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Synton 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yasengekebwa era n’ekozesebwa okukola ebirungo eby’enjawulo ebya heterocyclic ebikola ennyo okuyita mu kukwatagana kwayo ne nitrogen nucleophiles ez’enjawulo. Ensengekera ya buli kirungo kya heterocyclic ekisengekeddwa yamanyibwa bulungi nga tukozesa okwekenneenya kwa spectroscopic ne elemental. Ebirungo kkumi ku kkumi na bisatu ebipya ebiyitibwa heterocyclic compounds byalaga obulungi obuzzaamu amaanyi ku bacteria ezigumira eddagala eringi (MRSA). Mu byo, ebirungo 6, 7, 10, 13b, ne 14 byalaga nti bye bisinga okulwanyisa obuwuka nga biriko ebitundu ebiziyiza okumpi ne sentimita 4. Wabula okunoonyereza ku molekyu ku docking kwalaga nti ebirungo bino byalina enkolagana ey’enjawulo ey’okusiba ku penicillin-binding protein 2a (PBP2a), ekigendererwa ekikulu eky’okuziyiza MRSA. Ebirungo ebimu nga 7, 10 ne 14 byalaga enkolagana ey’okusiba ey’oku ntikko n’okutebenkera kw’enkolagana mu kifo ekikola ekya PBP2a bw’ogeraageranya ne ligandi ya quinazolinone eya co-crystallized. Okwawukana ku ekyo, ebirungo 6 ne 13b byalina obubonero obutono obw’okusiba naye nga bikyalaga obusobozi obw’amaanyi obw’okulwanyisa obuwuka, ng’ekirungo 6 kye kisinga okuba n’emiwendo gya MIC (9.7 μg/100 μL) ne MBC (78.125 μg/100 μL). Okwekenenya ku docking kwalaga enkolagana enkulu omuli okukwatagana kwa haidrojeni n’okusiba π naddala n’ebisigadde nga Lys 273, Lys 316 ne Arg 298, ebyazuulibwa nga bikwatagana ne ligandi eya co-crystallized mu nsengekera ya kirisitaalo ya PBP2a. Ebisigadde bino byetaagisa nnyo mu nkola y’enziyiza ya PBP2a. Ebivudde mu kunoonyereza kuno biraga nti ebirungo ebikoleddwa biyinza okukola ng’eddagala erisuubiza eriziyiza MRSA, nga kiraga obukulu bw’okugatta molekyu docking n’okukebera obulamu okuzuula eddagala erikola obulungi.
Mu myaka mitono egyasooka egy’ekyasa kino, kaweefube w’okunoonyereza yasinga kutunuulirwa ku kukola enkola empya, ennyangu n’enkola ez’okugatta enkola eziwerako eziyiiya ez’ekika kya heterocyclic ezirina emirimu gy’okulwanyisa obuwuka nga tukozesa ebintu ebitandikirawo ebyangu.
Ebitundu bya akirilonitrile bitwalibwa ng’ebintu ebikulu ebitandikira mu kusengejja ensengekera nnyingi ez’ekitalo eza heterocyclic kubanga bikozesebwa ebikola ennyo. Ekirala, ebiva mu 2-cyanoacryloyl chloride bibadde bikozesebwa nnyo mu myaka egiyise okukola n’okusengejja ebintu ebikulu ennyo mu kisaawe ky’okukozesa eddagala, gamba ng’ebirungo ebiziyiza akawuka ka siriimu1,2,3, ebisookerwako eby’okulwanyisa akawuka ka siriimu, eddagala eriziyiza kookolo, eritta obuwuka, eriweweeza ku kweraliikirira n’ery’okuziyiza obuwuka obuleeta obulwadde bwa siriimu4,5,6,7,8,9,10. Gye buvuddeko, obulungi bw’ebiramu obwa anthracene n’ebivaamu, omuli eddagala lyayo eritta obuwuka, eritta kookolo11,12, eritta obuwuka13,14,15 n’eddagala eritta ebiwuka16,17, busikiriza nnyo okufaayo18,19,20,21. Ebirungo ebitta obuwuka ebirimu ebitundu bya acrylonitrile ne anthracene biragiddwa mu bifaananyi 1 ne 2.
Okusinziira ku kitongole ky’ebyobulamu mu nsi yonna (WHO) (2021), okuziyiza obuwuka (AMR) kya bulabe eri obulamu n’enkulaakulana mu nsi yonna22,23,24,25. Abalwadde tebasobola kuwona, ekivaamu okumala ebbanga eddene mu ddwaaliro n’obwetaavu bw’eddagala ery’ebbeeyi, awamu n’okufa n’obulema okweyongera. Obutabeera na ddagala ddene eritta obuwuka litera okuvaako obujjanjabi okulemererwa ku yinfekisoni ez’enjawulo naddala mu kiseera ky’okujjanjaba eddagala n’okulongoosebwa okunene.
Okusinziira ku alipoota y’ekitongole ky’ebyobulamu mu nsi yonna eya 2024, obulwadde bwa Staphylococcus aureus (MRSA) obuziyiza methicillin ne E. coli biri ku lukalala lw’obuwuka obuleeta endwadde obusookerwako. Bakitiriya zombi zigumira eddagala lingi eritta obuwuka, n’olwekyo zikiikirira yinfekisoni enzibu okujjanjaba n’okufuga, era waliwo obwetaavu obw’amangu okukola ebirungo ebipya era ebikola obulungi ebitta obuwuka okusobola okukola ku kizibu kino. Anthracene n’ebivaamu ddagala erimanyiddwa ennyo eritta obuwuka eriyinza okukola ku bakitiriya zombi eza Gram-positive ne Gram-negative. Ekigendererwa ky’okunoonyereza kuno kwe kukola ekintu ekipya ekivaamu ekiyinza okulwanyisa obuwuka buno obw’obulabe eri obulamu.
Ekitongole ky’ebyobulamu mu nsi yonna (WHO) kigamba nti obuwuka bungi obulwaza obuwuka bugumira eddagala eritta obuwuka eritali limu, omuli n’obulwadde bwa Staphylococcus aureus (MRSA) obuziyiza methicillin, ekitera okuvaako obulwadde mu bantu n’ebifo eby’obulamu. Abalwadde abalina obulwadde bwa MRSA kigambibwa nti bafa ebitundu 64% okusinga abo abalina yinfekisoni eziyinza okukozesebwa eddagala. Okugatta ku ekyo, E. coli eriko akabi mu nsi yonna kubanga layini esembayo ey’okwekuuma Enterobacteriaceae ezigumira carbapenem (kwe kugamba, E. coli) ye colistin, naye obuwuka obugumira colistin gye buvuddeko bwategeezebwa mu nsi eziwerako. 22,23,24,25
N’olwekyo, okusinziira ku nteekateeka y’ensi yonna ey’ekitongole ky’ebyobulamu ey’ensi yonna ekola ku kuziyiza obuwuka26, waliwo obwetaavu obw’amangu obw’okuzuula n’okusengejja eddagala eppya eritta obuwuka. Obusobozi obunene obwa anthracene ne acrylonitrile nga antibacterial27, antifungal28, anticancer29 ne antioxidant30 agents bulagibwa mu mpapula nnyingi ezifulumiziddwa. Mu nsonga eno, kiyinza okugambibwa nti ebiva mu bikozesebwa bino birungi okukozesebwa okulwanyisa obulwadde bwa Staphylococcus aureus (MRSA) obuziyiza methicillin.
Okwekenenya ebiwandiiko okwakolebwa emabegako kwatukubiriza okugatta ebipya ebiva mu bibiina bino. Nolwekyo, okunoonyereza kuno kwagenderera okukola enkola empya eza heterocyclic ezirimu ebitundu bya anthracene ne acrylonitrile, okwekenneenya obulungi bwazo obw’okulwanyisa obuwuka n’obuwuka, n’okunoonyereza ku nkolagana yaabwe eyinza okusiba ne penicillin-binding protein 2a (PBP2a) nga bakozesa molekyu docking. Nga tuzimba ku kunoonyereza okwakolebwa emabegako, okunoonyereza kuno kwagenda mu maaso n’okusengejja, okwekenneenya ebiramu, n’okwekenneenya enkola za heterocyclic mu kubala okuzuula ebirungo ebisuubiza ebiziyiza antimethicillin-resistant Staphylococcus aureus (MRSA) ebiziyiza PBP2a eby’amaanyi omulimu31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Okunoonyereza kwaffe okuliwo kati kwesigamye ku kusengejja n’okwekenneenya obuwuka obutta obuwuka obw’ebirungo ebipya eby’ekika kya heterocyclic ebirimu ebitundu bya anthracene ne acrylonitrile. 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yategekebwa era n’ekozesebwa ng’ekizimbe okuzimba enkola empya eza heterocyclic.
Ensengekera y’ekirungo 4 yazuulibwa nga tukozesa data ya spectral. 1H-NMR spectrum yalaga okubeerawo kwa CH= ku 9.26 ppm, IR spectrum yalaga okubeerawo kw’ekibinja kya carbonyl ku 1737 cm−1 n’ekibinja kya cyano ku 2224 cm−1, ate 13CNMR spectrum nayo yakakasa ensengekera eteeseddwa (laba ekitundu eky’okugezesa).
Okusengejja 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kwatuukirira nga okusengejja ebibinja ebiwunya 250, 41, 42, 53 n’omusulo gwa ethanolic sodium hydroxide (10%) okusobola okufuna asidi 354, 45, 56, oluvannyuma ne zirongoosebwa ne thionyl chloride ku kinaabiro ky’amazzi okuwa acryloyl chloride derivative 4 mu makungula amangi (88.5%), nga bwe kiragibwa mu kifaananyi 3.
Okukola ebirungo ebipya ebya heterocyclic ebirina obusobozi obusuubirwa obw’okulwanyisa obuwuka, okukwatagana kwa acyl chloride 4 ne dinucleophiles ez’enjawulo kwakolebwa.
Asidi chloride 4 yalongoosebwa ne hydrazine hydrate ku 0° okumala essaawa emu. Ebyembi, pyrazolone 5 teyafunibwa. Ekintu kino kyali kiva mu acrylamide nga ensengekera yaakyo yakakasibwa okusinziira ku biwandiiko ebiyitibwa spectral data. Ensengekera yaayo eya IR yalaga bbandi z’okunyiga eza C=O ku 1720 cm−1, C≡N ku 2228 cm−1 ne NH ku 3424 cm−1. Ekifaananyi kya 1H-NMR kyalaga akabonero k’okuwanyisiganya akabonero ka pulotoni za olefin ne pulotoni za NH ku 9.3 ppm (laba Ekitundu eky’okugezesa).
Mole bbiri eza asidi chloride 4 zaakwatagana ne molekyo emu eya phenylhydrazine okusobola okufuna ekiva mu N-phenylacryloylhydrazine 7 mu makungula amalungi (77%) (Ekifaananyi 5). Ensengekera ya 7 yakakasibwa data ya infrared spectroscopy, eyalaga okunyiga kw’ebibinja bya C=O bibiri ku 1691 ne 1671 cm−1, okunyiga kw’ekibinja kya CN ku 2222 cm−1 n’okunyiga kw’ekibinja kya NH ku 3245 cm−1, ate spectrum yaayo eya 1H-NMR yalaga ekibinja kya CH ku 9.15 ne 8.81 ppm ne NH pulotoni ku 10.88 ppm (laba ekitundu eky’okugezesa).
Mu kunoonyereza kuno, enkolagana ya acyl chloride 4 ne 1,3-dinucleophiles yanoonyezebwa. Okujjanjaba acyl chloride 4 ne 2-aminopyridine mu 1,4-dioxane ne TEA nga base ku bbugumu erya bulijjo kyawa acrylamide derivative 8 (Figure 5), ensengekera yaayo yazuulibwa nga tukozesa spectral data. IR spectra zalaga bbandi z’okunyiga eza cyano nga ziwanvuwa ku 2222 cm−1, NH ku 3148 cm−1, ne carbonyl ku 1665 cm−1; 1H NMR spectra zakakasa okubeerawo kwa olefin protons ku 9.14 ppm (laba Ekitundu eky’okugezesa).
Ekirungo 4 kikola ne thiourea ne kiwa pyrimidinethione 9; ekirungo 4 kikola ne thiosemicarbazide ne kiwa ekirungo kya thiopyrazole 10 (Ekifaananyi 5). Ensengekera z’ebirungo 9 ne 10 zakakasibwa mu kwekenneenya okw’embala n’okw’eby’obutonde (laba ekitundu eky’okugezesa).
Tetrazine-3-thiol 11 yategekebwa nga ekwatagana n’ekirungo 4 ne thiocarbazide nga 1,4-dinucleophile (Ekifaananyi 5), era ensengekera yaakyo yakakasibwa okuyita mu spectroscopy n’okwekenneenya elementi. Mu spektrum ya infrared, ekiyungo kya C=N kyalabika ku 1619 cm−1. Mu kiseera kye kimu, ekisengejjo kyayo ekya 1H-NMR kyakuuma obubonero bwa multiplate obwa pulotoni eziwunya ku 7.78–8.66 ppm ne pulotoni za SH ku 3.31 ppm (laba Ekitundu ky’okugezesa).
Acryloyl chloride 4 ekolagana ne 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, ne ethanolamine nga 1,4-dinucleophiles okukola ensengekera empya eza heterocyclic (13–16).
Ensengekera z’ebirungo bino ebipya ebikoleddwa zakakasibwa mu kwekenneenya okw’ekika kya spectral ne elemental (laba ekitundu eky’okugezesa). 2-Hydroxyphenylacrylamide derivative 17 yafunibwa nga ekwatagana ne 2-aminophenol nga dinucleophile (Ekifaananyi 6), era ensengekera yaayo yakakasibwa mu kwekenneenya kwa spectral ne elemental. Ekifaananyi kya infrared eky’ekirungo 17 kyalaga nti obubonero bwa C=O ne C≡N bwalabika ku 1681 ne 2226 cm−1, okusinziira ku. Mu kiseera kino, ekisengejjo kyayo ekya 1H-NMR kyakuuma akabonero ka singlet aka pulotoni ya olefin ku 9.19 ppm, ate pulotoni ya OH n’erabika ku 9.82 ppm (laba ekitundu ky’okugezesa).
Enkolagana ya asidi klorayidi 4 ne nucleophile emu (okugeza, ethylamine, 4-toluidine, ne 4-methoxyaniline) mu dioxane nga ekizimbulukusa ne TEA nga catalyst ku bbugumu erya bulijjo kyawa ebiva mu green crystalline acrylamide derivatives 18, 19a, ne 19b. Ebiwandiiko bya elementi n’eby’embala eby’ebirungo 18, 19a, ne 19b byakakasa ensengekera z’ebivaamu bino (laba Ekitundu eky’okugezesa) (Ekifaananyi 7).
Oluvannyuma lw’okukebera emirimu gy’okulwanyisa obuwuka egy’ebirungo eby’enjawulo ebikoleddwa, ebivuddemu eby’enjawulo byafunibwa nga bwe kiragibwa mu kipande 1 ne mu kifaananyi 8 (laba fayiro y’ekifaananyi). Ebirungo byonna ebyakeberebwa byalaga diguli ez’enjawulo ez’okuziyiza obuwuka bwa Gram-positive MRSA, ate obuwuka bwa Gram-negative Escherichia coli bwalaga okuziyiza okujjuvu eri ebirungo byonna. Ebirungo ebikebereddwa bisobola okwawulwamu ebika bisatu okusinziira ku dayamita y’ekitundu ekiziyiza MRSA. Ekika ekisooka kye kyasinga okukola era nga kirimu ebirungo bitaano (6, 7, 10, 13b ne 14). Dyaamu y’ekitundu ekiziyiza ebirungo bino yali kumpi ne sentimita 4; ebirungo ebisinga okukola mu kiti kino byali birungo 6 ne 13b. Ekika ekyokubiri kyali kya kigero era nga kirimu ebirungo ebirala bitaano (11, 13a, 15, 18 ne 19a). Ekitundu ekiziyiza ebirungo bino kyali wakati wa sentimita 3.3 okutuuka ku 3.65, nga ekirungo 11 kiraga ekitundu ekiziyiza ekisinga obunene ekya sentimita 3.65 ± 0.1. Ku luuyi olulala, ekibinja ekyasembayo kyalimu ebirungo bisatu (8, 17 ne 19b) ebirina obusobozi obutono obw’okulwanyisa obuwuka (obutasukka sentimita 3). Ekifaananyi 9 kiraga ensaasaanya y’ebitundu eby’enjawulo ebiziyiza.
Okwongera okunoonyereza ku nkola y’okulwanyisa obuwuka mu birungo ebyakeberebwa kwalimu okuzuula MIC ne MBC ku buli kirungo. Ebivuddemu byawukana katono (nga bwe kiragibwa mu bipande 2, 3 ne kifaananyi 10 (laba fayiro y’ekifaananyi)), nga kirabika ebirungo 7, 11, 13a ne 15 byaddamu okusengekebwa ng’ebirungo ebisinga obulungi. Baali balina emiwendo gya MIC ne MBC egya wansi gye gimu (39.06 μg/100 μL). Wadde nga ebirungo 7 ne 8 byalina emiwendo gya MIC egya wansi (9.7 μg/100 μL), emiwendo gyabyo egya MBC gyali waggulu (78.125 μg/100 μL). N’olwekyo, zaali zitwalibwa ng’enafu okusinga ebirungo ebyogeddwako emabegako. Wabula ebirungo bino omukaaga bye byasinga okukola obulungi ku ebyo ebyakeberebwa, kubanga emiwendo gyabyo egya MBC gyali wansi wa 100 μg/100 μL.
Ebirungo (10, 14, 18 ne 19b) byali tebikola nnyo bw’ogeraageranya n’ebirungo ebirala ebyakeberebwa kuba emiwendo gyabyo egya MBC gyali wakati wa 156 ne 312 μg/100 μL. Ku luuyi olulala, ebirungo (8, 17 ne 19a) bye byasinga obutasuubiza kuba byalina emiwendo gya MBC egya waggulu (625, 625 ne 1250 μg/100 μL, okusinziira ku).
N’ekisembayo, okusinziira ku mitendera gy’okugumiikiriza egyalagiddwa mu kipande 3, ebirungo ebikebereddwa bisobola okwawulwamu ebika bibiri okusinziira ku ngeri gye bikolamu: ebirungo ebirina eddagala eritta obuwuka (7, 8, 10, 11, 13a, 15, 18, 19b) n’ebirungo ebirina eddagala eritta obuwuka (6, 13b, 14, 17, 19a). Mu byo, ebirungo 7, 11, 13a ne 15 bye bisinga okwettanirwa, ebiraga omulimu gw’okutta ku kigero ekitono ennyo (39.06 μg/100 μL).
Ebirungo kkumi ku kkumi na bisatu ebyakeberebwa byalaga nti bisobola okulwanyisa obulwadde bwa Staphylococcus aureus (MRSA) obuziyiza eddagala eritta obuwuka. N’olwekyo, okwongera okwekenneenya n’obuwuka obuziyiza obuwuka obusinga okuziyiza obuwuka (naddala obuwuka obwawuddwa mu kitundu obubikka obuwuka obuleeta endwadde Gram-positive ne Gram-negative) n’ebizimbulukusa ebireeta endwadde kirungi, wamu n’okukebera obutwa mu buli kirungo okwekenneenya obukuumi bwakyo.
Okunoonyereza ku kusiba molekyu kwakolebwa okwekenneenya obusobozi bw’ebirungo ebikoleddwa ng’ebiziyiza puloteyina 2a esiba penicillin (PBP2a) mu Staphylococcus aureus (MRSA) agumira methicillin. PBP2a ye enzyme enkulu eyenyigira mu biosynthesis y’obutoffaali bwa bakitiriya, era okuziyiza enziyiza eno kutaataaganya okutondebwa kw’obutoffaali bw’obutoffaali, okukkakkana nga kivaako okusasika kwa bakitiriya n’okufa kw’obutoffaali1. Ebivudde mu docking biwandiikiddwa mu kipande 4 era ne binnyonnyolwa mu bujjuvu mu fayiro ya data ey’okugatta, era ebivuddemu biraga nti ebirungo ebiwerako byalaga enkolagana ey’amaanyi ey’okusiba ku PBP2a, naddala ebisigalira by’ekifo ebikulu ebikola nga Lys 273, Lys 316, ne Arg 298. Enkolagana, omuli okusiba haidrojeni ne π-stacking, zaali zifaanagana nnyo n’ezo eza co-crystallized quinazolinone ligand (CCL), ekiraga obusobozi bw’ebirungo bino ng’ebiziyiza eby’amaanyi.
Ebiwandiiko ebikwata ku molekyu, awamu n’ebipimo ebirala eby’okubalirira, byalaga nnyo nti okuziyiza PBP2a ye nkola enkulu evunaanyizibwa ku nkola y’okulwanyisa obuwuka eyatunuuliddwa ey’ebirungo bino. Ebipimo by’okusiba n’emiwendo gya root mean square deviation (RMSD) byayongera okulaga enkolagana y’okusiba n’okutebenkera, nga biwagira endowooza eno. Nga bwe kiragibwa mu kipande 4, wadde nga ebirungo ebiwerako byalaga enkolagana ennungi ey’okusiba, ebirungo ebimu (okugeza, 7, 9, 10, ne 14) byalina obubonero bw’okusiba obusinga ku ligandi eya co-crystallized, ekiraga nti biyinza okuba n’enkolagana ey’amaanyi n’ebisigadde eby’ekifo ekikola ekya PBP2a. Wabula ebirungo ebisinga okukola ebiramu 6 ne 13b byalaga obubonero bw’okusiba obutono (-5.98 ne -5.63, okusinziira ku) bw’ogeraageranya ne ligandi endala. Kino kiraga nti wadde ng’obubonero bw’okusimba (docking scores) busobola okukozesebwa okulagula enkolagana y’okusiba, ensonga endala (okugeza, okutebenkera kwa ligandi n’enkolagana ya molekyu mu mbeera y’ebiramu) nazo zikola kinene mu kusalawo emirimu gy’okulwanyisa obuwuka. Ekikulu, emiwendo gya RMSD egy’ebirungo byonna ebisengekeddwa gyali wansi wa 2 Å, nga gikakasa nti ebifo byabwe eby’okusimba bikwatagana mu nsengeka n’ensengekera y’okusiba eya ligandi eya co-crystallized, okwongera okuwagira obusobozi bwabyo ng’ebiziyiza PBP2a eby’amaanyi.
Newankubadde obubonero bw’okusimba n’emiwendo gya RMS biwa okulagula okw’omuwendo, enkolagana wakati w’ebivudde mu kusimba bino n’emirimu gy’okulwanyisa obuwuka bulijjo tetegeerekeka bulungi ku kusooka okulaba. Newankubadde nga okuziyiza PBP2a kuwagirwa nnyo ng’ensonga enkulu ekwata ku mirimu gy’okulwanyisa obuwuka, enjawulo eziwerako ziraga nti eby’obutonde ebirala nabyo bikola kinene. Ebirungo 6 ne 13b byalaga omulimu ogusinga obunene ogw’okulwanyisa obuwuka, nga byombi biriko obuwanvu bw’ekitundu ekiziyiza (inhibition zone diameter) bwa sentimita 4 n’emiwendo gya MIC (9.7 μg/100 μL) ne MBC (78.125 μg/100 μL) egya wansi, wadde nga obubonero bwabyo obw’okusimba wansi bw’ogeraageranya n’ebirungo 7, 9, 10 ne 14. Kino kiraga nti wadde nga PBP2a okuziyiza kuyamba ku mirimu gy’okulwanyisa obuwuka, ensonga nga okusaanuuka, okubeerawo kw’ebiramu n’enkyukakyuka y’enkolagana mu mbeera ya bakitiriya nazo zikwata ku mirimu okutwalira awamu. Ekifaananyi 11 kiraga ebifo byabwe eby’okusimba, ekiraga nti ebirungo byombi, ne bwe biba n’obubonero bw’okusiba obutono, bikyasobola okukwatagana n’ebisigadde ebikulu ebya PBP2a, ekiyinza okutebenkeza ekizibu ky’okuziyiza. Kino kiraga nti wadde nga okusimba molekyu kuwa amagezi amakulu ku kuziyiza PBP2a, ensonga endala ez’ebiramu zirina okulowoozebwako okutegeera mu bujjuvu ebikolwa eby’ensi entuufu eby’okulwanyisa obuwuka eby’ebirungo bino.
Nga tukozesa ensengekera ya kirisitaalo ya PBP2a (PDB ID: 4CJN), maapu z’enkolagana ya 2D ne 3D ez’ebirungo ebisinga okukola 6 ne 13b ebisibiddwa ne puloteyina ekwata penicillin 2a (PBP2a) eya Staphylococcus aureus (MRSA) egumira methicillin zakolebwa. Maapu zino zigeraageranya enkola z’enkolagana y’ebirungo bino ne re-docked co-crystallized quinazolinone ligand (CCL), nga ziraga enkolagana enkulu nga okuyungibwa kwa haidrojeni, π-stacking, n’enkolagana ya ayoni.
Enkola efaananako bwetyo yalabibwa ku kirungo 7, ekyalaga obubonero bw’okusimba waggulu ennyo (-6.32) n’obuwanvu bw’ekitundu ekiziyiza (3.9 cm) okufaanagana n’ekirungo 10. Wabula, MIC yaakyo (39.08 μg/100 μL) ne MBC (39.06 μg/100 μL) zaali waggulu nnyo, ekiraga nti kyetaagisa ebirungo ebingi okulaga ekikolwa ekiziyiza obuwuka. Kino kiraga nti wadde nga ekirungo 7 kyalaga enkolagana ey’amaanyi ey’okusiba mu kunoonyereza ku docking, ensonga nga bioavailability, cellular uptake, oba ebirala eby’obutonde biyinza okukomya obulungi bwakyo mu biramu. Wadde nga ekirungo 7 kyalaga obusobozi bw’okutta obuwuka, kyali tekikola bulungi mu kuziyiza okukula kwa bakitiriya bw’ogeraageranya n’ekirungo 6 ne 13b.
Ekirungo 10 kyalaga enjawulo ey’amaanyi ennyo n’obubonero obusinga obunene obw’okusimba (-6.40), ekiraga enkolagana ey’amaanyi ey’okusiba ku PBP2a. Wabula, zone yaayo ey’okuziyiza diameter (3.9 cm) yali egeraageranyizibwa ku compound 7, era MBC yaayo (312 μg/100 μL) yali waggulu nnyo okusinga compounds 6, 7, ne 13b, ekiraga nti omulimu gw’okutta obuwuka gunafu. Kino kiraga nti wadde nga waaliwo okulagula okulungi okw’okusimba, ekirungo 10 tekyali kikola kinene mu kutta MRSA olw’ensonga endala ezikoma nga okusaanuuka, okutebenkera, oba obutayita bulungi mu luwuzi lwa bakitiriya. Ebivudde mu kunoonyereza kuno biwagira okutegeera nti wadde ng’okuziyiza PBP2a kukola kinene mu mirimu gy’okulwanyisa obuwuka, tekinnyonnyola mu bujjuvu njawulo mu mirimu gy’ebiramu egyalabibwa mu bikozesebwa ebikebereddwa. Enjawulo zino ziraga nti okwekenneenya okugezesa okulala n’okwekenneenya mu bujjuvu ebiramu kyetaagisa okusobola okunnyonnyola mu bujjuvu enkola z’okulwanyisa obuwuka ezizingirwamu.
Ebivudde mu molekyu docking mu Table 4 ne Supplementary Data File biraga enkolagana enzibu wakati w’obubonero bw’okusiba n’emirimu gy’okulwanyisa obuwuka. Wadde nga ebirungo 6 ne 13b birina obubonero obutono obw’okusiba okusinga ebirungo 7, 9, 10, ne 14, biraga obusobozi obusinga obunene obw’okulwanyisa obuwuka. Maapu zaabwe ez’enkolagana (eziragiddwa mu kifaananyi 11) ziraga nti wadde nga zirina obubonero bwazo obw’okusiba obutono, zikyakola enkolagana ya haidrojeni ey’amaanyi n’enkolagana ya π-stacking n’ebisigadde ebikulu ebya PBP2a ebiyinza okutebenkeza ekizibu ky’enziyiza-ekiziyiza mu ngeri ey’omugaso mu biramu. Wadde nga obubonero bwa docking butono nnyo obwa 6 ne 13b, emirimu gyazo egy’okuziyiza obuwuka egyongezeddwa kulaga nti eby’obugagga ebirala nga okusaanuuka, okutebenkera, n’okutwalibwa kw’obutoffaali birina okulowoozebwako awamu n’ebikwata ku docking nga twekenneenya obusobozi bw’ekiziyiza. Kino kiraga obukulu bw’okugatta okunoonyereza ku docking n’okugezesa antimicrobial analysis okusobola okwekenneenya obulungi obusobozi bw’obujjanjabi bw’ebirungo ebipya.
Ebivudde mu kunoonyereza kuno biraga nti wadde nga molekyu docking kye kimu ku bikozesebwa eby’amaanyi mu kuteebereza enkolagana y’okusiba n’okuzuula enkola eziyinza okuziyiza, tekisaanye kwesigamwako kyokka okuzuula obulungi bw’okulwanyisa obuwuka. Ebiwandiiko bya molekyu biraga nti okuziyiza PBP2a nsonga nkulu ekwata ku mirimu gy’okulwanyisa obuwuka, naye enkyukakyuka mu mirimu gy’ebiramu ziraga nti eby’obugagga ebirala eby’obutonde n’eby’eddagala birina okulongoosebwa okutumbula obulungi bw’obujjanjabi. Okunoonyereza mu biseera eby’omu maaso kulina okussa essira ku kulongoosa ensengekera y’eddagala ly’ebirungo 7 ne 10 okulongoosa obutonde bw’ebiramu n’okutwalibwa kw’obutoffaali, okukakasa nti enkolagana ey’amaanyi ey’okusimba emmeeri evvuunulwa mu nkola entuufu ey’okulwanyisa obuwuka. Okunoonyereza okulala, omuli okukebera ebiramu ebirala n’okwekenneenya enkolagana n’enzimba n’emirimu (SAR), kijja kuba kikulu nnyo okwongera okutegeera kwaffe ku ngeri ebirungo bino gye bikolamu ng’ebiziyiza PBP2a n’okukola eddagala eritta obuwuka erikola obulungi.
Ebirungo ebikoleddwa okuva mu 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 byalaga diguli ez’enjawulo ez’emirimu gy’okulwanyisa obuwuka, nga ebirungo ebiwerako biraga okuziyiza okw’amaanyi okwa Staphylococcus aureus (MRSA) egumira methicillin. Okwekenenya enkolagana y’enzimba n’emirimu (SAR) kwalaga ebifaananyi ebikulu eby’enzimba ebisibukako obulungi bw’ebirungo bino okulwanyisa obuwuka.
Okubeerawo kw’ebibinja byombi ebya acrylonitrile ne anthracene kwalaga nti kikulu nnyo mu kwongera ku mirimu gy’okulwanyisa obuwuka. Ekibinja kya nitrile ekikola ennyo mu acrylonitrile kyetaagisa okwanguyiza enkolagana ne puloteyina za bakitiriya, bwe kityo ne kiyamba ku mpisa z’ekirungo kino ezitta obuwuka. Ebirungo ebirimu byombi acrylonitrile ne anthracene bulijjo byalaga ebikolwa eby’amaanyi eby’okulwanyisa obuwuka. Obuwoowo bw’ekibinja kya anthracene bwayongera okutebenkeza ebirungo bino, ekiyinza okutumbula emirimu gyabyo egy’ebiramu.
Okuleeta empeta za heterocyclic kyalongoosa nnyo obusobozi bw’okulwanyisa obuwuka obuva mu bikozesebwa ebiwerako. Okusingira ddala, benzothiazole derivative 13b ne acrylhydrazide derivative 6 zalaga nti zisinga okulwanyisa obuwuka nga zirina ekitundu ekiziyiza nga sentimita 4. Ebintu bino ebiva mu heterocyclic byalaga ebikolwa eby’amaanyi ennyo mu biramu, ekiraga nti ensengekera ya heterocyclic ekola kinene mu bikolwa eby’okulwanyisa obuwuka. Mu ngeri y’emu, pyrimidinethione mu kirungo 9, thiopyrazole mu kirungo 10, n’empeta ya tetrazine mu kirungo 11 byayamba ku butonde bw’ebirungo ebiziyiza obuwuka, ne kyongera okulaga obukulu bw’okukyusakyusa mu ngeri ya heterocyclic.
Mu bikozesebwa ebyakolebwa, 6 ne 13b byasingako olw’emirimu gyabyo egy’okulwanyisa obuwuka obulungi. Ekipimo ekitono eky’okuziyiza (MIC) eky’ekirungo 6 kyali 9.7 μg/100 μL, ate ekitono eky’okutta obuwuka (MBC) kyali 78.125 μg/100 μL, ekiraga obusobozi bwakyo obulungi ennyo okugogola obulwadde bwa Staphylococcus aureus (MRSA) obugumira methicillin. Mu ngeri y’emu, ekirungo 13b kyalina ekitundu ekiziyiza ekya sentimita 4 n’emiwendo gya MIC ne MBC emitono, ekikakasa obusobozi bwakyo obw’amaanyi obw’okulwanyisa obuwuka. Ebivuddemu bino biraga emirimu emikulu egy’ebibinja ebikola acrylohydrazide ne benzothiazole mu kuzuula obulungi bw’ebirungo bino.
Okwawukana ku ekyo, ebirungo 7, 10, ne 14 byalaga obusobozi obw’ekigero obw’okulwanyisa obuwuka nga zoni eziziyiza zitandikira ku sentimita 3.65 okutuuka ku 3.9. Ebirungo bino byali byetaaga ebirungo ebingi okutta ddala obuwuka, nga bwe kyeyolekera mu miwendo gyabyo egya MIC ne MBC egy’amaanyi ennyo. Newankubadde ebirungo bino byali tebikola nnyo okusinga ebirungo 6 ne 13b, byali bikyalaga obusobozi obw’amaanyi obw’okulwanyisa obuwuka, ekiraga nti okuyingiza ebitundu bya acrylonitrile ne anthracene mu mpeta ya heterocyclic kiyamba ku buzibu bwabyo obw’okulwanyisa obuwuka.
Ebirungo bino birina engeri ez’enjawulo ez’okukola, ebimu biraga obusobozi bw’okutta obuwuka ate ebirala biraga ebikolwa eby’okutta obuwuka. Ebirungo 7, 11, 13a, ne 15 bitta obuwuka era byetaaga ebirungo ebitono okutta ddala obuwuka. Okwawukana ku ekyo, ebirungo 6, 13b, ne 14 biziyiza obuwuka era bisobola okuziyiza okukula kwa bakitiriya ku bungi obutono, naye byetaaga ebirungo ebingi okutta ddala obuwuka.
Okutwaliza awamu, okwekenneenya enkolagana y’ensengekera n’emirimu kulaga obukulu bw’okuleeta ebitundu bya acrylonitrile ne anthracene n’ensengekera za heterocyclic okutuuka ku mirimu egy’amaanyi egy’okulwanyisa obuwuka. Ebivudde mu kunoonyereza kuno biraga nti okulongoosa ebitundu bino eby’enzimba n’okunoonyereza ku nkyukakyuka endala okulongoosa okusaanuuka n’okuyita mu lususu kiyinza okuvaako okukola eddagala erisinga okukola obulungi eriziyiza MRSA.
Ebirungo byonna n’ebizimbulukusa byalongoosebwa ne bikalizibwa nga tukozesa enkola eza bulijjo (El Gomhouria, Egypt). Ebifo ebisaanuuka byazuulibwa nga tukozesa ekyuma kya GallenKamp electronic melting point apparatus era bitegeezebwa awatali kulongoosebwa. Infrared (IR) spectra (cm−1) zawandiikibwa mu kitongole kya Chemistry, Faculty of Science, Ain Shams University nga tukozesa obukuta bwa potassium bromide (KBr) ku Thermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
1H NMR spectra zafunibwa ku 300 MHz nga tukozesa ekipima kya GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) ne BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.). Tetramethylsilane (TMS) yakozesebwa nga omutindo ogw’omunda nga guliko deuterated dimethyl sulfoxide (DMSO-d7). Ebipimo bya NMR byakolebwa mu kitongole kya Sayansi, Cairo University, Giza, Egypt. Okwekenenya ebirungo (CHN) kwakolebwa nga tukozesa ekintu ekiyitibwa Perkin-Elmer 2400 Elemental Analyzer era ebivuddemu bikwatagana bulungi n’emiwendo egyabaliriddwa.
Omutabula gwa asidi 3 (5 mmol) ne thionyl chloride (5 ml) gwabuguma mu kinaabiro ky’amazzi ku 65 °C okumala essaawa 4. Thionyl chloride eyasukkiridde yaggyibwawo nga efuumuulwa wansi wa puleesa ekendedde. Ekikalu ekimyufu ekyavaamu kyakuŋŋaanyizibwa ne kikozesebwa awatali kwongera kulongoosebwa. Ekifo ky’okusaanuuka: 200-202 °C, amakungula: 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, okuwunya obutafaanagana). 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. Omukenkufu. Okubalirirwa ku C18H10ClNO (291.73): C, 74.11; H, ebitundu 3.46; N, 4.80. Ebizuuliddwa: C, 74.41; H, ebitundu 3.34; N, ebitundu 4.66%.
Ku 0°C, 4 (2 mmol, 0.7 g) yasaanuusibwa mu dioxane atalina mazzi (20 ml) era hydrazine hydrate (2 mmol, 0.16 ml, 80%) yayongerwako amatondo ne gatabulwa okumala essaawa emu. Ekikalu ekitonnye kyakuŋŋaanyizibwa nga kisengejebwa ne kiddamu okufuuka ekiristaayo okuva mu ethanol okusobola okufuna ekirungo 6.
Kiristaalo za kiragala, ekifo we zisaanuuka 190-192°C, zikola ebitundu 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, ekyusibwakyusibwa), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH =), 8.54 (s, 1H, CH =); Omuwendo ogwabalirirwa ku C33H21N3O (475.53): C, 83.35; H, ebitundu 4.45; N, 8.84. Ebizuuliddwa: C, 84.01; H, ebitundu 4.38; N, ebitundu 8.05%.
Saanuula 4 (2 mmol, 0.7 g) mu 20 ml za dioxane solution ezitaliimu mazzi (erimu amatondo matono aga triethylamine), ssaako phenylhydrazine/2-aminopyridine (2 mmol) era otabule ku bbugumu erya bulijjo okumala essaawa emu ne 2. Yiwa omutabula gw’ensengekera mu ice oba amazzi osse asidi ne asidi wa hydrochloric omutono. Sekula ekikalu ekyawuddwamu oddemu okufuuka ekiristaayo okuva mu ethanol okufuna 7 era oddemu okukikola okuva mu benzene okufuna 8.
Kiristaalo za kiragala, ekifo we zisaanuuka 160-162°C, zikola ebitundu 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, ekyusibwakyusibwa), 9.15 (s, 1H, CH =), 8.81 (s, 1H, CH =), 6.78-8.58 (m, 23H, heteroaromatic); Omuwendo ogwabalirirwa ku C42H26N4O2 (618.68): C, 81.54; H, ebitundu 4.24; N, 9.06. Ebizuuliddwa: C, 81.96; H, 3.91, ne 3.91; N, ebitundu 8.91%.
4 (2 mmol, 0.7 g) yasaanuusibwa mu 20 ml za dioxane solution ezitaliimu mazzi (erimu amatondo matono aga triethylamine), 2-aminopyridine (2 mmol, 0.25 g) yayongerwamu era omutabula ne gutabulwa ku bbugumu erya bulijjo okumala essaawa 2. Omutabula gw’ensengekera gwayiibwa mu mazzi ga ice ne gufuulibwa asidi ne asidi wa hydrochloric omutono. Ekitonnyeze ekyakolebwa kyasengejebwa ne kiddamu okufuuka ekiristaalo okuva mu benzene, ne kiwa kirisitaalo eza kiragala eza 8 nga zirina ekifo ky’okusaanuuka kwa 146-148 °C n’amakungula ga 82.5%; ekisengejjo ekitali kya kiragala (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, ekyusibwakyusibwa), 9.14 (s, 1H, CH =), 7.36-8.55 (m, 13H, heteroaromatization); Okubalirirwa ku C23H15N3O (348.38): C, 79.07; H, ebitundu 4.33; N, 12.03. Ebizuuliddwa: C, 78.93; H, ebitundu 3.97; N, ebitundu 12.36%.
Ekirungo 4 (2 mmol, 0.7 g) kyasaanuusibwa mu 20 ml za dioxane omukalu (erimu amatondo matono aga triethylamine ne 2 mmol za thiourea/semicarbazide) ne kibuguma wansi w’okuddamu okufuluma okumala essaawa 2. Ekizimbulukusa kyafuumuulwa mu vacuum. Ekisigadde kyaddamu okufuuka ekiristaayo okuva mu dioxane okusobola okufuna omutabula.