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I-synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yakhiwa begodu yasetjenziselwa ukwenza iinhlobo ezihlukahlukeneko zama-heterocyclic asebenza khulu ngokusabela kwayo nama-nitrogen nucleophiles ahlukahlukeneko. Isakhiwo sekhompawundi ngayinye ye-heterocyclic eyakhiweko sahlathululwa kuhle ngokusebenzisa ukuhlaziywa kwe-spectroscopic ne-elemental. Amakhompawundi alitjhumi kwalitjhumi nantathu we-heterocyclic atjengise ukusebenza okukhuthazako malungana namabhaktheriya ajamelana nemithi eminengi (i-MRSA). Hlangana nawo, amakhompawundi 6, 7, 10, 13b, kanye no-14 atjengisa ukusebenza okuphezulu khulu kokulwa namagciwane ngeendawo zokuvimbela eziseduze ne-4 cm. Kodwana, iimfundo zokuhlanganisa amamolekhyuli ziveze bona amakhompawundi la anendlela ehlukileko yokubopha iphrotheyini ebopha i-penicillin 2a (PBP2a), okuyinhloso eqakathekileko yokujamelana ne-MRSA. Amanye amakhompawundi afana ne-7, 10 kanye ne-14 atjengisa ukubophelela okuphezulu nokuzinza kokusebenzisana endaweni esebenzako ye-PBP2a nayiqathaniswa ne-co-crystallized quinazolinone ligand. Ngokuphikisako, amakhompawundi 6 no-13b bekanama-docking aphasi kodwana atjengisa ukusebenza okukhulu kokulwa namagciwane, lapho ikhompawundi 6 inamazinga aphasi khulu we-MIC (9.7 μg/100 μL) kanye ne-MBC (78.125 μg/100 μL). Ukuhlaziywa kokudosa kuveze ukusebenzisana okuqakathekileko okufaka hlangana ukubopha kwe-hydrogen kanye ne-π-stacking, khulukhulu ngeensalela ezifana ne-Lys 273, i-Lys 316 kanye ne-Arg 298, ezabonwa njengezisebenzisana ne-co-crystallized ligand esakhiweni se-crystal se-PBP2a. Iinsalela lezi ziqakathekile emsebenzini we-enzymatic we-PBP2a. Imiphumela le iveza bona amakhompawundi akhiqiziweko angasebenza njengemithi ethembisako yokulwa ne-MRSA, okuveza ukuqakatheka kokuhlanganisa ukudosa kwamamolekhyuli nama-bioassays ukukhomba iindlela zokwelapha eziphumelelako.
Eminyakeni embalwa yokuthoma yekhulu leminyaka, imizamo yokurhubhulula beyigxile khulu ekuthuthukiseni iindlela ezitjha, ezilula neendlela zokuhlanganisa amahlelo amanengi amatjha we-heterocyclic anomsebenzi wokulwa namagciwane ngokusebenzisa izinto zokuthoma ezitholakala lula.
Iingcenye ze-acrylonitrile zithathwa njengezinto eziqakathekileko zokuthoma zokwakhiwa kweenhlelo ezinengi eziphawulekako ze-heterocyclic ngombana ziinhlanganisela eziphendula khulu. Ngaphezu kwalokho, i-2-cyanoacryloyl chloride derivatives sele isetjenziswe khulu eminyakeni esanda kwedlula ekuthuthukisweni nasekuhlanganisweni kwemikhiqizo eqakathekileko emkhakheni wokusetjenziswa kwemithi, njengemithi ephakathi1,2,3, ama-precursors we-anti-HIV, antiviral, anticancer, antibacterial, antidepressant kanye ne-antioxidant ama-ejenti4,5,6,7,8,9,10. Mhlapha nje, ukusebenza kwezinto eziphilako kwe-anthracene kanye nezinto ezivela kiyo, okufaka hlangana i-antibiotic yayo, i-anticancer11,12, i-antibacterial13,14,15 kanye nezakhiwo zokubulala iinunwana16,17, zidose ukutjhejwa okukhulu18,19,20,21. Amakhompawundi we-antimicrobial ane-acrylonitrile kanye nama-anthracene atjengiswa emifanekisweni 1 no-2.
Ngokuya kwe-World Health Organization (WHO) (2021), ukujamelana nama-antimicrobial (AMR) kuyingozi ephasini loke epilweni nentuthukweni22,23,24,25. Iingulani angeze zalapheka, okwenza bona zihlale isikhathi eside esibhedlela begodu zitlhoge imithi ebiza khulu, kanye nokuhlongakala nokukhubazeka okukhulu. Ukutlhogeka kwama-antimicrobial asebenzako kuvamise ukurholela ekutheni kube nokubhalelwa ukwelatjhwa kwemiraro ehlukahlukeneko, khulukhulu ngesikhathi sokwelatjhwa ngamakhemikhali nokuhlinzwa okukhulu.
Ngokuya kombiko we-World Health Organization 2024, i-Staphylococcus aureus (MRSA) ne-E. coli ezijamelana ne-methicillin zifakwe erhelweni lamagciwane aqakathekileko. Bobabili amabhaktheriya ajamelana nama-anthibhayothikhi amanengi, njeke ajamele ukutheleleka okubudisi ukuwelapha nokulawulwa, begodu kunesidingo esirhabekileko sokuthuthukisa amakhompawundi amatjha asebenzako wokulwisana nama-microbial ukurarulula umraro lo. I-Anthracene kanye nama-antimicrobials aziwako angasebenza emagciwaneni ama-Gram-positive nama-Gram-negative. Umnqopho waloluphenyo kukwenza umkhiqizo omutjha ongalwisana namagciwani ayingozi epilwenakho.
Ihlangano yezamaphilo yephasi loke (i-WHO) ibika bona amagciwani amanengi ajamelana nama-antibiotic amanengi, kufaka hlangana i-staphylococcus aureus (MRSA) engajamelani ne-methicillin, okuyimbangela evamileko yokutheleleka emphakathini neendaweni zokunakekelwa kwezamaphilo. Iingulani ezine-MRSA zibikwa bona zinezinga lokuhlongakala eliphezulu ngama-64% kunalezo ezineemraro ezitheleleka ngeendakamizwa. Ukungezelela, i-E. coli ibeka ingozi ephasini loke ngombana indlela yokugcina yokuzivikela e-Enterobacteriaceae (okutjho, i-E. coli) ejamelana ne-carbapenem yi-colistin, kodwana amagciwani ajamelana ne-colistin asanda kubikwa emazweni amanengi. 22,23,24,25
Ngalokho-ke, ngokuya kwehlelo lokusebenza le-World Health Organization on Antimicrobial Resistance26, kunesidingo esiphuthumako sokutholwa nokuhlanganiswa kwama-antimicrobials amatjha. Amandla amakhulu we-anthracene ne-acrylonitrile njenge-antibacterial27, antifungal28, anticancer29 kanye nama-antioxidant30 kuvezwe emaphepheni amanengi agadangisiweko. Malungana nalokhu, kungatjhiwo bona ama-derivatives la alungele ukusetjenziswa malungana ne-methicillin-resistant Staphylococcus aureus (MRSA).
Ukubuyekezwa kwemibhalo yangaphambilini kwasikhuthaza bona sihlanganise ama-derivative amatjha emakilasini la. Ngalokho-ke, irhubhululo lamanje belihlose ukuthuthukisa amahlelo amatjha we-heterocyclic ane-anthracene kanye ne-acrylonitrile moieties, ukuhlola ukusebenza kwawo kokulwa namagciwane nokulwisana namagciwane, nokuphenya ukusebenzisana kwawo okungenzeka kokubopha ne-penicillin-binding protein 2a (PBP2a) ngokusebenzisa i-molecular docking. Ukwakha phezu kweemfundo zangaphambilini, irhubhululo lamanje liragele phambili nokuhlanganiswa, ukuhlolwa kwezinto eziphilako, nokuhlaziywa kwekhomphyutha kwamahlelo we-heterocyclic ukukhomba ama-ejenti we-antimethicillin-resistant Staphylococcus aureus (MRSA) ane-PBP2a enamandla yokuvimbela umsebenzi31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Irhubhululo lethu lamanje ligxile ekuhlanganisweni nokuhlolwa kwe-antimicrobial yamakhompawundi amasha we-heterocyclic ane-anthracene kanye nama-acrylonitrile moieties. I-3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yalungiswa begodu yasetjenziswa njengesisekelo sokwakha amahlelo amatjha we-heterocyclic.
Isakhiwo sekhompawundi 4 satholwa kusetjenziswa idatha ye-spectral. I-1H-NMR spectrum itjengise ubukhona be-CH= ku-9.26 ppm, i-IR spectrum itjengise ubukhona beqembu le-carbonyl ku-1737 cm−1 kanye neqembu le-cyano ku-2224 cm−1, begodu i-13CNMR spectrum nayo yaqinisekisa isakhiwo esiphakanyisiweko (bona isigaba sokulinga).
Ukuhlanganiswa kwe-3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kwenziwa ngokusebenzisa i-hydrolysis yamaqembu we-aromatic 250, 41, 42, 53 ngesisombululo se-ethanolic sodium hydroxide (10%) ukunikela ama-asidi 354, 45, 66, bese aphathwa nge-thionyl yamanzi ukugeza ukunikela i-acryloyl chloride derivative 4 ngesivuno esiphezulu (88.5%), njengombana kutjengiswe kuMfanekiso 3.
Ukwenza amakhompawundi amatjha we-heterocyclic anekghono elilindelweko lokulwa namagciwani, ukusabela kwe-acyl chloride 4 nama-dinucleophiles ahlukahlukeneko kwenziwa.
I-esidi ye-chloride 4 yaphathwa nge-hydrazine hydrate ku-0° nge-awa elilodwa. Ngebhadi, i-pyrazolone 5 azange itholakale. Umkhiqizo bewuyi-acrylamide derivative isakhiwo sayo saqinisekiswa yidatha ye-spectral. I-IR spectrum yayo itjengise amabhande wokumuncwa we-C=O ku-1720 cm−1, C≡N ku-2228 cm−1 kanye ne-NH ku-3424 cm−1. I-1H-NMR spectrum itjengise isiginali yokutjhinisana yamaphrothoni we-olefin namaphrothoni we-NH ku-9.3 ppm (qala iSigaba sokuHlola).
Ama-mole amabili we-acid chloride 4 ahlanganiswa ne-mole eyodwa ye-phenylhydrazine ukukhiqiza i-N-phenylacryloylhydrazine derivative 7 ngesivuno esihle (77%) (Umfanekiso 5). Isakhiwo se-7 saqinisekiswa yidatha ye-infrared spectroscopy, eyatjengisa ukumuncwa kwamaqembu amabili we-C=O ku-1691 no-1671 cm−1, ukumuncwa kweqembu le-CN ku-2222 cm−1 kanye nokumuncwa kweqembu le-NH ku-3245 cm−1, begodu i-spectrum yayo ye-1H-NMR itjengise isiqhema se-CCH ku-15 no-18 ppm. Iprothoni ye-NH ku-10.88 ppm (qala isigaba sokulinga).
Kulesi sifundo, ukusabela kwe-acyl chloride 4 nama-1,3-dinucleophiles kwaphenywa. Ukuphathwa kwe-acyl chloride 4 nge-2-aminopyridine ku-1,4-dioxane nge-TEA njengesisekelo emazingeni womtjhiso wegumbi kwanikela nge-acrylamide derivative 8 (Umfanekiso 5), isakhiwo sayo sakhonjwa kusetjenziswa idatha ye-spectral. I-IR spectra itjengise amabhande wokudonsa we-cyano alula ku-2222 cm−1, i-NH ku-3148 cm−1, kanye ne-carbonyl ku-1665 cm−1; I-1H NMR spectra iqinisekise ubukhona bamaphrothoni we-olefin ku-9.14 ppm (qala iSigaba sokuHlola).
Ikhompawundi 4 ihlangana ne-thiourea ukunikela i-pyrimidinethione 9; ikhompawundi 4 isabelana ne-thiosemicarbazide ukunikela i-thiopyrazole derivative 10 (Umfanekiso 5). Izakhiwo zamakhompawundi 9 no-10 zaqinisekiswa ngokuhlaziywa kwe-spectral ne-elemental (bona isigaba sokulinga).
I-Tetrazine-3-thiol 11 yalungiswa ngokusabela kwe-compound 4 ne-thiocarbazide njenge-1,4-dinucleophile (Umfanekiso 5), begodu isakhiwo sayo saqinisekiswa nge-spectroscopy nokuhlaziywa kwe-elemental. Ku-infrared spectrum, isibopho se-C=N sivele ku-1619 cm−1. Ngesikhathi esifanako, i-1H-NMR spectrum yayo igcine amatshwayo we-multiplate wamaphrothoni we-aromatic ku-7.78–8.66 ppm kanye namaphrothoni we-SH ku-3.31 ppm (qala iSigaba sokuHlola).
I-Acryloyl chloride 4 ihlangana ne-1,2-diaminobenzene, 2-aminothiophenol, i-anthranilic acid, i-1,2-diaminoethane, kanye ne-ethanolamine njenge-1,4-dinucleophiles ukwakha amahlelo amatjha we-heterocyclic (13–16).
Izakhiwo zamakhompawundi asanda kwenziwa zaqinisekiswa ngokuhlaziywa kwe-spectral ne-elemental (bona isigaba sokulinga). I-2-Hydroxyphenylacrylamide derivative 17 yatholwa ngokusabelana ne-2-aminophenol njenge-dinucleophile (Umfanekiso 6), begodu isakhiwo sayo saqinisekiswa ngokuhlaziywa kwe-spectral ne-elemental. I-infrared spectrum ye-compound 17 itjengise bona amatshwayo we-C=O kanye ne-C≡N avela ku-1681 no-2226 cm−1, ngokulandelana. Ngalesosikhathi, i-1H-NMR spectrum yayo igcine isignali ye-olefin proton ku-9.19 ppm, begodu i-OH proton yavela ku-9.82 ppm (qala isigaba sokulinga).
Ukusabela kwe-acid chloride 4 nge-nucleophile eyodwa (isib., i-ethylamine, 4-toluidine, kanye ne-4-methoxyaniline) ku-dioxane njengesisombululo kanye ne-TEA njenge-catalyst emazingeni womtjhiso wegumbi kwanikela nge-green crystalline acrylamide derivatives 18, 19a, kanye ne-19b. Idatha ye-elementi neye-spectral yamakhompawundi 18, 19a, kanye ne-19b iqinisekise izakhiwo zalezi ezikhiqizwako (qala iSigaba sokuHlola) (Umfanekiso 7).
Ngemva kokuhlola ukusebenza kwama-antimicrobial wamakhompawundi ahlukahlukeneko wokwenziwa, imiphumela ehlukileko yatholakala njengombana kutjengisiwe kuThebuli 1 noMfanekiso 8 (qala ifayela lomfanekiso). Woke amakhompawundi ahloliweko atjengisa amazinga ahlukileko wokuvimbela i-Gram-positive bacterium MRSA, lokha i-Gram-negative bacterium Escherichia coli itjengise ukujamelana okupheleleko kiwo woke amakhompawundi. Amakhompawundi ahloliweko angahlukaniswa abe ziinkoro ezintathu ngokuya ngobubanzi bendawo yokuvimbela i-MRSA. Isigaba sokuthoma besisebenza khulu begodu besinamakhompawundi amahlanu (6, 7, 10, 13b no-14). Ububanzi bendawo yokuvimbela yalezi zinhlanganisela bebuseduze ne-4 cm; amakhompawundi asebenzako khulu esigabeni lesi bekumakhompawundi 6 no-13b. Isigaba sesibili besisebenza ngokulingeneko begodu besinamanye amakhompawundi amahlanu (11, 13a, 15, 18 no-19a). Indawo yokuvimbela yamakhompawundi la isukela ku-3.3 ukuya ku-3.65 cm, lapho ikhompawundi 11 itjengisa indawo ekulu yokuvimbela ye-3.65 ± 0.1 cm. Ngakelinye ihlangothi, isiqhema sokugcina besinamakhompawundi amathathu (8, 17 kanye no-19b) anomsebenzi ophasi khulu wokulwa namagciwane (ngaphasi kwe-3 cm). Umfanekiso 9 utjengisa ukusabalala kweendawo ezihlukileko zokuvimbela.
Ukuragela phambili nokuphenya ngomsebenzi wokulwisana namagciwani wamakhompawundi ahloliweko kufaka hlangana ukuqunta i-MIC ne-MBC yekhompawundi ngayinye. Imiphumela yahluka kancani (njengombana kutjengisiwe kumaThebuli 2, 3 kanye nomfanekiso 10 (qala ifayela lomfanekiso)), lapho amakhompawundi 7, 11, 13a kanye no-15 abonakala ahlukaniswa kabutjha njengamakhompawundi amahle khulu. Bebanama-MIC aphasi khulu kanye nama-MBC (39.06 μg/100 μL). Nanyana amakhompawundi 7 no-8 bekanama-MIC aphasi (9.7 μg/100 μL), ama-MBC wawo bekaphezulu (78.125 μg/100 μL). Ngalokho-ke, bezithathwa njengezibuthakathaka ukudlula amakhompawundi akhulunywe ngaphambilini. Kodwana, amakhompawundi asithandathu la bekasebenza khulu kilawo ahloliweko, njengoba amanani wawo we-MBC bekangaphasi kwe-100 μg/100 μL.
Amakhompawundi (10, 14, 18 kanye no-19b) bekangasebenzi kangako nayimadaniswa namanye amakhompawundi ahloliweko njengoba amanani we-MBC wawo bekasuka ku-156 ukuya ku-312 μg/100 μL. Ngakelinye ihlangothi, amakhompawundi (8, 17 kanye no-19a) bekangathembisi kangako ngombana bekanezinga eliphezulu le-MBC (625, 625 kanye ne-1250 μg/100 μL, ngokulandelana).
Ekugcineni, ngokuya ngamazinga wokubekezelelana atjengiswa kuThebuli 3, amakhompawundi ahloliweko angahlukaniswa abe ziinkoro ezimbili ngokuya ngendlela asebenza ngayo: amakhompawundi anomphumela wokubulala amagciwani (7, 8, 10, 11, 13a, 15, 18, 19b) kanye namakhompawundi anomphumela wokulwa namagciwane (6, 13b, 19b, 19a). Hlangana nazo, amakhompawundi 7, 11, 13a kanye no-15 akhethwa, atjengisa umsebenzi wokubulala ngezinga eliphasi khulu (39.06 μg/100 μL).
Amakhompawundi alitjhumi kwalitjhumi nantathu ahloliweko atjengisa amandla wokujamelana ne-antibiotic-resistant methicillin-resistant Staphylococcus aureus (MRSA). Ngalokho-ke, ukuhlolwa okungeziweko ngama-pathogens ajamelana nama-antibiotic (khulukhulu ama-isolate wendawo ahlanganisa ama-pathogenic ama-Gram-positive nama-Gram-negative bacteria) kanye nama-yeast we-pathogenic kuyaphakanyiswa, kanye nokuhlolwa kwe-cytotoxic kwekhompawundi ngayinye ukuhlola ukuphepha kwayo.
Iimfundo zokufaka amamolekhyuli zenziwa ukuhlola amandla wamakhompawundi akhiqiziweko njengabavimbeli bephrotheyini ehlanganisa i-penicillin 2a (PBP2a) ku-Staphylococcus aureus (MRSA) engamelani ne-methicillin. I-PBP2a yi-enzayimu eqakathekileko ebandakanyeka ekubunjweni kweendonga zamaseli wamagciwane, begodu ukuvinjelwa kwale-enzayimu kuphazamisa ukwakheka kweendonga zamaseli, ekugcineni kudosela ekutheni amagciwane aphele begodu amaseli afe1. Imiphumela yokudosa ibhalwe kuThebuli 4 begodu ichazwe ngokunabileko efayeleni ledatha yokungezelela, begodu imiphumela itjengisa bona amakhompawundi amanengi atjengisa ukubopha okunamandla kwe-PBP2a, khulukhulu iinsalela eziqakathekileko ezifana ne-Lys 273, i-Lys 316, kanye ne-Arg 298. Ukusebenzisana, okufaka hlangana ukubopha kwe-hydrogen kanye ne-π-stacking, bekufana khulu nalezo i-co-crystallized quinazolinone ligand (CCL), etjengisa amandla wamakhompawundi la njengabavimbeli abanamandla.
Idatha yokufaka amamolekhyuli, kanye neminye imikhawulo yokubala, iphakamise khulu bona ukuvinjelwa kwe-PBP2a bekuyindlela eqakathekileko enesibopho somsebenzi wokulwisana namagciwani wamakhompawundi la. Amaphuzu wokubopha kanye namagugu wokuphambuka kwesikwere esiphakathi (i-RMSD) aphinde aveza ukuhlobana kokubopha nokuzinza, okusekela umbono lo. Njengombana kutjengisiwe kuThebuli 4, ngitjho nanyana amakhompawundi amanengi atjengisa ukubopha okuhle, amanye amakhompawundi (isib., 7, 9, 10, no-14) bekanemiphumela ephezulu yokubophelela kune-ligand ehlangeneko, okutjengisa bona angaba nokusebenzisana okunamandla namasalela wendawo esebenzako ye-PBP2a. Kodwana, amakhompawundi aphilako khulu 6 no-13b atjengisa amaphuzu aphasi kancani (-5.98 no--5.63, ngokulandelana) nayiqathaniswa namanye ama-ligand. Lokhu kuveza bona nanyana amaphuzu wokudosa angasetjenziswa ukubikezela ukuhlobana kokubopha, ezinye izinto (isib., ukuzinza kwe-ligand nokusebenzisana kwamamolekhyuli endaweni yezinto eziphilako) nazo zidlala indima eqakathekileko ekunqumeni ukusebenza kwamagciwane. Ngokuphawulekako, amanani we-RMSD wawo woke amakhompawundi akhiqiziweko bekangaphasi kwe-2 Å, okuqinisekisa bona ukuma kwawo kokudosa kuhambisana ngokwesakhiwo nokubophelela kwe-ligand ehlangeneko, okuragela phambili nokusekela amandla wawo njengabavimbeli abanamandla be-PBP2a.
Nanyana amaphuzu wokudosa kanye namanani we-RMS anikela ngokubikezela okuqakathekileko, ukuhlobana hlangana nemiphumela yokudosa kanye nomsebenzi we-antimicrobial akukacaci ngaso soke isikhathi ekuqaleni. Nanyana ukuvinjelwa kwe-PBP2a kusekelwa khulu njengesici esiqakathekileko esithonya ukusebenza kwama-antimicrobial, umehluko omnengi utjengisa bona ezinye izakhiwo zezinto eziphilako nazo zidlala indima eqakathekileko. Amakhompawundi 6 no-13b atjengisa ukusebenza okuphezulu khulu kokulwa namagciwani, ngobubanzi bendawo yokuvimbela eyi-4 cm kanye nama-MIC (9.7 μg/100 μL) kanye nama-MBC (78.125 μg/100 μL) amanani aphasi khulu, nanyana amaphuzu wawo wokudosa aphasi nawuqathaniswa namakhompawundi 7, 90, 141 nanyana kunjalo. Ukuvinjelwa kwe-PBP2a kufaka isandla emsebenzini we-antimicrobial, izinto ezifana nokuncibilika, ukutholakala kwezinto eziphilako kanye nokusebenzisana kwamandla endaweni yamagciwane nakho kunomthelela emsebenzini woke. Umfanekiso 11 utjengisa ukujamelana kwawo, okutjengisa bona zombili iinhlanganisela, ngitjho nanyana zinamaphuzu aphasi wokubopha, zisakwazi ukusebenzisana neensalela eziqakathekileko ze-PBP2a, okungenzeka ziqinise ukuvimbela okuyinkimbinkimbi. Lokhu kuveza bona ngitjho nanyana ukudosa kwamamolekhyuli kunikela ilwazi eliqakathekileko lokuvimbela i-PBP2a, ezinye izinto zebhayoloji kufanele ziqalwe ukuzwisisa ngokuzeleko imiphumela yama-microbial yamakhompawundi la.
Ngokusebenzisa isakhiwo sekristalu se-PBP2a (PDB ID: 4CJN), imephu yokusebenzisana ye-2D ne-3D yamakhompawundi asebenzako khulu 6 no-13b ahlanganiswe nephrotheyini ehlanganisa i-penicillin 2a (PBP2a) ye-Staphylococcus aureus (MRSA) engamelani ne-methicillin yakhiwa. Imephu le iqathanisa amaphetheni wokuthintana kwamakhompawundi la ne-re-docked co-crystallized quinazolinone ligand (CCL), iveza ukusebenzisana okuqakathekileko okufana nokuhlangana kwe-hydrogen, i-π-stacking, nokusebenzisana kwe-ionic.
Iphetheni efanako yabonwa nge-compound 7, eyatjengisa izinga eliphezulu lokudosa (-6.32) kanye nobubanzi bendawo yokuvimbela efanako (3.9 cm) ku-compound 10. Kodwana, i-MIC yayo (39.08 μg/100 μL) kanye ne-MBC (39.06 μg/100 μL) bekutlhogeka khulu, okutjengisa bona itjengise ukugxila okuphezulu khulu umphumela wokulwa namagciwane. Lokhu kuveza bona nanyana ikhompawundi 7 itjengise ukubophelela okunamandla eemfundweni zokudosa, izinto ezifana nokutholakala kwezinto eziphilako, ukuthathwa kwamaseli, nofana ezinye izakhiwo ze-physicochemical zinganciphisa ukusebenza kwayo kwezinto eziphilako. Nanyana ikhompawundi 7 itjengise izakhiwo zokubulala amagciwani, beyingasebenzi kuhle ekuvimbeleni ukukhula kwamagciwane nayiqathaniswa nekhompawundi 6 no-13b.
Ikhompawundi 10 itjengise umehluko omkhulu khulu nge-docking score ephezulu (-6.40), okutjengisa ukubophelela okunamandla ku-PBP2a. Kodwana, indawo yayo yobubanzi bokuvimbela (3.9 cm) beyifaniswa nekhompawundi 7, begodu i-MBC yayo (312 μg/100 μL) beyiphezulu khulu kunamakhompawundi 6, 7, kanye ne-13b, okutjengisa ukusebenza okubuthakathaka kokubulala amagciwane. Lokhu kuveza bona nanyana kuneenbikezelo ezihle zokudosa, ikhompawundi 10 beyingasebenzi kuhle ekubulaleni i-MRSA ngebanga lezinye izinto ezilinganiselako ezifana nokuncibilika, ukuzinza, nofana ukungena okumbi kwelwelwesi lebhaktheriya. Imiphumela le isekela ukuzwisisa bona ngitjho nanyana ukuvinjelwa kwe-PBP2a kudlala indima eqakathekileko emsebenzini wokulwa namagciwane, akuchazi ngokuzeleko umehluko emsebenzini wezinto eziphilako obonwe hlangana namakhompawundi ahloliweko. Umehluko lo utjengisa bona ukuhlaziywa okungeziweko nokuhlolwa okujulileko kwezinto eziphilako kuyatlhogeka ukucacisa ngokuzeleko iindlela zokulwa namagciwane ezibandakanyekako.
Imiphumela yokufaka amamolekhyuli kuThebuli 4 kanye neFayili yeDatha yokuNgezelela kuveza ubudlelwano obuyinkimbinkimbi phakathi kwamaphuzu wokuhlanganisa nomsebenzi we-antimicrobial. Nanyana amakhompawundi 6 no-13b anamazinga aphasi wokudosa ukudlula amakhompawundi 7, 9, 10, no-14, atjengisa umsebenzi ophakemeko wokulwa namagciwane. Imephu yazo yokusebenzisana (etjengiswe kuMfanekiso 11) itjengisa bona nanyana inamaphuzu aphasi wokubopha, isakha amabhondi we-hydrogen aqakathekileko kanye nokusebenzisana kwe-π-stacking neensalela eziqakathekileko ze-PBP2a ezingazinzisa i-enzyme-inhibitor complex ngendlela ezuzisako. Nanyana kunamaphuzu aphasi wokudosa we-6 no-13b, umsebenzi wabo wokulwa namagciwani othuthukisiweko uveza bona ezinye izakhiwo ezifana nokuncibilika, ukuzinza, nokuthathwa kwamaseli kufanele ziqalwe ngokuhlanganyela nedatha yokudosa lokha nakuhlolwa amandla wokuvimbela. Lokhu kuveza ukuqakatheka kokuhlanganisa iimfundo zokudosa nokuhlaziywa kwe-antimicrobial ukuhlola ngokunembileko amandla wokwelapha wamakhompawundi amatjha.
Imiphumela le iveza bona ngitjho nanyana ukudosa kwamamolekhyuli kulithulusi elinamandla lokubikezela ukuhlobana kokubopha nokukhomba iindlela ezingabakhona zokuvimbela, akukafaneli kuthembele kikho kwaphela ukuthola ukusebenza kwama-antimicrobial. Idatha yamamolekhyuli iveza bona ukuvinjelwa kwe-PBP2a kuyinto eqakathekileko ethonya ukusebenza kwama-antimicrobial, kodwana amatjhuguluko emsebenzini wezinto eziphilako atjengisa bona ezinye izakhiwo ze-physicochemical kanye ne-pharmacokinetic kufanele zilungiswe ngcono ukuthuthukisa ukusebenza kwezokwelapha. Iimfundo zesikhathi esizako kufanele zidzimelele ekwenzeni ngcono isakhiwo samakhemikhali samakhompawundi 7 no-10 ukwenza ngcono ukutholakala kwezinto eziphilako nokuthathwa kwamaseli, ukuqinisekisa bona ukusebenzisana okuqinileko kokudosa kutjhugululwa kube msebenzi wamambala wokulwa namagciwane. Iimfundo ezilandelako, ezifaka hlangana ama-bioassays angezelelweko nokuhlaziywa kobudlelwano nomsebenzi wesakhiwo (i-SAR), kuzokuba yinto eqakathekileko ukuthuthukisa ukuzwisisa kwethu ukuthi amakhompawundi la asebenza njani njenge-PBP2a inhibitors nokuthuthukisa ama-ejenti asebenzako wokulwisana namagciwane.
Amakhompawundi enziwe nge-3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 atjengisa amazinga ahlukileko wokulwa namagciwani, begodu amakhompawundi amanengi atjengisa ukukhandela okukhulu kwe-Staphylococcus aureus (MRSA) engamelani ne-methicillin. Ukuhlaziywa kobudlelwano nomsebenzi wesakhiwo (i-SAR) kuveze iimpawu eziqakathekileko zesakhiwo ezisekela ukusebenza kwama-antimicrobial kwamakhompawundi la.
Ukuba khona kwamaqembu womabili we-acrylonitrile kanye ne-anthracene kwabonakala kuqakathekile ekuthuthukiseni ukusebenza kwama-antimicrobial. Iqembu le-nitrile elisebenza khulu ku-acrylonitrile liyatlhogeka ukwenza lula ukusebenzisana namaphrotheyini webhaktheriya, ngaleyo ndlela libe negalelo ekwakhiweni kwe-antimicrobial kwekhompawundi. Amakhompawundi ane-acrylonitrile ne-anthracene ahlala atjengisa imiphumela enamandla yokulwa namagciwane. Iphunga leqembu le-anthracene laqinisa amakhompawundi la, okungenzeka lakhulisa ukusebenza kwawo kwezinto eziphilako.
Ukwethulwa kwamasongo we-heterocyclic kwathuthukisa khulu ukusebenza kwama-antibacterial kwama-derivatives amanengi. Ngokukhethekileko, i-benzothiazole derivative 13b kanye ne-acrylhydrazide derivative 6 itjengise ukusebenza okuphezulu khulu kwe-antibacterial ngendawo yokuvimbela engaba yi-4 cm. Ama-heterocyclic derivatives la atjengisa imiphumela eqakathekileko yezinto eziphilako, okutjengisa bona isakhiwo se-heterocyclic sidlala indima eqakathekileko emiphumeleni yokulwa namagciwane. Ngokufanako, i-pyrimidinethione ku-compound 9, i-thiopyrazole ku-compound 10, kanye ne-tetrazine ring ku-compound 11 kwaba negalelo ekwakhiweni kwe-antibacterial yama-compound, okuveza ukuqakatheka kokuguqulwa kwe-heterocyclic.
Hlangana namakhompawundi akhiqiziweko, i-6 ne-13b yagqama ngemisebenzi yayo emihle yokulwisana namagciwane. Ubuncani bokuvimbela ukugxila (i-MIC) ye-compound 6 bekungu-9.7 μg/100 μL, begodu ubuncani bokuhlushwa kokubulala amagciwane (MBC) bekungu-78.125 μg/100 μL, okuveza ikghono layo elihle khulu lokususa i-Staphylococcus aureus (MRSA) engamelani ne-methicillin. Ngokufanako, ikhompawundi 13b beyinendawo yokuvimbela eyi-4 cm kanye namanani aphasi we-MIC ne-MBC, okuqinisekisa umsebenzi wayo onamandla wokulwa namagciwani. Imiphumela le iveza iindima eziqakathekileko zamaqembu asebenzako we-acrylohydrazide ne-benzothiazole ekutholeni ukusebenza kuhle kwamakhompawundi la.
Ngokuphikisako, amakhompawundi 7, 10, no-14 atjengisa ukusebenza okulinganiselweko kokulwa namagciwani ngeendawo zokuvimbela ezisukela ku-3.65 ukuya ku-3.9 cm. Amakhompawundi la atlhoga amazinga aphezulu ukubulala amagciwani, njengombana kutjengiswe ngamanani wawo aphezulu we-MIC ne-MBC. Nanyana amakhompawundi la bekangasebenzi kangako ukudlula amakhompawundi 6 no-13b, bekasatjengisa amandla amakhulu wokulwisana namagciwani, okutjengisa bona ukufakwa kwe-acrylonitrile kanye ne-anthracene ngaphakathi kwendandatho ye-heterocyclic kufaka isandla emphumeleni wawo wokulwisana namagciwani.
Amakhompawundi aneendlela ezihlukileko zokusebenza, amanye atjengisa izakhiwo zokubulala amagciwane kuthi amanye atjengisa imiphumela yokubulala amagciwane. Amakhompawundi 7, 11, 13a, kanye no-15 abulala amabhaktheriya begodu atlhoga ukugxila okuphasi ukubulala amabhaktheriya ngokupheleleko. Ngokuphikisako, amakhompawundi 6, 13b, kanye no-14 avikela amagciwani begodu angavimbela ukukhula kwamagciwani lokha nakumazinga aphasi, kodwana atlhoga amazinga aphezulu ukubulala amabhaktheriya ngokupheleleko.
Ngokupheleleko, ukuhlaziywa kobudlelwano besakhiwo nomsebenzi kuveza ukuqakatheka kokwethula i-acrylonitrile kanye ne-anthracene moieties kanye nezakhiwo ze-heterocyclic ukufezekisa umsebenzi oqakathekileko wokulwisana namagciwane. Imiphumela le iveza bona ukwenza ngcono iingcenye zesakhiwo nokuhlola ezinye iinguquko ukwenza ngcono ukuncibilika nokungena kwe-membrane kungaholela ekuthuthukisweni kwemithi esebenzako yokulwisana ne-MRSA.
Zoke iinsetjenziswa nama-solvent ahlanjululwa begodu omiswa kusetjenziswa iindlela ezijayelekileko (i-El Gomhouria, e-Egypt). Iindawo zokuncibilika zatholwa kusetjenziswa isisetjenziswa se-elekthronikhi se-GallenKamp begodu zibikwa ngaphandle kokulungisa. I-infrared (IR) spectra (cm⁻1) yarekhodwa eMnyangweni weKhemistri, i-Faculty yeSayensi, e-Ain Shams University kusetjenziswa ama-potassium bromide (KBr) ku-Thermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
I-1H NMR spectra yatholwa ku-300 MHz kusetjenziswa i-GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) kanye ne-BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.). I-Tetramethylsilane (TMS) yasetjenziswa njengezinga langaphakathi nge-deuterated dimethyl sulfoxide (DMSO-d₆). Ukulinganisa kwe-NMR kwenziwa e-Faculty of Science, e-Cairo University, e-Giza, e-Egypt. Ukuhlaziywa kwe-Elemental (CHN) kwenziwa kusetjenziswa i-Perkin-Elmer 2400 Elemental Analyzer begodu imiphumela etholakeleko iyavumelana kuhle namanani abalweko.
Umxube we-asidi 3 (5 mmol) kanye ne-thionyl chloride (5 ml) wafuthunyelwa ngaphakathi kwebhadi yamanzi ku-65 °C ama-awa amane. I-thionyl chloride enengi yasuswa ngokuvundiswa ngaphasi kwengcindezi ephasi. Iinsetjenziswa ezibomvu eziqinileko zabuthelelwa begodu zasetjenziswa ngaphandle kokuhlanjululwa okungeziweko. Indawo yokuncibilika: 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); I-HRMS (ESI) m/z [M + H]+: 291.73111. Umhlaziyi. Ibalwe nge-C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Kutholwe: C, 74.41; H, 3.34; N, 4.66%.
Ku-0°C, i-4 (2 mmol, 0.7 g) yancibilikiswa ku-anhydrous dioxane (20 ml) begodu i-hydrazine hydrate (2 mmol, 0.16 ml, 80%) yengezwa ngamathonsi begodu yavuselelwa i-1 h. Into eqinileko eyabuthelelwa ngokuhlunga begodu yabuyiselwa e-ethanol ukukhiqiza ikhompawundi 6.
Amakristalu aluhlaza, iphuzu lokuncibilika elingu-190-192°C, akhiqiza ama-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, exchangeable), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Inani elibalwe le-C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Kutholwe: C, 84.01; H, 4.38; N, 8.05%.
Ncibilikisa i-4 (2 mmol, 0.7 g) ku-20 ml yesisombululo se-anhydrous dioxane (esiqukethe amathonsi ambalwa we-triethylamine), faka i-phenylhydrazine/2-aminopyridine (2 mmol) bese ugoqa emazingeni womtjhiso wegumbi i-1 ne-2 h, ngokulandelana. Thela ingxube yokusabela ngaphakathi kwe-ayisi nofana emanzini bese uyenza i-asidi nge-hydrochloric acid ehlanjululweko. Hlunga okuqinileko okuhlukanisiweko bese ubuyisela ikristalu kusuka ku-ethanol ukuthola i-7 bese uphinde wenze ikristalu kusuka ku-benzene ukuthola i-8.
Amakristalu aluhlaza, iphuzu lokuncibilika 160-162°C, akhiqiza ama-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, exchangeable), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23 H, heteromatic); Inani elibalwe le-C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Kutholwe: C, 81.96; H, 3.91; N, 8.91%.
4 (2 mmol, 0.7 g) yancibilikiswa ku-20 ml yesixazululo se-anhydrous dioxane (esiqukethe amathonsi ambalwa we-triethylamine), i-2-aminopyridine (2 mmol, 0.25 g) yengezwa begodu ingxube yavuselelwa emazingeni womtjhiso wegumbi ama-awa ama-2. Umxube wokusabela wathululelwa emanzini weqhwa begodu wafakwa i-asidi nge-hydrochloric acid ehlanjululweko. I-precipitate eyakhiweko yahlungwa begodu yenziwa kabutjha i-benzene, yanikela amakristalu ahlaza satjani angu-8 anephuzu lokuncibilika elingu-146-148 °C kanye nokukhiqiza okungu-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, exchangeable), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); Ibalwe nge-C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Kutholwe: C, 78.93; H, 3.97; N, 12.36%.
Ikhompawundi 4 (2 mmol, 0.7 g) yancibilikiswa ku-20 ml ye-dioxane eyomileko (equkethe amathonsi ambalwa we-triethylamine kanye ne-2 mmol ye-thiourea/semicarbazide) begodu yafuthunyelwa ngaphasi kwe-reflux ama-awa ama-2. I-solvent yahwamuka ngaphakathi kwe-vacuo. Iinsalela zabuyiselwa kabutjha kusuka ku-dioxane ukunikela ingxube.