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I-synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yenziwe yaza yasetyenziswa ukwenza iintlobo ngeentlobo zeekhompawundi ze-heterocyclic ezisebenzayo kakhulu ngokusebenzisa i-reaction yayo kunye nee-nucleophiles ezahlukeneyo ze-nitrogen. Ulwakhiwo lwekhompawundi nganye ye-heterocyclic eyenziweyo luchazwe kakuhle kusetyenziswa uhlalutyo lwe-spectroscopic kunye ne-elemental. Iikhompawundi ezilishumi kwezilishumi elinesithathu ezintsha ze-heterocyclic zibonise ukusebenza okukhuthazayo ngokuchasene neebhaktheriya ezinganyangekiyo ngamayeza amaninzi (MRSA). Phakathi kwazo, iikhompawundi 6, 7, 10, 13b, kunye ne-14 zibonise umsebenzi ophezulu we-antibacterial kunye neendawo zokuthintela ezikufutshane ne-4 cm. Nangona kunjalo, izifundo ze-molecular docking zityhile ukuba ezi khompawundi zazine-affinities ezahlukeneyo zokubopha kwi-penicillin-binding protein 2a (PBP2a), eyona nto iphambili ekuchaseni kwe-MRSA. Ezinye iikhompawundi ezifana ne-7, 10 kunye ne-14 zibonise ukuzinza okuphezulu kokubopha kunye nokunxibelelana kwindawo esebenzayo ye-PBP2a xa kuthelekiswa ne-co-crystallized quinazolinone ligand. Ngokwahlukileyo koko, iikhompawundi 6 kunye ne-13b zazinamanqaku aphantsi okufaka iidoksi kodwa zisabonisa umsebenzi obalulekileyo wokulwa neentsholongwane, apho ikhompawundi 6 inexabiso eliphantsi le-MIC (9.7 μg/100 μL) kunye ne-MBC (78.125 μg/100 μL). Uhlalutyo lokufaka iidoksi lubonise ukusebenzisana okubalulekileyo kubandakanya ukubopha i-hydrogen kunye nokufaka i-π, ngakumbi ngeentsalela ezifana neLys 273, Lys 316 kunye neArg 298, ezachongwa njengezisebenzisana ne-ligand edibeneyo kwisakhiwo sekristale sePBP2a. Ezi residues zibalulekile kumsebenzi we-enzymatic wePBP2a. Ezi ziphumo zibonisa ukuba iikhompawundi ezidityanisiweyo zinokusebenza njengeziyobisi ezithembisayo ze-anti-MRSA, zigxininisa ukubaluleka kokudibanisa i-molecular docking kunye ne-bioassays ukuchonga abagqatswa abasebenzayo bonyango.
Kwiminyaka embalwa yokuqala yale nkulungwane, imizamo yophando yayigxile kakhulu ekuphuhliseni iinkqubo ezintsha nezilula kunye neendlela zokudibanisa iinkqubo ezininzi ezintsha ze-heterocyclic ezine-antimicrobial activity kusetyenziswa izixhobo zokuqala ezifumanekayo ngokulula.
Ii-Acrylonitrile moieties zithathwa njengezinto ezibalulekileyo zokuqala ukwenziwa kweenkqubo ezininzi ezimangalisayo ze-heterocyclic kuba ziyimixube ephendula kakhulu. Ngaphezu koko, i-2-cyanoacryloyl chloride derivatives isetyenzisiwe kakhulu kwiminyaka yakutshanje kuphuhliso kunye nokuhlanganiswa kweemveliso ezibaluleke kakhulu kwicandelo lezicelo ze-pharmacological, ezifana ne-drug intermediates1,2,3, izinto ezibangela i-HIV, i-antiviral, i-anticancer, i-antibacterial, i-antidepressant kunye ne-antioxidant4,5,6,7,8,9,10. Kutshanje, ukusebenza kakuhle kwe-anthracene kunye ne-derivatives yayo, kubandakanya i-antibiotic yayo, i-anticancer11,12, i-antibacterial13,14,15 kunye neempawu zokubulala izinambuzane16,17, kuye kwatsala ingqalelo enkulu18,19,20,21. Iikhompawundi ze-antimicrobial eziqulethe i-acrylonitrile kunye ne-anthracene moieties ziboniswe kwiMifanekiso 1 kunye ne-2.
Ngokutsho kwe-World Health Organisation (WHO) (2021), ukumelana neentsholongwane (AMR) sisongelo sehlabathi kwimpilo nophuhliso22,23,24,25. Izigulana azinakuphiliswa, nto leyo ebangela ukuhlala ixesha elide esibhedlele kunye nesidingo samayeza abiza kakhulu, kunye nokwanda kokufa kunye nokukhubazeka. Ukungabikho kweentsholongwane ezisebenzayo kudla ngokukhokelela ekusileleni konyango kwiintsholongwane ezahlukeneyo, ingakumbi ngexesha le-chemotherapy kunye notyando olukhulu.
Ngokwengxelo ye-World Health Organisation ka-2024, i-Staphylococcus aureus (MRSA) kunye ne-E. coli ezinganyangekiyo ne-methicillin zibandakanyiwe kuluhlu lwezifo eziphambili. Zombini iintsholongwane ziyamelana neentsholongwane ezininzi, ngoko ke zimele usulelo olunzima ukunyanga nokulawula, kwaye kukho imfuneko engxamisekileyo yokuphuhlisa iikhompawundi ezintsha nezisebenzayo zokulwa namagciwane ukujongana nale ngxaki. I-Anthracene kunye neziphumo zayo zii-antimicrobial ezaziwayo ezinokusebenza kwiintsholongwane ze-Gram-positive kunye ne-Gram-negative. Injongo yolu phononongo kukwenza i-derivative entsha enokumelana nezi zifo ziyingozi empilweni.
I-World Health Organisation (WHO) ibika ukuba iintsholongwane ezininzi ezibangela iintsholongwane ziyamelana neentsholongwane ezininzi, kuquka i-methicillin-resistant Staphylococcus aureus (MRSA), unobangela oqhelekileyo wosulelo kuluntu nakwiindawo zokhathalelo lwempilo. Izigulane ezineentsholongwane ze-MRSA zixelwe ukuba zinezinga lokufa eliphezulu ngama-64% kunezo zineentsholongwane ezichaphazeleka ngamayeza. Ukongeza, i-E. coli ibeka umngcipheko wehlabathi kuba umgca wokugqibela wokuzikhusela kwi-Enterobacteriaceae enganyangekiyo yi-carbapenem (oko kukuthi, i-E. coli) yi-colistin, kodwa iintsholongwane ezinganyangekiyo yi-colistin zixelwe kutshanje kumazwe aliqela. 22,23,24,25
Ngoko ke, ngokweSicwangciso seNtshukumo seHlabathi se-World Health Organisation kwi-Antimicrobial Resistance26, kukho imfuneko engxamisekileyo yokufunyanwa kunye nokuhlanganiswa kwamayeza amatsha okulwa neentsholongwane. Amandla amakhulu e-anthracene kunye ne-acrylonitrile njengee-antibacterial27, antifungal28, anticancer29 kunye ne-antioxidant30 agqanyisiwe kwiincwadi ezininzi ezipapashiweyo. Kule nkalo, kunokuthiwa ezi zinto zilungele ukusetyenziswa kwi-Staphylococcus aureus (MRSA) enganyangekiyo ne-methicillin.
Uphononongo lwangaphambili lweencwadi lusishukumisele ekubeni senze izinto ezintsha ezifumaneka kwezi klasi. Ke ngoko, olu phononongo lujolise ekuphuhliseni iinkqubo ezintsha ze-heterocyclic eziqulethe i-anthracene kunye ne-acrylonitrile moieties, ukuvavanya ukusebenza kwazo kwe-antimicrobial kunye ne-antibacterial, kunye nokuphanda ukusebenzisana kwazo okunokwenzeka ne-penicillin-binding protein 2a (PBP2a) ngokufaka i-molecular docking. Ukwakha kwizifundo zangaphambili, olu phononongo luqhubekile nokudibanisa, uvavanyo lwebhayoloji, kunye nohlalutyo lwekhompyutha lweenkqubo ze-heterocyclic ukuchonga ii-agents ezithembisayo ze-antimethicillin-resistant Staphylococcus aureus (MRSA) ezine-antimethicillin-resistant activity enamandla yokuthintela i-PBP2a31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Uphando lwethu lwangoku lugxile ekuhlanganisweni nasekuvavanyweni kwee-antimicrobial kwee-compounds ezintsha ze-heterocyclic eziqulethe i-anthracene kunye ne-acrylonitrile moieties. I-3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yalungiswa yaza yasetyenziswa njengebhloko yokwakha iinkqubo ezintsha ze-heterocyclic.
Ulwakhiwo lwe-compound 4 luchongiwe kusetyenziswa idatha ye-spectral. I-spectrum ye-1H-NMR ibonise ubukho be-CH= kwi-9.26 ppm, i-spectrum ye-IR ibonise ubukho beqela le-carbonyl kwi-1737 cm−1 kunye neqela le-cyano kwi-2224 cm−1, kwaye i-spectrum ye-13CNMR nayo iqinisekisile ubume obucetywayo (jonga icandelo lovavanyo).
Ukwenziwa kwe-3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kwenziwe nge-hydrolysis yamaqela e-aromatic 250, 41, 42, 53 ngesisombululo se-ethanolic sodium hydroxide (10%) ukunika ii-asidi 354, 45, 56, ezathi emva koko zanyangwa nge-thionyl chloride kumanzi okuhlamba ukuze zinike i-acryloyl chloride derivative 4 kwisivuno esiphezulu (88.5%), njengoko kubonisiwe kuMfanekiso 3.
Ukudala iikhompawundi ezintsha ze-heterocyclic ezinomphumo olindelekileyo wokulwa neentsholongwane, kwenziwa i-reaction ye-acyl chloride 4 kunye nee-dinucleophiles ezahlukeneyo.
I-acid chloride 4 yanyangwa nge-hydrazine hydrate kwi-0° kangangeyure enye. Ngelishwa, i-pyrazolone 5 ayizange ifumaneke. Le mveliso yayiyi-acrylamide derivative enesakhiwo sayo esiqinisekiswe yidatha ye-spectral. I-spectrum yayo ye-IR ibonise amabhendi okufunxa e-C=O kwi-1720 cm−1, i-C≡N kwi-2228 cm−1 kunye ne-NH kwi-3424 cm−1. I-spectrum ye-1H-NMR ibonise isignali ye-exchange singlet yee-olefin protons kunye nee-NH protons kwi-9.3 ppm (jonga iCandelo lovavanyo).
Iimole ezimbini ze-acid chloride 4 zaphendulwa ngemole enye ye-phenylhydrazine ukuze kufumaneke i-N-phenylacryloylhydrazine derivative 7 kwisivuno esihle (77%) (Umfanekiso 5). Ulwakhiwo lwe-7 luqinisekiswe yidatha ye-infrared spectroscopy, ebonise ukufunxwa kwamaqela amabini e-C=O kwi-1691 kunye ne-1671 cm−1, ukufunxwa kweqela le-CN kwi-2222 cm−1 kunye nokufunxwa kweqela le-NH kwi-3245 cm−1, kwaye i-spectrum yayo ye-1H-NMR ibonise iqela le-CH kwi-9.15 kunye ne-8.81 ppm kunye ne-NH proton kwi-10.88 ppm (jonga icandelo lovavanyo).
Kolu phononongo, kuphandwe ngempendulo ye-acyl chloride 4 ene-1,3-dinucleophiles. Unyango lwe-acyl chloride 4 ene-2-aminopyridine kwi-1,4-dioxane ene-TEA njengesiseko kubushushu begumbi lunike i-acrylamide derivative 8 (Umfanekiso 5), isakhiwo sayo esichongiweyo kusetyenziswa idatha ye-spectral. Ii-IR spectra zibonise iibhendi zokufunxa ze-cyano ezolula kwi-2222 cm−1, i-NH kwi-3148 cm−1, kunye ne-carbonyl kwi-1665 cm−1; Ii-spectra ze-1H NMR ziqinisekisile ukubakho kwee-olefin protons kwi-9.14 ppm (jonga iCandelo lovavanyo).
I-Compound 4 isabela ne-thiourea ukuze inike i-pyrimidinethione 9; i-compound 4 isabela ne-thiosemicarbazide ukuze inike i-thiopyrazole derivative 10 (Umfanekiso 5). Ulwakhiwo lwee-compounds 9 kunye ne-10 luqinisekiswe ngohlalutyo lwe-spectral kunye ne-elemental (jonga icandelo lovavanyo).
I-Tetrazine-3-thiol 11 yalungiswa nge-reaction ye-compound 4 kunye ne-thiocarbazide njenge-1,4-dinucleophile (Umfanekiso 5), kwaye isakhiwo sayo saqinisekiswa yi-spectroscopy kunye nohlalutyo lwe-elemental. Kwi-spectrum ye-infrared, i-C=N bond yabonakala kwi-1619 cm−1. Kwangaxeshanye, i-spectrum yayo ye-1H-NMR igcine imiqondiso ye-multiplate yee-protons ze-aromatic kwi-7.78–8.66 ppm kunye nee-SH protons kwi-3.31 ppm (jonga iCandelo lovavanyo).
I-Acryloyl chloride 4 iphendula ne-1,2-diaminobenzene, i-2-aminothiophenol, i-anthranilic acid, i-1,2-diaminoethane, kunye ne-ethanolamine njenge-1,4-dinucleophiles ukuze yenze iinkqubo ezintsha ze-heterocyclic (13–16).
Izakhiwo zezi compounds zisandula ukwenziwa ziqinisekiswe ngohlalutyo lwe-spectral kunye nolwe-elemental (jonga icandelo lovavanyo). I-2-Hydroxyphenylacrylamide derivative 17 ifunyenwe ngokusabela nge-2-aminophenol njenge-dinucleophile (Umfanekiso 6), kwaye isakhiwo sayo siqinisekiswe ngohlalutyo lwe-spectral kunye nolwe-elemental. I-infrared spectrum ye-compound 17 ibonise ukuba imiqondiso ye-C=O kunye ne-C≡N ivele kwi-1681 kunye ne-2226 cm−1, ngokulandelelana. Okwangoku, i-spectrum yayo ye-1H-NMR igcine isibonakaliso se-singlet se-olefin proton kwi-9.19 ppm, kwaye i-OH proton ivele kwi-9.82 ppm (jonga icandelo lovavanyo).
I-reaction ye-acid chloride 4 kunye ne-nucleophile enye (umz., i-ethylamine, i-4-toluidine, kunye ne-4-methoxyaniline) kwi-dioxane njenge-solvent kunye ne-TEA njenge-catalyst kubushushu begumbi inike i-green crystalline acrylamide derivatives 18, 19a, kunye ne-19b. Idatha ye-elemental kunye ne-spectral yee-compounds 18, 19a, kunye ne-19b iqinisekisile izakhiwo zezi derivatives (jonga iCandelo lovavanyo) (Umfanekiso 7).
Emva kokuhlola umsebenzi wee-antimicrobial wee-compounds ezahlukeneyo zokwenziwa, kufunyenwe iziphumo ezahlukeneyo njengoko kubonisiwe kwiTheyibhile 1 kunye noMfanekiso 8 (jonga ifayile yomfanekiso). Zonke ii-compounds ezivavanyiweyo zibonise amanqanaba ahlukeneyo okuthintela i-bacterium MRSA ene-Gram-positive, ngelixa i-Gram-negative bacterium Escherichia coli ibonise ukumelana ngokupheleleyo nazo zonke ii-compounds. Ii-compounds ezivavanyiweyo zinokwahlulwa zibe ziindidi ezintathu ngokusekelwe kububanzi bendawo yokuthintela i-MRSA. Udidi lokuqala belulo olusebenzayo kakhulu kwaye lwaluquka ii-compounds ezintlanu (6, 7, 10, 13b kunye ne-14). Ububanzi bendawo yokuthintela yale compounds babusondele kwi-4 cm; ii-compounds ezisebenzayo kakhulu kolu didi yayiyi-compounds 6 kunye ne-13b. Udidi lwesibini belusebenza ngokuphakathi kwaye lwaluquka ezinye ii-compounds ezintlanu (11, 13a, 15, 18 kunye ne-19a). Indawo yokuthintela yale compounds yayiqala kwi-3.3 ukuya kwi-3.65 cm, apho i-compound 11 ibonisa indawo enkulu yokuthintela eyi-3.65 ± 0.1 cm. Kwelinye icala, iqela lokugqibela lalinazo iikhompawundi ezintathu (8, 17 kunye ne-19b) ezinomsebenzi ophantsi kakhulu wokulwa neentsholongwane (ngaphantsi kwe-3 cm). Umfanekiso 9 ubonisa ukusasazwa kweendawo ezahlukeneyo zokuthintelwa.
Uphando olongezelelekileyo ngomsebenzi we-antimicrobial weekhompawundi ezivavanyiweyo lubandakanye ukufunyanwa kwe-MIC kunye ne-MBC kwikhompawundi nganye. Iziphumo zahluka kancinci (njengoko kubonisiwe kwiTheyibhile 2, 3 kunye noMfanekiso 10 (jonga ifayile yomfanekiso)), apho iikhompawundi 7, 11, 13a kunye ne-15 kubonakala ngathi zihlelwe ngokutsha njengeekhompawundi ezilungileyo. Zazinamaxabiso aphantsi e-MIC kunye ne-MBC (39.06 μg/100 μL). Nangona iikhompawundi 7 kunye ne-8 zazinamaxabiso aphantsi e-MIC (9.7 μg/100 μL), amaxabiso azo e-MBC ayephezulu (78.125 μg/100 μL). Ke ngoko, zazithathwa njengezibuthathaka kuneekhompawundi ezikhankanyiweyo ngaphambili. Nangona kunjalo, ezi khompawundi zintandathu zazizezona zisebenzayo kwezo zivavanyiweyo, njengoko amaxabiso azo e-MBC ayengaphantsi kwe-100 μg/100 μL.
Iikhompawundi (10, 14, 18 kunye ne-19b) bezingasebenzi kangako xa kuthelekiswa nezinye iikhompawundi ezivavanyiweyo njengoko amaxabiso azo e-MBC ayeqala kwi-156 ukuya kwi-312 μg/100 μL. Kwelinye icala, iikhompawundi (8, 17 kunye ne-19a) bezingengathembisi kangako njengoko zazinamaxabiso aphezulu e-MBC (625, 625 kunye ne-1250 μg/100 μL, ngokulandelelana).
Okokugqibela, ngokwemigangatho yokunyamezelana eboniswe kwiTheyibhile 3, iikhompawundi ezivavanyiweyo zingahlulwa zibe ngamacandelo amabini ngokusekwe kwindlela yazo yokusebenza: iikhompawundi ezinefuthe lokubulala iintsholongwane (7, 8, 10, 11, 13a, 15, 18, 19b) kunye neekhompawundi ezinefuthe lokubulala iintsholongwane (6, 13b, 14, 17, 19a). Phakathi kwazo, iikhompawundi 7, 11, 13a kunye ne-15 ziyathandwa, ezibonisa umsebenzi wokubulala ngoxinzelelo oluphantsi kakhulu (39.06 μg/100 μL).
Iikhompawundi ezilishumi kwezilishumi elinesithathu ezivavanyiweyo zibonise ukuba zinamandla okulwa ne-methicillin-resistant Staphylococcus aureus (MRSA) engamelani namayeza okulwa neentsholongwane. Ke ngoko, kucetyiswa ukuba kuhlolwe ngakumbi iintsholongwane ezimelana namayeza okulwa neentsholongwane (ingakumbi iintsholongwane zasekuhlaleni ezigubungela iintsholongwane zeGram-positive kunye neGram-negative) kunye negwele ezibangela iintsholongwane, kunye novavanyo lwe-cytotoxic lwekhompawundi nganye ukuze kuhlolwe ukhuseleko lwayo.
Izifundo zokufaka iimolekyuli kwi-molecular docking zenziwe ukuvavanya amandla eekhompawundi ezidityanisiweyo njengezithinteli zeproteni yokubopha i-penicillin 2a (PBP2a) kwi-methicillin-resistant Staphylococcus aureus (MRSA). I-PBP2a yi-enzyme ephambili ebandakanyeka kwi-biosynthesis yodonga lweeseli zebhaktiriya, kwaye ukuthintela le enzyme kuphazamisa ukwakheka kodonga lweeseli, ekugqibeleni okukhokelela kwi-bacterial lysis kunye nokufa kweeseli1. Iziphumo zokufaka iikhompawundi zidweliswe kwiTheyibhile 4 kwaye zichazwe ngokweenkcukacha kwifayile yedatha eyongezelelweyo, kwaye iziphumo zibonisa ukuba iikhompawundi ezininzi zibonise ulwalamano oluqinileyo lokubopha kwi-PBP2a, ngakumbi iintsalela zesiza ezisebenzayo eziphambili ezifana neLys 273, Lys 316, kunye ne-Arg 298. Ukusebenzisana, kubandakanya ukubophelela i-hydrogen kunye ne-π-stacking, kwakufana kakhulu nokwe-co-crystallized quinazolinone ligand (CCL), ebonisa amandla ezi khompawundi njengezithinteli ezinamandla.
Idatha ye-molecular docking, kunye nezinye iiparameter zokubala, icebisa ngamandla ukuba i-PBP2a inhibition yeyona ndlela iphambili enoxanduva lomsebenzi we-antibacterial obonweyo wezi compounds. Amanqaku e-docking kunye ne-root mean square deviation (RMSD) values ​​​​zityhile ngakumbi i-binding affinity kunye nozinzo, zixhasa le ngcamango. Njengoko kubonisiwe kwiTheyibhile 4, ngelixa ii-compounds ezininzi zibonise i-binding affinity elungileyo, ezinye ii-compounds (umz., 7, 9, 10, kunye ne-14) zazinamanqaku aphezulu e-docking kune-ligand edibeneyo, ebonisa ukuba zinokuba nokusebenzisana okunamandla nee-residues ezisebenzayo ze-PBP2a. Nangona kunjalo, ii-compounds ezisebenzayo kakhulu ze-bio 6 kunye ne-13b zibonise amanqaku aphantsi kancinci e-docking (-5.98 kunye ne--5.63, ngokulandelelana) xa kuthelekiswa nezinye ii-ligands. Oku kubonisa ukuba nangona amanqaku e-docking angasetyenziselwa ukuqikelela i-binding affinity, ezinye izinto (umz., uzinzo lwe-ligand kunye nokusebenzisana kwee-molecular kwindawo yendalo) nazo zidlala indima ebalulekileyo ekumiseleni umsebenzi we-antibacterial. Okuphawulekayo kukuba, amaxabiso e-RMSD azo zonke iikhompawundi ezenziweyo ayengaphantsi kwe-2 Å, nto leyo eqinisekisa ukuba ukuma kwazo kwe-docking kuhambelana ngokwesakhiwo nokwakheka kokubopha kwe-ligand edibeneyo, exhasa ngakumbi amandla azo njenge-inhibitors ezinamandla ze-PBP2a.
Nangona amanqaku okufaka i-docking kunye namaxabiso e-RMS ebonelela ngezibikezelo ezixabisekileyo, ulwalamano phakathi kwezi ziphumo zokufaka i-docking kunye nomsebenzi we-antimicrobial alusoloko lucacile ekuqaleni. Nangona ukuthintela kwe-PBP2a kuxhaswa kakhulu njengento ephambili echaphazela umsebenzi we-antimicrobial, umahluko oliqela ubonisa ukuba ezinye iipropati zebhayoloji nazo zidlala indima ebalulekileyo. Iikhompawundi 6 kunye ne-13b zibonise umsebenzi ophezulu we-antimicrobial, zombini ububanzi bendawo yokuthintela obuyi-4 cm kunye namaxabiso aphantsi e-MIC (9.7 μg/100 μL) kunye ne-MBC (78.125 μg/100 μL), nangona amanqaku azo aphantsi okufaka i-docking xa kuthelekiswa neekhompawundi 7, 9, 10 kunye ne-14. Oku kubonisa ukuba nangona ukuthintela kwe-PBP2a kunegalelo kumsebenzi we-antimicrobial, izinto ezinje ngokunyibilika, ukufumaneka kwezinto eziphilayo kunye ne-dynamics yokusebenzisana kwindawo yebhaktheriya nazo zichaphazela umsebenzi uphela. Umfanekiso 11 ubonisa iindlela zazo zokufaka i-docking, obonisa ukuba zombini iikhompawundi, nokuba zinamanqaku okubopha aphantsi, zisenako ukusebenzisana neentsalela eziphambili ze-PBP2a, ezinokuzinzisa i-inhibition complex. Oku kugxininisa ukuba nangona i-molecular docking inika ulwazi olubalulekileyo malunga nokuthintela i-PBP2a, ezinye izinto zebhayoloji kufuneka ziqwalaselwe ukuze ziqonde ngokupheleleyo imiphumo yokwenyani ye-antimicrobial yezi zinto.
Kusetyenziswa isakhiwo sekristale sePBP2a (PDB ID: 4CJN), kwakhiwe iimephu zentsebenziswano ze-2D kunye ne-3D zeekhompawundi ezisebenzayo kakhulu i-6 kunye ne-13b ezifakwe kwi-penicillin-binding protein 2a (PBP2a) ye-methicillin-resistant Staphylococcus aureus (MRSA). Ezi mephu zithelekisa iipateni zentsebenziswano zezi khompawundi kunye ne-re-docked co-crystallized quinazolinone ligand (CCL), zigxininisa ukusebenzisana okubalulekileyo okufana ne-hydrogen bonding, i-π-stacking, kunye nokusebenzisana kwe-ionic.
Kubonwe umzekelo ofanayo kwi-compound 7, ebonise amanqaku aphezulu okubeka i-docking (-6.32) kunye nobubanzi obufanayo be-inhibition zone (3.9 cm) kwi-compound 10. Nangona kunjalo, i-MIC yayo (39.08 μg/100 μL) kunye ne-MBC (39.06 μg/100 μL) yayiphezulu kakhulu, nto leyo ebonisa ukuba ifuna uxinaniso oluphezulu ukuze ibonise isiphumo sokulwa neentsholongwane. Oku kuthetha ukuba nangona i-compound 7 ibonise ukuqina okuqinileyo kwizifundo zokubeka i-docking, izinto ezinje ngokufumaneka kwezinto eziphilayo, ukufunxwa kweeseli, okanye ezinye iipropati ze-physicochemical zinokunciphisa ukusebenza kwayo kwezinto eziphilayo. Nangona i-compound 7 ibonise iipropati ze-bactericidal, yayingasebenzi kakuhle ekuthinteleni ukukhula kweentsholongwane xa kuthelekiswa nee-compound 6 kunye ne-13b.
I-Compound 10 ibonise umahluko omkhulu ngakumbi ngenqaku eliphezulu lokumisa (-6.40), ebonisa ukuqina okuqinileyo kokubopha kwi-PBP2a. Nangona kunjalo, umda wayo wobubanzi bokuthintela (3.9 cm) wawufana ne-compound 7, kwaye i-MBC yayo (312 μg/100 μL) yayiphezulu kakhulu kune-compound 6, 7, kunye ne-13b, ebonisa umsebenzi obuthathaka we-bacterial. Oku kuthetha ukuba nangona uqikelelo oluhle lokumisa, i-compound 10 yayingasebenzi kakuhle ekubulaleni i-MRSA ngenxa yezinye izinto ezithintelayo ezifana nokunyibilika, ukuzinza, okanye ukungena kakuhle kwe-membrane yebhaktiriya. Ezi ziphumo zixhasa ukuqonda ukuba nangona ukumisa kwe-PBP2a kudlala indima ebalulekileyo kumsebenzi wokumisa, ayichazi ngokupheleleyo umahluko kwimisebenzi yebhayoloji ebonwe phakathi kwee-compounds ezivavanyiweyo. Olu mahluko lubonisa ukuba kufuneka uhlalutyo olongezelelweyo lovavanyo kunye novavanyo olunzulu lwebhayoloji ukuze kucaciswe ngokupheleleyo iindlela zokumisa ezibandakanyekayo.
Ukufakwa kweemolekyuli kwiTheyibhile 4 kunye neFayile yeDatha eyoNgezelelweyo igxininisa ubudlelwane obunzima phakathi kwamanqaku okufakwa kweedokhi kunye nomsebenzi wokulwa neentsholongwane. Nangona iikhompawundi 6 kunye ne-13b zinezinga eliphantsi lokufakwa kweedokhi kuneekhompawundi 7, 9, 10, kunye ne-14, zibonisa umsebenzi ophezulu wokulwa neentsholongwane. Iimephu zazo zokusebenzisana (eziboniswe kuMfanekiso 11) zibonisa ukuba nangona ziphantsi kakhulu, zisakha iibhondi zehydrogen kunye nokusebenzisana kwe-π-stacking kunye neentsalela eziphambili ze-PBP2a ezinokuzinzisa i-enzyme-inhibitor complex ngendlela enenzuzo ngokwebhayoloji. Nangona ziphantsi kakhulu ii-docking scores ze-6 kunye ne-13b, umsebenzi wazo wokulwa neentsholongwane ucebisa ukuba ezinye iimpawu ezifana nokunyibilika, ukuzinza, kunye nokufunxwa kweeseli kufuneka ziqwalaselwe kunye nedatha yokufakwa kweedokhi xa kuvavanywa amandla okuthintela. Oku kugxininisa ukubaluleka kokudibanisa izifundo zokufakwa kweedokhi kunye nohlalutyo lovavanyo lokulwa neentsholongwane ukuze kuvavanywe ngokuchanekileyo amandla okunyanga eekhompawundi ezintsha.
Ezi ziphumo zibonisa ukuba nangona i-molecular docking isisixhobo esinamandla sokuqikelela ukuhambelana kokubopha kunye nokuchonga iindlela ezinokubakho zokuthintela, akufanele kuthenjelwe kuyo yodwa ukumisela ukusebenza kakuhle kwe-antimicrobial. Idatha ye-molecular ibonisa ukuba ukuthintela kwe-PBP2a yinto ephambili echaphazela umsebenzi we-antimicrobial, kodwa utshintsho kwimisebenzi yebhayoloji lubonisa ukuba ezinye iipropati ze-physicochemical kunye ne-pharmacokinetic kufuneka ziphuculwe ukuphucula ukusebenza kakuhle kwezonyango. Izifundo zexesha elizayo kufuneka zigxile ekuphuculeni ulwakhiwo lweekhemikhali lwee-compounds 7 kunye ne-10 ukuphucula ukufumaneka kwe-bioavailability kunye nokuthathwa kweeseli, ukuqinisekisa ukuba ukusebenzisana okunamandla kwe-docking kuguqulelwa kumsebenzi wokwenyani we-antimicrobial. Izifundo ezongezelelweyo, kubandakanya uvavanyo olongezelelweyo lwe-bioassays kunye nohlalutyo lobudlelwane besakhiwo-umsebenzi (SAR), ziya kuba yimfuneko ekuqondeni ngakumbi indlela ezi compounds ezisebenza ngayo njengezithinteli ze-PBP2a kunye nokuphuhlisa ii-arhente ze-antimicrobial ezisebenzayo ngakumbi.
Iikhompawundi ezenziwe kwi-3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 zibonise amanqanaba ahlukeneyo omsebenzi wokulwa neentsholongwane, kunye neekhompawundi ezininzi ezibonisa ukuthintela okukhulu kwe-methicillin-resistant Staphylococcus aureus (MRSA). Uhlalutyo lobudlelwane bolwakhiwo (i-SAR) lutyhile iimpawu ezibalulekileyo zesakhiwo ezisisiseko sokusebenza kakuhle kweekhompawundi zokulwa neentsholongwane.
Ukubakho kwamaqela e-acrylonitrile kunye ne-anthracene kubonakalise ukuba kubalulekile ekuphuculeni umsebenzi we-antimicrobial. Iqela le-nitrile elisabela kakhulu kwi-acrylonitrile liyimfuneko ukuze kube lula ukusebenzisana neeproteni zebhaktiriya, ngaloo ndlela linegalelo kwiimpawu ze-antimicrobial zekhompawundi. Iikhompawundi eziqulethe i-acrylonitrile kunye ne-anthracene zibonise rhoqo iziphumo ezinamandla ze-antimicrobial. Ivumba elimnandi leqela le-anthracene lizinzise ngakumbi ezi khompawundi, nto leyo enokuphucula umsebenzi wazo webhayoloji.
Ukungeniswa kweeringi ze-heterocyclic kuphucule kakhulu ukusebenza kakuhle kwee-antibacterial kwee-derivatives ezininzi. Ngokukodwa, i-benzothiazole derivative 13b kunye ne-acrylhydrazide derivative 6 zibonise umsebenzi ophezulu we-antibacterial kunye nendawo yokuthintela malunga ne-4 cm. Ezi heterocyclic derivatives zibonise iziphumo ezibalulekileyo zebhayoloji, nto leyo ebonisa ukuba ulwakhiwo lwe-heterocyclic ludlala indima ebalulekileyo kwiziphumo ze-antibacterial. Ngokufanayo, i-pyrimidinethione kwi-compound 9, i-thiopyrazole kwi-compound 10, kunye ne-tetrazine ring kwi-compound 11 zinegalelo kwiimpawu ze-antibacterial zee-compounds, nto leyo egxininisa ngakumbi ukubaluleka kokuguqulwa kwe-heterocyclic.
Phakathi kweekhompawundi ezidityanisiweyo, i-6 kunye ne-13b zahlukile ngemisebenzi yazo emihle kakhulu yokulwa neentsholongwane. I-minimum inhibitory concentration (MIC) yekhompawundi 6 yayiyi-9.7 μg/100 μL, kwaye i-minimum bactericidal concentration (MBC) yayiyi-78.125 μg/100 μL, nto leyo ebonakalisa amandla ayo abalaseleyo okususa i-methicillin-resistant Staphylococcus aureus (MRSA). Ngokufanayo, i-compound 13b yayinendawo yokuthintela eyi-4 cm kunye namaxabiso aphantsi e-MIC kunye ne-MBC, okuqinisekisa umsebenzi wayo onamandla wokulwa neentsholongwane. Ezi ziphumo zibonisa iindima eziphambili zamaqela asebenzayo e-acrylohydrazide kunye ne-benzothiazole ekumiseleni ukusebenza kakuhle kwezi khompawundi.
Ngokwahlukileyo koko, iikhompawundi 7, 10, kunye ne-14 zibonise umsebenzi ophakathi wokulwa neentsholongwane kunye neendawo zokuthintela ukusuka kwi-3.65 ukuya kwi-3.9 cm. Ezi khompawundi zazifuna uxinaniso oluphezulu ukuze zibulale ngokupheleleyo iintsholongwane, njengoko kuboniswa ngamaxabiso azo aphezulu e-MIC kunye ne-MBC. Nangona ezi khompawundi zazingasebenzi kangako kuneekhompawundi 6 kunye ne-13b, zisabonisa amandla amakhulu okulwa neentsholongwane, nto leyo ebonisa ukuba ukufakwa kwee-acrylonitrile kunye ne-anthracene kwiringi ye-heterocyclic kunegalelo kwisiphumo sazo sokulwa neentsholongwane.
Ezi khompawundi zineendlela ezahlukeneyo zokusebenza, ezinye zibonisa iipropati zokubulala iintsholongwane kwaye ezinye zibonisa iziphumo zebhakteria. Iikhompawundi 7, 11, 13a, kunye ne-15 zibulala iintsholongwane kwaye zifuna amazinga aphantsi okubulala iintsholongwane ngokupheleleyo. Ngokwahlukileyo koko, iikhompawundi 6, 13b, kunye ne-14 zibulala iintsholongwane kwaye zinokuthintela ukukhula kweentsholongwane kumanqanaba aphantsi, kodwa zifuna amazinga aphezulu okubulala iintsholongwane ngokupheleleyo.
Ngokubanzi, uhlalutyo lobudlelwane bolwakhiwo nomsebenzi lubonisa ukubaluleka kokungenisa ii-acrylonitrile kunye ne-anthracene kunye nezakhiwo ze-heterocyclic ukufezekisa umsebenzi obalulekileyo wokulwa neentsholongwane. Ezi ziphumo zibonisa ukuba ukwenziwa ngcono kwezi nxalenye zesakhiwo kunye nokuhlolwa kotshintsho olongezelelweyo ukuphucula ukunyibilika kunye nokuvuleka kwe-membrane kunokukhokelela ekuphuhlisweni kwamayeza alwa ne-MRSA asebenzayo ngakumbi.
Zonke ii-reagents kunye nezinyibilikisi zacocwa zaza zomiswa kusetyenziswa iinkqubo eziqhelekileyo (e-El Gomhouria, e-Egypt). Amanqaku okunyibilika afunyenwe kusetyenziswa isixhobo se-elektroniki se-GallenKamp melting point kwaye axelwa ngaphandle kokulungiswa. Ii-infrared (IR) spectra (cm⁻1) zarekhodwa kwiSebe leKhemistri, kwi-Faculty of Science, kwiYunivesithi yase-Ain Shams kusetyenziswa ii-pellets ze-potassium bromide (KBr) kwi-Thermo Electron Nicolet iS10 FTIR spectrometer (e-Thermo Fisher Scientific, e-Waltham, e-MA, e-USA).
Iispectra ze-1H NMR zifunyenwe kwi-300 MHz kusetyenziswa i-GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) kunye ne-BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.). I-Tetramethylsilane (TMS) isetyenziswe njengomgangatho wangaphakathi one-deuterated dimethyl sulfoxide (DMSO-d₆). Ukulinganiswa kwe-NMR kwenziwe kwi-Faculty of Science, kwiYunivesithi yaseCairo, eGiza, e-Egypt. Uhlalutyo lwe-Elemental (CHN) lwenziwe kusetyenziswa i-Perkin-Elmer 2400 Elemental Analyzer kwaye iziphumo ezifunyenweyo ziyavumelana kakuhle namaxabiso abaliweyo.
Umxube we-asidi 3 (5 mmol) kunye ne-thionyl chloride (5 ml) ufudunyezwe kumanzi okuhlamba kwi-65 °C kangangeeyure ezi-4. I-thionyl chloride engaphezulu isuswe ngokuhluzwa phantsi koxinzelelo oluncitshisiweyo. I-red solid ephumayo yaqokelelwa yaza yasetyenziswa ngaphandle kokucocwa ngakumbi. Iqondo lokunyibilika: 200-202 °C, isivuno: 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. Umhlalutyi. Ibalwe kwi-C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Ifunyenwe: C, 74.41; H, 3.34; N, 4.66%.
Kwi-0°C, ii-4 (2 mmol, 0.7 g) zanyibilika kwi-anhydrous dioxane (20 ml) kwaye i-hydrazine hydrate (2 mmol, 0.16 ml, 80%) yongezwa ngokuhla yaza yaxutywa iyure e-1. I-precipitated solid yaqokelelwa ngokuhluzwa yaza yaphinda yafakwa kwi-ethanol ukuze inike i-compound 6.
Iikristale eziluhlaza, iqondo lokunyibilika eliyi-190-192℃, isivuno singu-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, iyatshintshwa), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Ixabiso elibaliweyo le-C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Ifunyenwe: C, 84.01; H, 4.38; N, 8.05%.
Nyibilikisa i-4 (2 mmol, 0.7 g) kwi-20 ml yesisombululo se-anhydrous dioxane (equlethe amaconsi ambalwa e-triethylamine), yongeza i-phenylhydrazine/2-aminopyridine (2 mmol) uze uyixube kubushushu begumbi iyure e-1 neye-2, ngokulandelelana. Galela umxube we-reaction kwiqhwa okanye emanzini uze wenze i-acidify nge-dilute hydrochloric acid. Hluza i-solid ehlukanisiweyo uze uphinde uyixube kwi-ethanol ukuze ufumane i-7 uze uphinde uyixube kwi-benzene ukuze ufumane i-8.
Iikristale eziluhlaza, iqondo lokunyibilika eliyi-160-162℃, isivuno singu-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, iyatshintshwa), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Ixabiso elibaliweyo le-C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Ifunyenwe: C, 81.96; H, 3.91; N, 8.91%.
I-4 (2 mmol, 0.7 g) yanyibilika kwi-20 ml yesisombululo se-anhydrous dioxane (equlethe amaconsi ambalwa e-triethylamine), kongezwa i-2-aminopyridine (2 mmol, 0.25 g) kwaye umxube wavuselelwa kubushushu begumbi iiyure ezi-2. Umxube we-reaction wagalelwa emanzini omkhenkce waza wafakwa i-asidi nge-dilute hydrochloric acid. I-precipitate eyenziweyo yahluzwa yaza yaphinda yasetyenziswa kwi-benzene, yanika iikristale eziluhlaza ze-8 kunye nendawo yokunyibilika ye-146-148 °C kunye nesivuno se-82.5%; i-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, iyatshintshwa), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); Ibalwe kwi-C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Ifunyenwe: C, 78.93; H, 3.97; N, 12.36%.
I-Compound 4 (2 mmol, 0.7 g) yanyibilikiswa kwi-20 ml ye-dioxane eyomileyo (equlethe amaconsi ambalwa e-triethylamine kunye ne-2 mmol ye-thiourea/semicarbazide) yaza yafudunyezwa phantsi kwe-reflux iiyure ezi-2. I-solvent yatshintshwa yaba ngumphunga kwi-vacuo. Intsalela yaphinda yatshintshwa yaba yi-dioxane ukuze inike umxube.