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Synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yakozwe kandi ikoreshwa mu gukora ubwoko butandukanye bw'ibinyabutabire bitagira ingaruka ku mubiri binyuze mu gukorana na nucleophiles zitandukanye za azote. Imiterere ya buri kinyabutabire gikozwe muri heterocyclic yagaragajwe neza hakoreshejwe isesengura rya spectroscopic na elemental. Icumi muri cumi na bitatu bishya bya heterocyclic byagaragaje ko bitera imbaraga mu kurwanya bagiteri zirwanya imiti myinshi (MRSA). Muri byo, ibinyabutabire 6, 7, 10, 13b, na 14 byagaragaje imikorere yo hejuru ya bagiteri zifite uduce two gukumira hafi cm 4. Ariko, ubushakashatsi bwo gufunga molekile bwagaragaje ko ibinyabutabire bifite isano itandukanye na poroteyine ifata penisiline 2a (PBP2a), intego y'ingenzi yo kudahangana na MRSA. Ibinyabutabire bimwe nka 7, 10 na 14 byagaragaje ko bifitanye isano yo gufatana no kudahungabana ku buryo bugaragara aho PBP2a ikora ugereranije na quinazolinone ligand ikora. Mu buryo bunyuranye, ibinyabutabire 6 na 13b byari bifite amanota make yo gufunga ariko byagaragaje imikorere ikomeye ya bagiteri, aho ibinyabutabire 6 bifite agaciro ka MIC gake cyane (9.7 μg/100 μL) na MBC (78.125 μg/100 μL). Isesengura rya Docking ryagaragaje imikoranire y'ingenzi irimo guhuza hydrogen na π-stacking, cyane cyane hamwe n'ibisigazwa nka Lys 273, Lys 316 na Arg 298, byagaragaye ko bikorana na ligand ya co-crystallized mu miterere ya crystal ya PBP2a. Ibi bisigazwa ni ingenzi ku gikorwa cya enzyme cya PBP2a. Ibi byavuye mu bushakashatsi bigaragaza ko ibinyabutabire bya synthetic bishobora kuba imiti irwanya MRSA, bigaragaza akamaro ko guhuza molekile docking n'ibipimo bya bioassays kugira ngo hamenyekane imiti ivura neza.
Mu myaka mike ya mbere y'iki kinyejana, ubushakashatsi bwibanze cyane cyane ku guteza imbere uburyo bushya kandi bworoshye bwo guhuza sisitemu nyinshi nshya zikoresha imiti yica udukoko hakoreshejwe ibikoresho byo gutangira biboneka byoroshye.
Acrylonitrile moieties zifatwa nk'ibikoresho by'ingenzi byo gutangira gukora sisitemu nyinshi zitangaje za heterocyclic kuko ari ibintu bikunze kugira ingaruka mbi. Byongeye kandi, 2-cyanoacryloyl chloride derivatives zakoreshejwe cyane mu myaka ya vuba aha mu guteza imbere no gukora ibintu by'ingenzi cyane mu bijyanye n'imiti, nk'imiti ihuza 1, 2, 3, ibibanziriza irwanya agakoko gatera SIDA, kurwanya virusi itera kanseri, kurwanya bagiteri, kurwanya indwara zica intege no kurwanya antioxydants4, 5, 6, 7, 8, 9, 10. Vuba aha, ubushobozi bwa anthracene n'ibiyikomokaho mu binyabuzima, harimo antibiyotike, kurwanya kanseri11, 12, antibiyotike13, 14, 15 n'imiti yica udukoko16, 17, byakuruye abantu benshi18, 19, 20, 21. Ibinyabutabire birimo acrylonitrile na anthracene bigaragazwa ku Ishusho ya 1 na 2.
Nk’uko bivugwa n’Ishami ry’Umuryango w’Abibumbye ryita ku Buzima (OMS) (2021), kurwanya ubudahangarwa bw’imiti irwanya udukoko (AMR) ni ikibazo gikomeye ku buzima n’iterambere ku isi. Abarwayi ntibashobora gukira, bigatuma bamara igihe kirekire mu bitaro kandi bagakenera imiti ihenze, ndetse n’impfu n’ubumuga byiyongera. Kutagira imiti irwanya udukoko ivura udukoko akenshi bituma indwara zitandukanye zigabanuka, cyane cyane mu gihe cy’imiti ivura indwara za kanseri no kubagwa bikomeye.
Nk’uko raporo y’Ishami ry’Umuryango w’Abibumbye ryita ku Buzima yo mu 2024 ibivuga, Staphylococcus aureus (MRSA) na E. coli birwanya methicillin biri ku rutonde rw’indwara zikunze kwibasirwa n’uturemangingo. Bagiteri zombi zirwanya antibiyotike nyinshi, bityo zikaba zigaragaza indwara zigoye kuvura no kugenzura, kandi hari hakenewe cyane gukora imiti mishya kandi ikora neza yo kurwanya iyi ndwara kugira ngo iki kibazo gikemuke. Anthracene n’ibiyikomokaho ni imiti izwi cyane ishobora gukora kuri bagiteri za Gram-positive na Gram-negative. Intego y’ubu bushakashatsi ni ugukora indi miti mishya ishobora kurwanya izi ndwara zibangamiye ubuzima.
Ishami ry’Umuryango w’Abibumbye ryita ku Buzima (OMS) ritangaza ko udukoko twinshi twa bagiteri turwanya imiti myinshi, harimo na Staphylococcus aureus irwanya methicillin (MRSA), ikunze gutera ubwandu mu baturage no mu bigo by’ubuvuzi. Abarwayi banduye MRSA bavugwaho kuba bafite igipimo cy’impfu kiri hejuru ya 64% ugereranyije n’abafite indwara zishobora kwandura imiti. Byongeye kandi, E. coli itera ibyago ku isi kuko umurongo wa nyuma wo kwirinda Enterobacteriaceae irwanya carbapenem (ni ukuvuga E. coli) ari colistin, ariko bagiteri zirwanya colistin ziherutse kugaragara mu bihugu byinshi. 22, 23, 24, 25
Kubera iyo mpamvu, nk'uko bigaragazwa n'Ishami ry'Umuryango w'Abibumbye ryita ku Buzima ku Isi, Gahunda y'Ibikorwa Mpuzamahanga ku Kurwanya Ubudahangarwa bwa Mikorobe26, hakenewe byihutirwa kuvumburwa no gukora imiti mishya irwanya udukoko. Ubushobozi bukomeye bwa anthracene na acrylonitrile nk'imiti irwanya bagiteri27, irwanya ubudahangarwa bwa mikorobe28, irwanya kanseri29 na antioxidant30 bwagaragajwe mu nyandiko nyinshi zasohotse. Muri urwo rwego, twavuga ko iyi miti ikomoka kuri iyo miti ari myiza yo gukoreshwa mu kurwanya Staphylococcus aureus (MRSA) irwanya methicillin.
Isuzuma ry’ibitabo byabanje ryadushishikarije gukora ibintu bishya biva muri ibi byiciro. Kubwibyo, ubu bushakashatsi bwari bugamije guteza imbere sisitemu nshya za heterocyclic zirimo anthracene na acrylonitrile, gusuzuma ubushobozi bwazo bwo kurwanya mikorobe na antibacterial, no gusuzuma uburyo zishobora gufatana na poroteyine 2a ifata penisiline (PBP2a) binyuze mu gufunga molekile. Dushingiye ku bushakashatsi bwabanje, ubu bushakashatsi bwakomeje gukora, gusuzuma ibinyabuzima, no gusesengura uburyo bwo kubara sisitemu za heterocyclic kugira ngo hamenyekane imiti irwanya antimethicillin Staphylococcus aureus (MRSA) ifite ubushobozi bwo gukumira PBP2a31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Ubushakashatsi bwacu buriho bwibanze ku ikorwa n'isuzuma rya mikorobe ku bintu bishya bya heterocyclic birimo anthracene na acrylonitrile. 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yateguwe kandi ikoreshwa nk'inkingi y'ubwubatsi mu kubaka sisitemu nshya za heterocyclic.
Imiterere y'icyiciro cya 4 yagenwe hakoreshejwe amakuru ya spectral. 1H-NMR spectrum yagaragaje ko hari CH= kuri 9.26 ppm, IR spectrum yagaragaje ko hari itsinda rya karuboni kuri 1737 cm−1 n'itsinda rya cyano kuri 2224 cm−1, kandi 13CNMR spectrum nayo yemeje imiterere yatanzwe (reba igice cy'igerageza).
Gukora 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 byakozwe hifashishijwe hydrolysis y'amatsinda aromatic 250, 41, 42, 53 hifashishijwe umuti wa ethanolique sodium hydroxide (10%) kugira ngo habeho aside 354, 45, 56, hanyuma zigaterwa umuti wa thionyl chloride mu mazi kugira ngo habeho acryloyl chloride derivative 4 mu bwinshi (88.5%), nk'uko bigaragara ku Ishusho ya 3.
Kugira ngo hakorwe ibinyabutabire bishya bya heterocyclic bifite ubushobozi bwo kurwanya bagiteri, hakozwe uburyo acyl chloride 4 ikoreshwa na dinucleophiles zitandukanye.
Aside chloride 4 yavuwe na hydrazine hydrate kuri 0° mu gihe cy'isaha imwe. Ikibabaje ni uko pyrazolone 5 itabonetse. Uyu muti wari ukomoka kuri acrylamide, imiterere yawo yemejwe n'amakuru ya spectral. Interuro yayo ya IR yagaragaje imirongo yo kwinjizamo C=O kuri 1720 cm−1, C≡N kuri 2228 cm−1 na NH kuri 3424 cm−1. Interuro ya 1H-NMR yagaragaje ikimenyetso cyo guhinduranya protoni za olefin na protoni za NH kuri 9.3 ppm (reba Igice cy'Igerageza).
Imisokoro ibiri ya aside chloride 4 yakozwe hamwe na mole imwe ya phenylhydrazine kugira ngo itange umusaruro mwiza ukomoka kuri N-phenylacryloylhydrazine 7 (77%) (Ishusho ya 5). Imiterere ya 7 yemejwe n'amakuru ya infrared spectroscopy, yagaragaje ko amatsinda abiri ya C=O ari kuri 1691 na 1671 cm−1, ko itsinda rya CN rifata 2222 cm−1 n'uko itsinda rya NH rifata 3245 cm−1, kandi spectrum yayo ya 1H-NMR yagaragaje itsinda rya CH kuri 9.15 na 8.81 ppm na protoni ya NH kuri 10.88 ppm (reba igice cy'igerageza).
Muri ubu bushakashatsi, hakozwe ubushakashatsi ku buryo acyl chloride 4 yakoreshejwe na 1,3-dinucleophiles. Uburyo acyl chloride 4 yakoreshejwe na 2-aminopyridine muri 1,4-dioxane hamwe na TEA nk'ishingiro ku bushyuhe bw'icyumba bwatanze acrylamide derivative 8 (Ishusho ya 5), ​​imiterere yayo ikaba yaragaragaye hakoreshejwe amakuru ya spectral. IR spectra yagaragaje imigozi yo kwinjiza cyano kuri 2222 cm−1, NH kuri 3148 cm−1, na carbonyl kuri 1665 cm−1; 1H NMR spectra yemeje ko protoni za olefin ziri kuri 9.14 ppm (reba Igice cy'Igerageza).
Ikinyabutabire cya 4 gihura na thiourea kigatanga pyrimidinethione 9; ikinyabutabire cya 4 kigahura na thiosemicarbazide kigatanga thiopyrazole derivative 10 (Ishusho ya 5). Imiterere y'ikinyabutabire cya 9 na 10 byemejwe hakoreshejwe isesengura rya spectral na elemental (reba igice cy'igerageza).
Tetrazine-3-thiol 11 yakozwe binyuze mu buryo bwa "compound 4" hamwe na thiocarbazide nka 1,4-dinucleophile (Ishusho ya 5), ​​kandi imiterere yayo yemejwe hakoreshejwe spectroscopy na elemental analysis. Muri spectrum ya infrared, C=N bond yagaragaye kuri 1619 cm−1. Muri icyo gihe, spectrum yayo ya 1H-NMR yagumanye ibimenyetso byinshi bya proton aromatic kuri 7.78–8.66 ppm na proton SH kuri 3.31 ppm (reba Igice cy'Igerageza).
Acryloyl chloride 4 ikorana na 1,2-diaminobenzene, 2-aminothiophenol, aside anthranilic, 1,2-diaminoethane, na ethanolamine nk'ibice 1,4-dinucleophiles kugira ngo bikore sisitemu nshya za heterocyclic (13–16).
Imiterere y'iyi mvange nshya yakozwe yemejwe hakoreshejwe isesengura rya spectral n'iry'ibintu (reba igice cy'igerageza). 2-Hydroxyphenylacrylamide derivative 17 yabonetse hakoreshejwe reaction hamwe na 2-aminophenol nk'ikinyabutabire (Ishusho ya 6), kandi imiterere yayo yemejwe hakoreshejwe isesengura rya spectral n'iry'ibintu. Intera ya infrared y'imvange 17 yagaragaje ko ibimenyetso bya C=O na C≡N byagaragaye kuri 1681 na 2226 cm−1, uko bikurikirana. Hagati aho, intera yayo ya 1H-NMR yagumanye ikimenyetso cya singlet cya proton ya olefin kuri 9.19 ppm, naho proton ya OH igaragara kuri 9.82 ppm (reba igice cy'igerageza).
Uburyo aside chloride 4 ikorana na nucleophile imwe (urugero, ethylamine, 4-toluidine, na 4-methoxyaniline) muri dioksani nk'umusemburo na TEA nk'umusemburo ku bushyuhe bw'icyumba byatanze ibikomoka kuri acrylamide y'icyatsi kibisi 18, 19a, na 19b. Amakuru y'ibice n'ibice bya spectral by'ibikomoka kuri aside chloride 18, 19a, na 19b yemeje imiterere y'ibi bikomoka kuri aside (reba Igice cy'Igerageza) (Ishusho ya 7).
Nyuma yo gusuzuma imikorere y’imiti itandukanye irwanya udukoko, habonetse ibisubizo bitandukanye nk’uko bigaragara ku mbonerahamwe ya 1 n’Ishusho ya 8 (reba dosiye y’ishusho). Imiti yose yageragejwe yagaragaje urwego rutandukanye rwo gukumira bagiteri ya Gram-positive MRSA, mu gihe bagiteri ya Gram-negative Escherichia coli yagaragaje ubudahangarwa bwuzuye ku miti yose. Imiti yageragejwe ishobora kugabanywamo ibyiciro bitatu hashingiwe ku murambararo w’agace kabuza MRSA. Icyiciro cya mbere cyari gikora cyane kandi cyari kigizwe n’imiti itanu (6, 7, 10, 13b na 14). Umurambararo w’agace kabuza imikorere y’iyi miti wari hafi cm 4; imiti ikora cyane muri iki cyiciro yari imiti ya 6 na 13b. Icyiciro cya kabiri cyari gikora neza kandi cyari kigizwe n’indi miti itanu (11, 13a, 15, 18 na 19a). Agace kabuza imikorere y’iyi miti kari hagati ya cm 3.3 na 3.65, aho icyiciro cya 11 kigaragaza agace kabuza imikorere y’imiti kari hagati ya cm 3.65 na 0.1. Ku rundi ruhande, itsinda rya nyuma ryari rifite ibintu bitatu (8, 17 na 19b) bifite ubushobozi bwo kurwanya mikorobe nkeya (munsi ya cm 3). Ishusho ya 9 igaragaza uko uturere dutandukanye two gukumira indwara dukwirakwira.
Iperereza ryinyongera ku mikorere ya antibiyotike y’ibinyabutabire byapimwe ryasabaga kumenya MIC na MBC kuri buri kinyabutabire. Ibisubizo byaratandukanye gato (nk’uko bigaragara mu mbonerahamwe ya 2, 3 n’Ishusho ya 10 (reba dosiye y’ishusho)), aho ibinyabutabire 7, 11, 13a na 15 bisa nkaho byasubiwemo nk’ibinyabutabire byiza. Byari bifite agaciro ka MIC na MBC gake cyane (39.06 μg/100 μL). Nubwo ibinyabutabire 7 na 8 byari bifite agaciro ka MIC gake cyane (9.7 μg/100 μL), agaciro ka MBC kari hejuru (78.125 μg/100 μL). Kubwibyo, byafatwaga nk'ibinyabutabire bito kurusha ibyavuzwe mbere. Ariko, ibi binyabutabire bitandatu ni byo byagaragaye ko ari byo byiza cyane mu byapimwe, kuko agaciro ka MBC kari munsi ya 100 μg/100 μL.
Ibinyabutabire (10, 14, 18 na 19b) ntibyari bikora cyane ugereranije n'ibindi binyabutabire byapimwe kuko agaciro kabyo ka MBC kari hagati ya 156 na 312 μg/100 μL. Ku rundi ruhande, ibinyabutabire (8, 17 na 19a) ni byo byari bifite icyizere gito kuko byari bifite agaciro ka MBC ko hejuru (625, 625 na 1250 μg/100 μL, uko bikurikirana).
Amaherezo, dukurikije urwego rw'ubuhanga bwo kwihanganira ibintu rugaragara mu mbonerahamwe ya 3, ibinyabutabire byageragejwe bishobora kugabanywamo ibyiciro bibiri hashingiwe ku buryo bikoreshwa: ibinyabutabire bifite ingaruka zo kwica bagiteri (7, 8, 10, 11, 13a, 15, 18, 19b) n'ibinyabutabire bifite ingaruka zo kurwanya bagiteri (6, 13b, 14, 17, 19a). Muri byo, ibinyabutabire 7, 11, 13a na 15 ni byo bikundwa, bigaragaza ibikorwa byo kwica ku rugero ruto cyane (39.06 μg/100 μL).
Ibinyabutabire icumi muri cumi na bitatu byapimwe byagaragaje ko bishobora kurwanya Staphylococcus aureus (MRSA) idashobora kurwanya antibiyotike (methicillin-resistant antibiotique). Kubwibyo, ni ngombwa gukomeza gusuzuma udukoko twinshi tudakunda antibiyotike (cyane cyane udukoko two mu gace kamwe dufata bagiteri za Gram-positive na Gram-negative) hamwe n'imisemburo itera indwara, ndetse no gupima buri kintu kugira ngo harebwe umutekano wacyo.
Inyigo zo gufunga ingirabuzimafatizo zakozwe kugira ngo harebwe ubushobozi bw'ibinyabutabire byakozwe nk'ibibuza poroteyine 2a ifata penicillin (PBP2a) muri Staphylococcus aureus (MRSA) idashobora guterwa na methicillin. PBP2a ni enzyme y'ingenzi igira uruhare mu gukora urukuta rw'uturemangingo twa bagiteri, kandi guhagarika iyi enzyme bibangamira ishingwa ry'urukuta rw'uturemangingo, amaherezo biganisha kuri lysis ya bagiteri no gupfa kw'uturemangingo1. Ibisubizo byo gufunga ingirabuzimafatizo biri mu mbonerahamwe ya 4 kandi bisobanurwa mu buryo burambuye mu idosiye y'amakuru y'inyongera, kandi ibisubizo bigaragaza ko ibinyabutabire byinshi byagaragaje imbaraga zikomeye zo gufata PBP2a, cyane cyane ibisigazwa by'ingenzi bikora ahantu nka Lys 273, Lys 316, na Arg 298. Imikoranire, harimo guhuza hydrogen na π-stacking, yari isa cyane n'iya quinazolinone ligand (CCL) ikora nk'ibibuza imbaraga.
Amakuru yerekeye uburyo bwo gufunga ibintu mu buryo bwa molekile, hamwe n'ibindi bipimo by'ikoranabuhanga, yagaragaje cyane ko uburyo bwo gukumira PBP2a ari bwo buryo bw'ingenzi butuma ibi binyabutabire bifatwa nk'ibinini. Amanota yo gufunga ibintu hamwe n'agaciro ka root mean square deviation (RMSD) byagaragaje uburyo bwo gufatana neza n'uburyo buhamye, bishyigikira iki gitekerezo. Nkuko bigaragara mu mbonerahamwe ya 4, nubwo ibinyabutabire byinshi byagaragaje uburyo bwiza bwo gufatana, ibinyabutabire bimwe (urugero, 7, 9, 10, na 14) byari bifite amanota menshi yo gufunga ibintu kurusha ligand ya co-crystallized, bigaragaza ko bishobora kugira imikoranire ikomeye n'ibisigazwa by'ahantu bikora bya PBP2a. Ariko, ibinyabutabire bikora cyane 6 na 13b byagaragaje amanota make yo gufunga ibintu (-5.98 na -5.63, uko bikurikirana) ugereranije n'ibindi binyabutabire. Ibi bigaragaza ko nubwo amanota yo gufunga ibintu ashobora gukoreshwa mu guhanura uburyo bwo gufatana, ibindi bintu (urugero, uburyo ligand ihagaze neza n'uburyo molekile ikorana n'ibinyabuzima) nabyo bigira uruhare runini mu kugena uburyo bwo kwicana. Igishimishije ni uko agaciro ka RMSD k'ibintu byose byakozwe mu buryo bwa "synthesis" kari munsi ya 2 Å, byemeza ko imiterere yabyo ijyanye n'imiterere y'ingufu za "co-crystallized ligand", birushaho gushyigikira ubushobozi bwabyo nk'ibibuza PBP2a bikomeye.
Nubwo amanota yo gufunga n'agaciro ka RMS bitanga ubuhanuzi bw'ingirakamaro, isano iri hagati y'ibi bisubizo byo gufunga n'imikorere ya antibiyotike ntabwo ihora isobanutse neza mu nshuro ya mbere. Nubwo gukumira PBP2a gushyigikiwe cyane nk'ikintu cy'ingenzi bigira ingaruka ku mikorere ya antibiyotike, itandukaniro rinini rigaragaza ko hari n'indi miterere y'ibinyabuzima igira uruhare runini. Ibinyabutabire 6 na 13b byagaragaje imikorere ya antibiyotike iri hejuru cyane, bifite umurambararo wa cm 4 wo gukumira hamwe n'agaciro ka MIC gake cyane (9.7 μg/100 μL) na MBC (78.125 μg/100 μL), nubwo amanota yabyo ari make ugereranije n'ibinyabutabire 7, 9, 10 na 14. Ibi bigaragaza ko nubwo gukumira PBP2a bigira uruhare mu mikorere ya antibiyotike, ibintu nk'uburyo bwo gushonga, kuba bioavailability n'imikorere y'imikoranire mu bidukikije bya bagiteri nabyo bigira ingaruka ku mikorere rusange. Ishusho ya 11 igaragaza aho bihagarara, bigaragaza ko ibinyabutabire byombi, nubwo bifite amanota make yo gufatana, biracyashobora gukorana n'ibisigazwa by'ingenzi bya PBP2a, bishobora gutuma imiterere ya antibiyotike ihagarara neza. Ibi bigaragaza ko nubwo gufunga molekile bitanga ubumenyi bw'ingenzi ku bijyanye no gukumira PBP2a, hari ibindi bintu bifatika bigomba kwitabwaho kugira ngo dusobanukirwe neza ingaruka nyazo z'iyi miti irwanya udukoko.
Hakoreshejwe imiterere ya kristu ya PBP2a (PDB ID: 4CJN), hakozwe amakarita y’imikoranire ya 2D na 3D y’ibinyabutabire bikora cyane 6 na 13b byashyizwemo poroteyine ifata penisiline 2a (PBP2a) ya Staphylococcus aureus idakira methicillin (MRSA). Aya makarita agereranya imiterere y’imikoranire y’ibi binyabutabire na quinazolinone ligand (CCL) yasubiwemo, agaragaza imikoranire y’ingenzi nko guhuza hydrogen, gukusanya π, no guhuza ioni.
Ishusho nk'iyo yagaragaye ku gice cya 7, cyagaragaje igipimo cyo hejuru cyo gufunga (-6.32) n'umurambararo w'agace kabuza (3.9 cm) nk'icya 10. Ariko, MIC yayo (39.08 μg/100 μL) na MBC (39.06 μg/100 μL) byari hejuru cyane, bigaragaza ko yasabaga ingano nyinshi kugira ngo igaragaze ingaruka za bagiteri. Ibi bigaragaza ko nubwo igice cya 7 cyagaragaje imbaraga zikomeye zo gufatana mu bushakashatsi bwo gufunga, ibintu nko kuba bioavailability, kwinjiza uturemangingo, cyangwa izindi mbaraga za fiziki bishobora kugabanya ubushobozi bwayo mu binyabuzima. Nubwo igice cya 7 cyagaragaje ubushobozi bwo kwica bagiteri, ntabwo cyagize ingaruka nziza mu kubuza gukura kwa bagiteri ugereranije n'ibindi bice bya 6 na 13b.
Ikiyiko cya 10 cyagaragaje itandukaniro rikomeye cyane hamwe n'amanota menshi yo gufunga (-6.40), bigaragaza ko gifite ubushobozi bukomeye bwo gufatanya na PBP2a. Ariko, akarere kayo k'umurambararo wo gukumira (3.9 cm) kari kagereranywa n'ikiyiko cya 7, kandi MBC yayo (312 μg/100 μL) yari hejuru cyane ugereranyije n'ikiyiko cya 6, 7, na 13b, bigaragaza ko imikorere yayo yo kwica bagiteri idakomeye. Ibi bigaragaza ko nubwo byari byavuzwe neza ko gufunga, ikiyiko cya 10 nticyagize ingaruka nziza mu kwica MRSA bitewe n'izindi mpamvu zibuza umubiri gushonga, guhagarara neza, cyangwa kwinjira nabi kw'urukiramende rwa bagiteri. Ibi bisubizo bishyigikira ko nubwo gufunga PBP2a bigira uruhare runini mu mikorere ya bagiteri, ntabwo bisobanura neza itandukaniro mu mikorere ya bagiteri ryagaragaye mu biyiko byageragejwe. Iri tandukaniro rigaragaza ko hakenewe ubundi bushakashatsi bw'igerageza n'isuzuma ryimbitse rya bagiteri kugira ngo hamenyekane neza uburyo bwa bagiteri bukoreshwa.
Gushyira mu kato k’uturemangingo mu turemangingo bigaragaza isano iri hagati y’ibipimo byo gufunga no gukora imiti yica udukoko. Nubwo ibintu 6 na 13b bifite ibipimo byo gufunga bike ugereranyije n’ibintu 7, 9, 10, na 14, bigaragaza imikorere yabyo yo kurwanya udukoko cyane. Amakarita y’imikoranire yabyo (yerekanywe ku Ishusho ya 11) agaragaza ko nubwo bifite amanota make yo gufata, biracyakora imigozi ikomeye ya hydrogen na π-stacking hamwe n’ibisigazwa by’ingenzi bya PBP2a bishobora gutuza enzyme-inhibitor complex mu buryo bw’ingirakamaro ku binyabuzima. Nubwo amanota make yo gufunga ari 6 na 13b, imikorere yabyo yongereye ya antibiyotike igaragaza ko indi miterere nko gushonga, gutuza, no kwinjira mu turemangingo bigomba kwitabwaho hamwe n’amakuru yo gufunga mu gihe cyo gusuzuma ubushobozi bwo gukumira. Ibi bigaragaza akamaro ko guhuza inyigo zo gufunga no gusesengura imiti yica udukoko mu bushakashatsi kugira ngo hamenyekane neza ubushobozi bwo kuvura bw’ibintu bishya.
Ibi bisubizo bigaragaza ko nubwo gufunga ingirabuzimafatizo ari igikoresho gikomeye cyo guhanura uburyo bwo gufatana no kumenya uburyo bushobora gutuma ingirabuzimafatizo zihagarara, ntabwo bikwiye kwishingikirizaho byonyine kugira ngo hamenyekane ubushobozi bwo kurwanya indwara ziterwa na mikorobe. Amakuru ya molekile agaragaza ko gufunga PBP2a ari ikintu cy'ingenzi bigira ingaruka ku mikorere ya mikorobe, ariko impinduka mu mikorere ya biyolojiya zigaragaza ko indi miterere ya fisikokemike na farumasike igomba kunozwa kugira ngo yongere ubushobozi bwo kuvura. Ubushakashatsi bw'ejo hazaza bugomba kwibanda ku kunoza imiterere ya shimi y'ibinyabutabire bya 7 na 10 kugira ngo hongerwe uburyo bwo kuboneka no kwinjira mu turemangingo, hamenyekane ko imikoranire ikomeye ya doki ihinduka imikorere nyayo ya mikorobe. Ubundi bushakashatsi, burimo isuzuma ryinyongera rya biyokeje n'isesengura ry'imibanire y'imiterere n'ibikorwa (SAR), bizaba ingenzi cyane kugira ngo dusobanukirwe neza uburyo ibi binyabutabire bikora nk'imiti igabanya PBP2a no guteza imbere imiti irwanya mikorobe ikoreshwa neza.
Ibinyabutabire byakozwe muri 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 byagaragaje imikorere itandukanye ya antibiyotike, aho ibinyabutabire byinshi bigaragaza ko Staphylococcus aureus (MRSA) idashobora kurwanya methicillin. Isesengura ry'imiterere n'imikorere (SAR) ryagaragaje imiterere y'ingenzi ishingiye ku miterere y'ibi binyabutabire.
Kuba hari amatsinda ya acrylonitrile na anthracene byagaragaye ko ari ingenzi cyane mu kongera imikorere ya antibiyotike. Itsinda rya nitrile rigira uruhare runini muri acrylonitrile ni ngombwa kugira ngo byorohereze imikoranire na poroteyine za bagiteri, bityo bikagira uruhare mu miterere ya antibiyotike y’icyo kinyabutabire. Ibinyabutabire birimo acrylonitrile na anthracene byagaragaje ingaruka zikomeye zo kurwanya antibiyotike. Impumuro nziza y’itsinda rya anthracene yarushijeho gutuma ibi binyabutabire bihagarara neza, bishobora kongera imikorere yabyo mu buzima.
Gushyiramo impeta za heterocyclic byazamuye cyane ubushobozi bwo kurwanya bagiteri z’ibintu byinshi bivamo imiti. By’umwihariko, benzothiazole derivative 13b na acrylhydrazide derivative 6 byagaragaje imikorere yo hejuru ya bagiteri aho uburebure bwa cm 4 bugera kuri. Izi heterocyclic derivatives zagaragaje ingaruka zikomeye ku buzima, bigaragaza ko imiterere ya heterocyclic igira uruhare runini mu ngaruka za bagiteri. Mu buryo nk’ubwo, pyrimidinethione mu gice cya 9, thiopyrazole mu gice cya 10, na tetrazine ring mu gice cya 11 byagize uruhare mu miterere ya bagiteri z’ibintu bivamo imiti, birushaho kugaragaza akamaro ko guhindura heterocyclic.
Mu bintu byakozwe, 6 na 13b byagaragaye cyane mu gukora neza kwabyo kwa antibacterial. Ingano ntoya yo gukumira (MIC) y’ikintu cya 6 yari 9.7 μg/100 μL, naho ingano ntoya yo kwica bagiteri (MBC) yari 78.125 μg/100 μL, bigaragaza ubushobozi bwayo bwiza bwo gukuraho Staphylococcus aureus (MRSA) idakira methicillin. Mu buryo nk'ubwo, ikintu cya 13b cyari gifite agace ka cm 4 gakingira indwara kandi gifite agaciro ka MIC na MBC gake, byemeza ko gifite imbaraga zo kurwanya bagiteri. Ibi bisubizo bigaragaza uruhare rw'ingenzi rw'amatsinda y'imikorere ya acrylohydrazide na benzothiazole mu kugena imikorere myiza y'ibi bintu.
Mu buryo bunyuranye, ibinyabutabire 7, 10, na 14 byagaragaje imikorere iri hagati ya bagiteri n’uduce two gukumira turi hagati ya cm 3.65 na 3.9. Ibi binyabutabire byasabaga ingano iri hejuru kugira ngo byice bagiteri burundu, nk’uko bigaragazwa n’agaciro kabyo ka MIC na MBC kari hejuru. Nubwo ibi binyabutabire bitari bikora cyane ugereranyije n’ibinyabutabire 6 na 13b, byagaragaje ubushobozi bunini bwo kurwanya bagiteri, bigaragaza ko gushyira acrylonitrile na anthracene mu ruziga rw’amaraso bituma bitera bagiteri ingaruka mbi.
Ibinyabutabire bifite uburyo butandukanye bwo gukora, bimwe bigaragaza ubushobozi bwo kwica bagiteri naho ibindi bigaragaza ingaruka za bagiteri. Ibinyabutabire 7, 11, 13a, na 15 birwanya bagiteri kandi bisaba urugero ruto kugira ngo byice bagiteri burundu. Ibinyabutabire 6, 13b, na 14 birwanya bagiteri kandi bishobora kubuza bagiteri gukura ku rugero ruto, ariko bisaba urugero rwinshi kugira ngo byice bagiteri burundu.
Muri rusange, isesengura ry’imiterere n’imikorere ryerekana akamaro ko gushyiramo acrylonitrile na anthracene moieties hamwe n’imiterere ya heterocyclic kugira ngo hagerwe ku musaruro ukomeye wa antibiyotike. Ibi bisubizo bigaragaza ko kunoza ibi bice by’imiterere no gushakisha izindi mpinduka kugira ngo hongerwe uburyo bwo gushonga no kwinjira mu ruhu bishobora gutuma habaho imiti irwanya MRSA ikora neza kurushaho.
Ibintu byose bisukura n'ibishongesha byasukuwe kandi byumishwa hakoreshejwe uburyo busanzwe (El Gomhouria, Misiri). Aho gushonga byapimwe hakoreshejwe igikoresho cya elegitoroniki cya GallenKamp kandi byatanzwe nta gukosorwa. Spektara ya infrared (IR) (cm⁻1) yafashwe mu ishami rya chimie, ishami rya siyansi, kaminuza ya Ain Shams hakoreshejwe uduce twa potasiyumu bromide (KBr) kuri spectrometer ya Thermo Electron Nicolet iS10 FTIR (Thermo Fisher Scientific, Waltham, MA, muri Amerika).
Spektara ya 1H NMR yabonetse kuri 300 MHz hakoreshejwe spectrometer ya GEMINI NMR (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) na spectrometer ya BRUKER 300 MHz NMR (BRUKER Manufacturing & Engineering, Inc.). Tetramethylsilane (TMS) yakoreshejwe nk'igipimo cy'imbere gifite deuterated dimethyl sulfoxide (DMSO-d₆). Ibipimo bya NMR byakorewe mu Ishami ry'Ubumenyi, Kaminuza ya Cairo, Giza, Misiri. Isesengura ry'ibintu (CHN) ryakozwe hakoreshejwe Perkin-Elmer 2400 Elemental Analyzer kandi ibisubizo byabonetse bihuye neza n'agaciro kabazwe.
Uruvange rwa aside 3 (5 mmol) na thionyl chloride (5 ml) byashyuhijwe mu bwogero bw'amazi kuri 65 °C mu gihe cy'amasaha 4. Thionyl chloride yarenze yakuweho hakoreshejwe uburyo bwo gushonga munsi y'igitutu gito. Ifu itukura yavuyemo yakusanyijwe ikoreshwa nta bundi buryo bwo kuyisukura. Aho ishonga ishongesha: 200-202 °C, umusaruro: 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. Umusesenguzi. Byabazwe kuri C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Byabonetse: C, 74.41; H, 3.34; N, 4.66%.
Ku bushyuhe bwa 0°C, 4 (2 mmol, 0.7 g) yashongeshejwe muri dioksani ya anhydrous (20 ml) maze hydrazine hydrate (2 mmol, 0.16 ml, 80%) yongerwamo amazi hanyuma irabyukwa mu gihe cy'isaha 1. Ingufu zavuyemo zakusanyijwe binyuze mu kuyungurura hanyuma zigashyirwa muri etanoli kugira ngo habeho imvange 6.
Amakristu y'icyatsi kibisi, aho ashongesha 190-192℃, atanga umusaruro 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, ishobora guhindurwa), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Agaciro kabazwe kuri C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Byabonetse: C, 84.01; H, 4.38; N, 8.05%.
Shyiraho 4 (2 mmol, 0.7 g) muri ml 20 z'umuti wa dioxane ya anhydrous (urimo ibitonyanga bike bya triethylamine), ongeramo phenylhydrazine/2-aminopyridine (2 mmol) hanyuma uvange ku bushyuhe bw'icyumba mu gihe cy'isaha 1 na 2, uko bikurikirana. Suka uruvange rw'ibisubizo mu rubura cyangwa mu mazi hanyuma ushyiremo aside hidrokloriki ivanze. Kuramo ikintu cyatandukanyijwe hanyuma uvange muri ethanol kugira ngo ubone 7 hanyuma uvange muri benzene kugira ngo ubone 8.
Amakristu y'icyatsi kibisi, aho ashongesha 160-162℃, atanga umusaruro 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, ishobora guhindurwa), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Agaciro kabazwe kuri C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Byabonetse: C, 81.96; H, 3.91; N, 8.91%.
4 (2 mmol, 0.7 g) yashongeshejwe muri mililitiro 20 z'umuti wa dioxane ya anhydrous (urimo ibitonyanga bike bya triethylamine), hongewemo 2-aminopyridine (2 mmol, 0.25 g) hanyuma uruvange rukabyutswa ku bushyuhe bw'icyumba mu gihe cy'amasaha 2. Uruvange rw'ibisubizo rwasutswe mu mazi y'urubura maze rushyirwamo aside hidrokloriki ivanze. Uduce twakozwe twayunguruwe hanyuma twongera gukurwamo benzene, bitanga kristu z'icyatsi kibisi za 8 hamwe n'ikigero cyo gushonga cya 146-148 °C n'umusaruro wa 82.5%; spectrum ya infrared (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, ishobora guhindurwa), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); Byabazwe kuri C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Byabonetse: C, 78.93; H, 3.97; N, 12.36%.
Ikinyabutabire cya 4 (2 mmol, 0.7 g) cyashongeshejwe muri 20 ml ya dioxane yumye (irimo ibitonyanga bike bya triethylamine na 2 mmol ya thiourea / semicarbazide) maze gishyushya munsi y'amazi mu gihe cy'amasaha 2. Ikinyabutabire cyashongeshejwe mu cyuma gifunze. Ibisigazwa byasubiwemo biva muri dioxane kugira ngo bibe uruvange.