chaiyo yemakemikari aya pakurwisa utachiona.
Kushandisa chimiro chekristaro chePBP2a (PDB ID: 4CJN), mamepu ekudyidzana kwe2D ne3D emakomichi anoshanda zvakanyanya 6 ne13b akaiswa ne penicillin-binding protein 2a (PBP2a) ye methicillin-resistant Staphylococcus aureus (MRSA) akagadzirwa. Mamepu aya anoenzanisa mapatani ekudyidzana kwemakomichi aya ne re-docked co-crystallized quinazolinone ligand (CCL), zvichiratidza kudyidzana kwakakosha kwakadai sehydrogen bonding, π-stacking, uye ionic interactions.
Patani yakafanana yakaonekwa kune compound 7, iyo yakaratidza chikero chepamusoro chedocking (-6.32) uye dhayamita yakafanana yeinhibition zone (3.9 cm) kune compound 10. Zvisinei, MIC yayo (39.08 μg/100 μL) uye MBC (39.06 μg/100 μL) zvaive zvakakwirira zvakanyanya, zvichiratidza kuti yaida huwandu hwakanyanya kuti iratidze simba rekurwisa mabhakitiriya. Izvi zvinoratidza kuti kunyangwe compound 7 yakaratidza kubatana kwakasimba muzvidzidzo zvedocking, zvinhu zvakaita se bioavailability, cellular uptake, kana zvimwe zvinhu zve physicochemical zvinogona kudzikamisa kushanda kwayo kwebhayoloji. Kunyangwe compound 7 yakaratidza zvinhu zvekuuraya mabhakitiriya, yakanga isinganyanyi kushanda mukudzivirira kukura kwebhakitiriya zvichienzaniswa ne compound 6 na 13b.
Compound 10 yakaratidza musiyano wakakura zvikuru nenhamba yepamusoro yedocking score (-6.40), zvichiratidza kubatana kwakasimba nePBP2a. Zvisinei, nzvimbo yayo yekudzivirira dhayamita (3.9 cm) yakaenzana necompound 7, uye MBC yayo (312 μg/100 μL) yaive yakakwira zvakanyanya kupfuura compounds 6, 7, uye 13b, zvichiratidza kushanda kusina simba kwebhakitiriya. Izvi zvinoratidza kuti kunyangwe paine kufanotaura kwakanaka kwedocking, compound 10 haina kushanda zvakanaka mukuuraya MRSA nekuda kwezvimwe zvinhu zvinodzivisa zvakaita sekunyunguduka, kugadzikana, kana kusapinda zvakanaka kwemembrane yebhakitiriya. Mhedzisiro iyi inotsigira kunzwisisa kwekuti nepo PBP2a inhibition ichiita basa guru mukuita kweantibacterial, haitsananguri zvizere mutsauko mukuita kwebiological wakaonekwa pakati pemacompounds akaedzwa. Misiyano iyi inoratidza kuti kuongorora kwakawanda kwekuyedza uye kuongororwa kwakadzama kwebiological zvinodiwa kuti kujekese zvizere nzira dzeantibacterial dzinobatanidzwa.
Kuiswa kwemasero mumasero muTafura 4 neSupplementary Data File zvinoratidza hukama hwakaoma pakati pema "docking scores" ne "antimicrobial activity". Kunyangwe ma "compounds" 6 ne 13b aine "docking scores" shoma pane ma "compounds" 7, 9, 10, uye 14, anoratidza "antimicrobial activity" yepamusoro. Mamepu avo ekubatana (anoratidzwa muMufananidzo 11) anoratidza kuti pasinei ne "bonding scores" shoma, achiri kuumba "hydrogen bonds" dzakakosha uye "π-stacking interactions" nema "key residues" ePBP2a anogona kudzikamisa "enzyme-inhibitor complex" nenzira inobatsira pakurarama. Pasinei ne "docking scores" shoma dze6 ne 13b, "expansion activity" yavo ye "antimicrobial activity" inoratidza kuti zvimwe zvinhu zvakaita sekunyunguduka, kugadzikana, uye kutorwa kwemasero zvinofanirwa kufungwa pamwe chete ne "docking data" pakuongorora "inhibitor potential". Izvi zvinoratidza kukosha kwekubatanidza zvidzidzo zve "docking" ne "experimental antimicrobial analysis" kuti vaongorore nemazvo kugona kwekurapa kwe "compounds" itsva.
Mhedzisiro iyi inoratidza kuti kunyangwe kuvharwa kwemamorekuru kuri chishandiso chine simba chekufanotaura kubatana kwekubatana uye kuona nzira dzinogona kuvharwa, hazvifanirwe kuvimbwa nazvo chete kuti zvione kushanda kwemishonga inorwisa utachiona. Ruzivo rwemamorekuru runoratidza kuti kuvharwa kwePBP2a chinhu chakakosha chinokanganisa kushanda kwemishonga inorwisa utachiona, asi shanduko mukushanda kwezvipenyu zvinoratidza kuti zvimwe zvinhu zvefizikisi nemakemikari zvinofanirwa kugadziriswa kuti zviwedzere kushanda kwemishonga. Zvidzidzo zveramangwana zvinofanirwa kutarisa pakuvandudza chimiro chemakemikari chemakemikari 7 ne10 kuti zvivandudze kuwanikwa kwemishonga uye kutorwa kwemasero, zvichiona kuti kushanda kwakasimba kwekushandisa mishonga kunoshandurwa kuita basa remishonga inorwisa utachiona. Zvidzidzo zvakare, zvinosanganisira kuongororwa kwezve bioassays uye ongororo yehukama hwechimiro-basa (SAR), zvichave zvakakosha kuti tiwedzere kunzwisisa kwedu kuti mishonga iyi inoshanda sei sePBP2a inhibitors uye kugadzira mishonga inorwisa utachiona inoshanda zvakanyanya.
Mishonga yakagadzirwa kubva ku3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yakaratidza kushanda kwakasiyana-siyana kwemishonga inorwisa utachiona, uye mishonga yakati wandei ichiratidza kudzivirira kwakakosha kweStaphylococcus aureus (MRSA) isingapindi mishonga yemethicillin. Ongororo yehukama hwechimiro nemabasa (SAR) yakaratidza zvinhu zvakakosha zviri pasi pesimba remishonga iyi inorwisa utachiona.
Kuvapo kwemapoka eacrylonitrile neanthracene kwakaratidza kuva kwakakosha pakuwedzera mashandiro emishonga inorwisa utachiona. Boka renitrile rinoita basa zvakanyanya muacrylonitrile rinodiwa kuti ribatsire kudyidzana nemapuroteni ebhakitiriya, nokudaro richibatsira mukugadzirwa kwemishonga inorwisa utachiona. Mishonga ine acrylonitrile neanthracene yakaramba ichiratidza simba rakasimba remishonga inorwisa utachiona. Kunhuhwirira kweboka reanthracene kwakawedzera kudzikamisa mishonga iyi, zvichigona kuwedzera mashandiro ayo emuviri.
Kuunzwa kwe heterocyclic rings kwakavandudza zvakanyanya kushanda kwe antibacterial kwe derivatives dzakasiyana-siyana. Kunyanya, benzothiazole derivative 13b uye acrylhydrazide derivative 6 zvakaratidza basa repamusoro re antibacterial ne inhibition zone inosvika 4 cm. Aya heterocyclic derivatives akaratidza mhedzisiro yakakura ye biological, zvichiratidza kuti heterocyclic structure ine basa guru mu antibacterial effects. Saizvozvowo, pyrimidinethione mu compound 9, thiopyrazole mu compound 10, uye tetrazine ring mu compound 11 zvakabatsira mu antibacterial properties ye compounds, zvichiratidza kukosha kwe heterocyclic modification.
Pakati pemakemikari akagadzirwa, 6 ne13b zvakaonekwa nemabasa avo akanaka ekurwisa mabhakitiriya. Kuwanda kwekudzivirira (MIC) kwemakemikari 6 kwaive 9.7 μg/100 μL, uye huwandu hwekudzivirira mabhakitiriya (MBC) hwaive 78.125 μg/100 μL, zvichiratidza kugona kwayo kubvisa methicillin-resistant Staphylococcus aureus (MRSA). Saizvozvowo, compound 13b yaive nenzvimbo yekudzivirira ye4 cm uye yakaderera MIC neMBC, zvichiratidza kushanda kwayo kwakasimba kwekurwisa mabhakitiriya. Mhedzisiro iyi inoratidza mabasa akakosha emapoka anoshanda eacrylohydrazide nebenzothiazole mukuona kushanda zvakanaka kwemakemikari aya.
Kusiyana neizvi, makemikari 7, 10, uye 14 akaratidza kushanda kwepakati kwekurwisa mabhakitiriya nenzvimbo dzekudzivirira dzinotangira pa3.65 kusvika 3.9 cm. Makemikoro aya aida huwandu hwakanyanya hwemabhakitiriya kuti auraye mabhakitiriya zvachose, sezvinoratidzwa nehuwandu hwavo hweMIC neMBC hwakakwira. Kunyangwe makemikari aya akanga asingashande zvakanyanya pane makemikari 6 ne13b, achiri kuratidza kugona kukuru kwekurwisa mabhakitiriya, zvichiratidza kuti kuiswa kweacrylonitrile neanthracene mu heterocyclic ring kunobatsira mukuita kwavo kurwisa mabhakitiriya.
Mishonga iyi ine nzira dzakasiyana dzekushanda, mimwe inoratidza hunhu hwekuuraya utachiona uye mimwe inoratidza mhedzisiro yebhakitiriya. Mishonga 7, 11, 13a, uye 15 inouraya utachiona uye inoda huwandu hwakaderera kuti iuraye mabhakitiriya zvachose. Kusiyana neizvi, mishonga 6, 13b, uye 14 inorwisa utachiona uye inogona kudzivirira kukura kwebhakitiriya pahuwandu hwakaderera, asi inoda huwandu hwakanyanya kuti iuraye mabhakitiriya zvachose.
Zvose, kuongorora hukama hwemaumbirwo nemabasa kunoratidza kukosha kwekuisa acrylonitrile neanthracene moieties uye heterocyclic structures kuti pave nekushanda kwakakosha kweantibacterial. Izvi zvinoratidza kuti kugadzirisa zvikamu izvi zvemaumbirwo uye kuongorora zvimwe zvigadziriso zvekuvandudza kunyunguduka uye kubvumidzwa kwemembrane zvinogona kutungamira mukugadzirwa kwemishonga inoshanda zvakanyanya yekurwisa MRSA.
Zvese zvinonyungudutsa zvakacheneswa uye zvakaomeswa uchishandisa nzira dzakajairwa (El Gomhouria, Egypt). Nzvimbo dzekunyungudutsa dzakaongororwa uchishandisa GallenKamp electronic melting point apparatus uye dzinotaurwa pasina kugadziriswa. Infrared (IR) spectra (cm⁻1) dzakanyorwa paDhipatimendi reChemistry, Faculty of Science, Ain Shams University uchishandisa potassium bromide (KBr) pellets paThermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
Maspectra e1H NMR akawanikwa pa300 MHz achishandisa GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) uye BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.). Tetramethylsilane (TMS) yakashandiswa sechiyero chemukati chine deuterated dimethyl sulfoxide (DMSO-d₆). Kuyerwa kweNMR kwakaitwa paFaculty of Science, Cairo University, Giza, Egypt. Elemental analysis (CHN) yakaitwa uchishandisa Perkin-Elmer 2400 Elemental Analyzer uye mhedzisiro yakawanikwa inoenderana zvakanaka nemitengo yakaverengerwa.
Musanganiswa weasidhi 3 (5 mmol) nethionyl chloride (5 ml) zvakadziiswa mumvura inodziya pa65 °C kwemaawa mana. Thionyl chloride yakawandisa yakabviswa nekudishwa nekumanikidzwa kwakaderera. Chinhu chitsvuku chakabuda chakaunganidzwa ndokushandiswa pasina kumwe kucheneswa. Nzvimbo yekunyunguduka: 200-202 °C, goho: 88.5%. IR (KBr, ν, cm−1): 2224 (C≡N), 1737 (C=O). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.26 (s, 1H, CH=), 7.27-8.57 (m, 9H, heteroaromatization). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 115.11 (C≡N), 124.82–130.53 (CH anthracene), 155.34, 114.93 (CH=C–C=O), 162.22 (C=O); HRMS (ESI) m/z [M + H]+: 291.73111. Nyanzvi. Yakaverengerwa C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Yakawanikwa: C, 74.41; H, 3.34; N, 4.66%.
Pa 0°C, 4 (2 mmol, 0.7 g) yakanyungudutswa mu anhydrous dioxane (20 ml) uye hydrazine hydrate (2 mmol, 0.16 ml, 80%) yakawedzerwa ichidonhedzwa ndokukurunga kweawa imwe chete. Chinhu chakaoma chakaunganidzwa nekusefa uye chakasanganiswazve kubva mu ethanol kuti chipe compound 6.
Makristasi egirini, pokunyunguduka 190-192℃, goho 69.36%; IR (KBr) ν=3424 (NH), 2228 (C≡N), 1720 (C=O), 1621 (C=N) cm−1. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.3 (br s, H, NH, inogona kuchinjwa), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Kukosha kwakaverengerwa kweC33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Yakawanikwa: C, 84.01; H, 4.38; Nhamba, 8.05%.
Nyungudutsa 4 (2 mmol, 0.7 g) mu 20 ml ye anhydrous dioxane solution (ine madonhwe mashoma e triethylamine), wedzera phenylhydrazine/2-aminopyridine (2 mmol) wobva wasanganisa patembiricha yemumba kweawa imwe neawa mbiri, zvichiteerana. Dururirai musanganiswa we reaction muchando kana mumvura moisa acid ne dilute hydrochloric acid. Sefai kubva pa solid yakaparadzaniswa moisa crystallize kubva mu ethanol kuti muwane 7 moisa crystallize kubva ku benzene kuti muwane 8.
Makristasi egirini, pokunyunguduka 160-162℃, goho 77%; IR (KBr, ν, cm−1): 3245 (NH), 2222 (C≡N), 1691 (C=O), 1671 (C=O) cm−1. 1H-NMR (400 MHz, DMSO-d6): δ (ppm): 10.88 (s, 1H, NH, inogona kuchinjwa), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Kukosha kwakaverengerwa kweC42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Yakawanikwa: C, 81.96; H, 3.91; Nhamba, 8.91%.
4 (2 mmol, 0.7 g) yakanyungudutswa mu20 ml ye anhydrous dioxane solution (ine madonhwe mashoma etriethylamine), 2-aminopyridine (2 mmol, 0.25 g) yakawedzerwa uye musanganiswa wacho wakakurunga patembiricha yemukamuri kwemaawa maviri. Musanganiswa we reaction wakadururwa mumvura yechando ndokuiswa acid ne diluted hydrochloric acid. Precipitate yakagadzirwa yakaseferwa ndokudzokororwa kubva kubenzene, zvichipa makristaro egirini e8 ane poindi yekunyunguduka ye146-148 °C uye goho re82.5%; infrared spectrum (KBr) ν: 3148 (NH), 2222 (C≡N), 1665 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ (ppm): 8.78 (s, H, NH, inogona kuchinjwa), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); Yakaverengerwa C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Yakawanikwa: C, 78.93; H, 3.97; N, 12.36%.
Musanganiswa wechina (2 mmol, 0.7 g) wakanyungudutswa mu20 ml ye dioxane yakaoma (ine madonhwe mashoma e triethylamine uye 2 mmol ye thiourea/semicarbazide) ndokupiswa pasi pe reflux kwemaawa maviri. Musanganiswa wacho wakabviswa mu vacuo. Zvasara zvakadzorerwa kubva ku dioxane kuti zvive musanganiswa.