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Ekirungo kya synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kikakorwa kandi kyakoresibwa kuhangaho ebirungo by’emiringo etari emwe n’emwe ebirikukora munonga kurabira omu kugaaniira kwakyo n’ebicweka by’omubiri ebitari bimwe na bimwe ebirikukora nk’eby’okurya ebirimu ebiriisa by’omubiri. Omubumbi wa buri kimwe ekikozirwe omu nkora ya heterocyclic kikashoboororwa gye barikukoresa okucondooza kwa spectroscopic n’okucondooza kw’ebintu. Ikumi ahari ikumi n‘eshatu z‘ebirungo bya heterocyclic ebisya byorekire oburungi oburikugaruramu amaani aha bukooko oburikurwanisa emibazi mingi (MRSA). Omuri ebyo, ebirungo 6, 7, 10, 13b, na 14 nibyoreka emirimo y’okurwanisa obukooko oburikukirayo n’ebicweka by’okuzibira ebiri haihi na sentimita 4. Kwonka okucondooza okwakozirwe aha molecule docking kukashohoza ngu ebirungo ebi biine enkoragana zitari zimwe na zimwe n’ebiriisa ebirikukwatanisa na penicillin 2a (PBP2a), ekigyendererwa kikuru eky’okuzibira MRSA. Ebimwe aha bikwatiraine na 7, 10 na 14 byorekire obukwatiraine bw‘ahaiguru n‘okugumaho kw‘okukoragana aha mwanya ogurikukoreramu ogwa PBP2a kugyeragyeranisa n‘ekirungo kya quinazolinone ekirikukora hamwe. Okutaana n‘ekyo, ebirungo 6 na 13b bikaba biine obubonero bw‘okutaho obukooko obukye kwonka bikaba bikyoreka emirimo y‘okurwanisa obukooko bw‘omubiri, ekirungo 6 kikaba kiine emihendo y‘ahansi ya MIC (9.7 μg/100 μL) na MBC (78.125 μg/100 μL). Okushwijuma okuteerana kukashohoza enkoragana nkuru ezirimu okuteerana kwa haidrojeni na π-stacking, namunonga n’ebisigarira nka Lys 273, Lys 316 na Arg 298, ebyabaire nibimanyirwa nk’ebirikukwatagana n’ekicweka ky’omubiri ekirikuteerana (co-crystallized ligand) omu nkora y’okuteerana kwa PBP2a. Ebisigarira ebi nibyetengyesa munonga omu mirimo y‘enzigye eya PBP2a. Ebirugire omu kucondooza oku nibyoreka ngu ebirungo ebikozirwe nibibaasa kukora nk‘emibazi erikuraganisa kurwanisa MRSA, ekirikworeka obukuru bw‘okugaita molecular docking n‘okucondooza aha bikwatiraine n‘amagara kubaasa kumanya abarikubaasa kujanjaba gye.
Omu myaka mikye ey‘okubanza ey‘ekyasha eki, okucondooza kukaba kutaire omutima munonga aha kuhangaho enkora nsya, eyorobi n‘emiringo y‘okuteerana enkora z‘obuhanguzi zitari zimwe na zimwe eza heterocyclic eziine emirimo y‘okurwanisa obukooko oburikureeta endwara barikukoresa ebintu by‘okutandikiraho ebiriho juba.
Ebicweka bya acrylonitrile nibitwarwa nk’ebintu bikuru by’okutandikiraho eby’okukora enkora nyingi z’okutangaaza eza heterocyclic ahabw’okuba nibikora munonga. Ekindi, ebirugire omu 2-cyanoacryloyl chloride bikoresiibwe munonga omu myaka ehweire omu kutunguura n’okuteerana ebintu by’omugasho munonga omu by’okukoresa omu by’emibazi, nk’ebintu ebiri ahagati y’emibazi1,2,3, ebirikubanza omu kurwanisa siriimu, okurwanisa obukooko, okurwanisa ekookoro, okurwanisa obukooko oburikureeta endwara, okurwanisa obukooko oburikureeta endwara. abakozi4,5,6,7,8,9,10. Enyimaho, oburungi bw’ebihangirwe eby’omubazi gwa anthracene n’ebirikurugamu, otwariremu n’omubazi gwabyo gw’okurwanisa obukooko, okurwanisa ekookoro11,12, okurwanisa obukooko13,14,15 n’okurwanisa obukooko16,17, bitungire omutima gw’abantu baingi18,19,20,21. Ebirungo ebirikurwanisa obukooko ebirimu ebicweka bya acrylonitrile na anthracene nibyorekwa omu bishushani 1 na 2.
Okurugirira aha kitongore ky‘eby‘amagara eky‘ensi yoona (WHO) (2021), okuzibira obukooko oburikureeta endwara (AMR) n‘akabi k‘ensi yoona aha magara n‘entunguuka22,23,24,25. Abarwaire tibarikubaasa kutambirwa, ekirikureetaho okumara obwire buraingwa omu irwariro n’okwetenga emibazi y’omuhendo, hamwe n’okufa n’oburema kweyongyera. Okubura emibazi y‘okurwanisa obukooko oburikukora gye nikikira kureetera okuremwa kujanjaba endwara zitari zimwe na zimwe, namunonga omu bwire bw‘okujanjaba n‘okushemezibwa kw‘amaani.
Okurugirira ahari ripoota y’ekitongore ky’eby’amagara eky’ensi yoona ekya 2024, obukooko obutarikubaasa kukwatwa endwara ya Staphylococcus aureus (MRSA) na E. coli niziteebwa omu runyiriri rw’obukooko oburikwebembezibwa. Obukooko bwombi nibubaasa kugumira emibazi mingi y’okurwanisa obukooko, n’ahabw’ekyo nibujwekyera oburwaire obugumire kujanjaba n’okutegyeka, kandi hariho ekyetengo ky’ahonaaho eky’okukora emibazi mirungi y’okurwanisa obukooko oburikubaasa kushoboorora ekizibu eki. Anthracene n’ebirikurugamu n’ebintu ebirikumanywa gye ebirikurwanisa obukooko oburikubaasa kukora aha bukooko oburikureeta oburwaire bwa Gram n’obutari bwa Gram. Ekigyendererwa ky’okwega oku n’okukora ekirungo kisya ekirikubaasa kurwanisa obukooko obu oburi obw’akabi aha magara.
Ekitongore ky‘eby‘amagara eky‘ensi yoona (WHO) nikigira ngu obukooko bwingi oburikureeta endwara nibubaasa kugumira emibazi mingi, otwariiremu n‘oburwaire obutarikurwanisa methicillin Staphylococcus aureus (MRSA), oburikukira kureetaho oburwaire omu bantu n‘omu myanya y‘okujanjaba. Abarwaire abaine oburwaire bwa MRSA nibateekateekwaho kuba baine omubaro gw‘okufa 64% kukira abo abaine oburwaire oburikukwatwa emibazi. Okwongyera ahari ekyo, E. coli neereeta akabi omu nsi yoona ahabw‘okuba omuringo gw‘okwerinda ogurikuhererukayo ahari Enterobacteriaceae ezitarikubaasa kukwatwa carbapenem (nikwo kugira ngu, E. coli) ni colistin, kwonka obukooko obutarikubaasa kukwatwa colistin bukagambwaho juba omu mahanga maingi. 22,23,24,25
Nahabwekyo, kurugiirira aha ntebeekanisa y‘okukora ey‘ensi yoona ey‘ekitongore ky‘eby‘amagara26, hariho ekyetengo ky‘ahonaaho eky‘okuzoora n‘okukora emibazi mirungi y‘okurwanisa obukooko. Obushoboorozi bwingi bwa anthracene na acrylonitrile nk’ebintu ebirikurwanisa obukooko27, obukooko oburikureeta obuhuta28, oburwaire bwa kansa29 n’ebirikurwanisa obukooko oburikureeta endwara30 bukagambwaho omu mpapura nyingi ezihandiikirwe. Omu nshonga egi, nikibaasa kugambwa ngu ebirugire omu bihingwa ebi nibibaasa kukoresibwa gye omu kurwanisa oburwaire bwa Staphylococcus aureus (MRSA) obutarikubaasa kukwatwa omubazi gwa methicillin.
Okushwijuma ebihandiiko ebyabaireho enyima kukatuhiga kuteerana ebigambo bisya ebirikuruga omu bibiina ebi. Nahabwekyo, okucondooza oku kukaba kugyendereire kukora enkora ensya eza heterocyclic ezirimu ebicweka bya anthracene na acrylonitrile, kukyebera obushoboorozi bwazo omu kurwanisa obukooko n’obukooko oburikureeta endwara, n’okucondooza aha nkoragana yaabo erikubaasa kukwatira hamwe na puroteyini 2a (PBP2a) erikukwatira hamwe penicillin kurabira omu kukwatira hamwe kwa molecule. Okwombekyera aha kucondooza okuhwaire, okucondooza okuriho hati kukagumizamu n‘okuteerana, okushwijuma eby‘amagara, n‘okucondooza kw‘eby‘amagara okwa kompyuta kw‘enkora za heterocyclic kubaasa kumanya ebirikuraganisa ebirikurwanisa Staphylococcus aureus (MRSA) ebiine amaani g‘okuzibira PBP2a . omurimo31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Okucondooza kwaitu okwa hati nikuta omutima aha kuteerana n’okushwijuma obukooko oburikurwanisa obukooko obusya oburimu ebicweka bya anthracene na acrylonitrile. 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ekatebeekanisibwa kandi yakoresibwa nk’ekyombeko ky’okwombeka enkora z’eby’obuhangwa ezitarikushushana.
Omuringo gw’ekirungo kya 4 gukamanyirwa aha kukoresa amakuru g’eby’okureeberaho. Ekishushani kya 1H-NMR nikyoreka okubaho kwa CH= ahari 9.26 ppm, ekicweka kya IR nikyoreka okubaho kwa guruupu ya carbonyl ahari 1737 cm−1 n’ekibiina kya cyano ahari 2224 cm−1, kandi ekicweka kya 13CNMR nakyo kikahamya omubumbi etebekanisiibwe (reeba ekicweka ky’okugyezesa).
Okuteerana kwa 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kukahikirizibwa kurabira omu kuhindura amaizi g’ebicweka by’omubazi 250, 41, 42, 53 n’omubazi gw’eby’okurya ebirimu ebiriisa by’omubiri (10%) kuha asidi 354, 45, 56. okunaaba kuha ekirungo kya acryloyl chloride 4 omu kutunga ebiriisa bingi (88.5%), nk’oku kirikworekwa omu kishushani 3.
Okubaasa kuhangaho ebirungo bisya ebya heterocyclic ebiine obushoboorozi oburikuteekateekwaho kurwanisa obukooko, okukoragana kwa acyl chloride 4 na dinucleophiles zitari zimwe na zimwe kukakorwa.
Asidi ya kloride 4 ekakyeberwa n’amaizi g’okukyebera hydrazine aha 0° kumara eshaaha emwe. Ekibi munonga, omubazi gwa pyrazolone 5 tiguratungirwe. Ekintu eki kikaba kiri ekirugire omu acrylamide eki omubumbi waakyo yaahamibwa n’ebihandiiko bya spectral. Eby’okureeberaho byayo ebya IR bikooreka ebicweka by’okunywanisa C=O ahari 1720 cm−1, C≡N ahari 2228 cm−1 na NH ahari 3424 cm−1. Ekishushani kya 1H-NMR kikayoreka akamanyiso k‘okuhindura singlet aka purotoni za olefin na purotoni za NH ahari 9.3 ppm (reeba Ekicweka ky‘okugyezesa).
Mole ibiri za asidi kloraidi 4 zikagambwaho na mole emwe ya phenylhydrazine kubaasa kutunga N-phenylacryloylhydrazine derivative 7 omu kutunga gye (77%) (ekishushani 5). Omubumbi wa 7 gukahamibwa n‘ebihandiiko bya infrared spectroscopy, ebyayorekire okunywanisa kwa guruupu ibiri za C=O ahari 1691 na 1671 cm−1, okunywanisa kwa guruupu ya CN ahari 2222 cm−1 n‘okunywanisa kwa guruupu ya NH ahari 3245 cm−1, kandi guruupu yaayo eya 1H-NMR1 and8m9ed. NH purotoni ahari 10.88 ppm (reeba ekicweka ky‘okugyezesa).
Omu kucondooza oku, oku acyl kloride 4 erikukoragana na 1,3-dinucleophiles kukacondoozibwa. Okujanjaba kwa acyl chloride 4 na 2-aminopyridine omu 1,4-dioxane na TEA nk’omusingi aha bwire bw’obutagatsi bw’omu kishengye kukaha ekirugire omu acrylamide 8 (ekishushani 5), omubumbi gwakyo gukamanyirwa aha kukoresa amakuru g’eby’okureeberaho. Ebishushani bya IR bikooreka ebicweka by’okunywanisa eby’omushana gwa cyano ebirikutambaara ahari 2222 cm−1, NH ahari 3148 cm−1, na carbonyl ahari 1665 cm−1; 1H NMR spectra ekahamya okubaho kwa purotoni za olefin ahari 9.14 ppm (reeba Ekicweka ky’okugyezesa).
Ekirungo kya 4 nikikwatagana na thiourea kuha pirimidinetiyoni 9; ekirungo 4 nikikwatagana na thiosemikarbazide kuha ekirungo kya thiopyrazole 10 (ekishushani 5). Emitwarize y’ebirungo 9 na 10 ekahamibwa okucondooza kw’erangi n’ebintu (reeba ekicweka ky’okugyezesa).
Tetrazine-3-thiol 11 ekatebeekanisibwa ahabw’okuteerana kw’ekirungo 4 na thiocarbazide nk’ekirungo kya 1,4-dinucleophile (ekishushani 5), kandi omubumbi gwayo gukahamibwa ahabw’okukyebera ebiri omu itaka n’okucondooza aha bintu. Omu nkora ya infrared, omukago gwa C=N gukareebeka ahari 1619 cm−1. Omu bwire nibwo bumwe, omubaro gwayo ogwa 1H-NMR gukaguma n‘obumanyiso bw‘ebicweka bingi eby‘ebicweka by‘omubiri ebiine omubazi gw‘okushemeza ahari 7.78–8.66 ppm na purotoni za SH ahari 3.31 ppm (reeba Ekicweka ky‘okugyezesa).
Acryloyl chloride 4 neekwatagana na 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoetane, na etanolamini nk’ebicweka 1,4-dinucleophiles kuhanga enkora nsya z’okutambura (13–16).
Emitwarize y’ebirungo ebi ebisya ebikozirwe ekahamibwa okucondooza kw’erangi n’ebintu (reeba ekicweka ky’okugyezesa). 2-Hydroxyphenylacrylamide ekirugire omu 17 kikatunga okukoragana na 2-aminophenol nk’ekirungo ky’omubiri (ekishushani 6), kandi omubumbi gwakyo gukahamibwa omu kucondooza kw’erangi n’ebintu. Eby’okureeberaho by’omushana gw’omunda eby’ekirungo 17 bikooreka ngu obumanyiso bwa C=O na C≡N bukareebeka ahari 1681 na 2226 cm−1, nk’oku biri. Omu bwire obwo, 1H-NMR spectrum yaayo ekaguma n’akamanyiso ka singlet aka purotoni ya olefin ahari 9.19 ppm, kandi purotoni ya OH ekareebeka ahari 9.82 ppm (reeba ekicweka ky’okugyezesa).
Okugarukamu kwa asidi kloraidi 4 n’ekirungo kimwe (nk’eky’okureeberaho, ethylamine, 4-toluidine, na 4-metoxyaniline) omu dioxane nk’ekirungo kandi TEA nk’ekirungo aha bwire bw’obutagatsi bw’omu kishengye kikaha ebirungo bya acrylamide eby’ekibira 18, 19a, na 19b. Ebihandiiko by’ebintu n’eby’okureeberaho eby’ebirungo 18, 19a, na 19b bikahamya emikorere y’ebintu ebi ebirugiremu (reeba Ekicweka ky’okugyezesa) (ekishushani 7).
Bwanyima y‘okushwijuma emirimo y‘okurwanisa obukooko bw‘omubiri ey‘ebintu ebitari bimwe na bimwe ebikozirwe abantu, ebyarugamu bitarikushushana bikatunga nk‘oku birikworekwa omu kipande 1 n‘ekishushani 8 (reeba fairo y‘ekishushani). Ebirungo byona ebyakyeberwa byorekire emiringo etari emwe n’emwe y’okuzibira obukooko bwa Gram-positive MRSA, kandi obukooko bwa Gram-negative Escherichia coli bworekire okuzibira okuhikire aha birungo byona. Ebirungo ebikyebeirwe nibibaasa kugabwa omu bicweka bishatu kurugiirira aha diamita y‘ekicweka ky‘okuzibira MRSA. Omuringo gw‘okubanza gukaba guri ogw‘okukora munonga kandi gukaba gurimu ebirungo bitaano (6, 7, 10, 13b na 14). Diamita y’ekicweka ky’okuzibira ebirungo ebi ekaba eri haihi na sentimita 4; ebirungo ebyabaire nibikora munonga omu kicweka eki bikaba biri ebirungo 6 na 13b. Omuringo gwa kabiri gukaba guri ogw‘omutindo gw‘ahaiguru kandi gukaba gurimu ebindi birungo bitaano (11, 13a, 15, 18 na 19a). Ekicweka ky’okuzibira ebirungo ebi kikaba kiri ahagati ya 3.3 kuhika ahari 3.65 cm, ekirungo 11 nikyoreka ekicweka ky’okuzibira ekihango kya 3.65 ± 0.1 cm. Aha rubaju orundi, guruupu eyahererukireyo ekaba eine ebirungo bishatu (8, 17 na 19b) ebiine amaani makye g‘okurwanisa obukooko (ahansi ya sentimita 3). Ekishushani 9 nikyoreka oku emyanya y‘okuzibira etari emwe n‘emwe erikugabwa.
Okwongyera kucondooza aha mirimo y‘okurwanisa obukooko bw‘omubiri ey‘ebirungo ebyakyeberwa kukaba kurimu okumanyisa MIC na MBC ahari buri kirungo. Ebirugiremu bikahinduka kakye (nk‘oku birikworekwa omu bipande 2, 3 n‘ekishushani 10 (reeba fairo y‘ekishushani)), n‘ebirungo 7, 11, 13a na 15 nibireebeka ngu bikagaruka byateebwa omu kicweka ky‘ebirungo ebirungi. Bakaba baine emihendo ya MIC na MBC eri ahansi munonga (39.06 μg/100 μL). N‘obu ebirungo 7 na 8 byabaire biine emihendo ya MIC eri ahansi (9.7 μg/100 μL), emihendo yaabo ya MBC ekaba eri ahaiguru (78.125 μg/100 μL). N’ahabw’ekyo, bakaba nibatwarwa nk’abaine amaani makye okukira ebirungo ebi twagambaho ​​enyima. Kwonka ebirungo ebi mukaaga nibyo byabaire nibikora gye munonga omu byakyeberwa, ahabw‘okuba emihendo yaabyo eya MBC ekaba eri ahansi ya 100 μg/100 μL.
Ebirungo (10, 14, 18 na 19b) bikaba bitarikukora munonga waagyeragyeranisa n‘ebindi birungo ebyakyeberwa ahabw‘okuba emihendo yaabyo eya MBC ekaba eri ahagati ya 156 kuhika ahari 312 μg/100 μL. Aha rubaju orundi, ebirungo (8, 17 na 19a) nibyo byabaire biine amatsiko makye ahabw‘okuba bikaba biine emihendo ya MBC erikukirayo (625, 625 na 1250 μg/100 μL, buri kimwe).
Eky‘aha muheru, kurugiirira aha rurengo rw‘okugumisiriza orurikworekwa omu kipande kya 3, ebirungo ebigyeziibwe nibibaasa kubaganisibwamu emiringo ebiri kurugiirira aha muringo gwabyo gw‘okukora: ebirungo ebiine obushoboorozi bw‘okurwanisa obukooko (7, 8, 10, 11, 13a, 15, 18, 19b) n‘ebirungo ebiine obushoboorozi bw‘okurwanisa obukooko (6,13 . 19a). Omuri ebyo, ebirungo 7, 11, 13a na 15 nibyo birikukirayo kushemeza, ebirikworeka emirimo y’okwita aha nkora nkye munonga (39.06 μg/100 μL).
Ebirungo ikumi ahari ikumi na bishatu ebyakyeberwa byorekire ngu nibibaasa kurwanisa obukooko oburikurwanisa endwara ya Staphylococcus aureus (MRSA). Nahabwekyo, okwongyera kukyebera n‘obukooko oburikureeta endwara obutarikukira emibazi y‘okurwanisa endwara (na munonga obutafaari bw‘omu kyanga oburikukingira obukooko oburikureeta endwara bwa Gram-positive na Gram-negative) n‘ebizimba ebirikureeta endwara nibihaburwa, hamwe n‘okukyebera obutwa bw‘omubiri (cytotoxic testing) bwa buri kirungo kureeba oburinzi bwakyo.
Okucondooza aha nkora ya molekyu kukakorwa kukyebera obushoboorozi bw’ebirungo ebikozirwe nk’ebirikuzibira puroteyini 2a (PBP2a) erikukwatira hamwe penicillin omu Staphylococcus aureus (MRSA) etarikukwatwa methicillin. PBP2a n’enzigye nkuru erikwejumba omu kuhangaho obutafaari bw’omubiri oburikwetwa bacteria, kandi okuzibira enzyme egi nikuteganisa okukora kw’obutafaari bw’omubiri, aha muheru nikireetaho okusheeshasheesha kwa bacteria n’okufa kw’obutafaari1. Ebirugire omu kukwatira aha mwaro biri omu runyiriri rwa 4 kandi nibishoboororwa omu bwijwire omu fairo y‘ebihandiiko by‘okwongyeraho, kandi ebyarugamu nibyoreka ngu ebirungo bitari bimwe na bimwe bikooreka omukago gw‘amaani gw‘okukwatiraine na PBP2a, namunonga ebisigarira by‘omu mwanya ebirikukora ebikuru nka Lys 273, Lys 316, na Arg 298. y’ekirungo kya quinazolinone ligand (CCL), ekirikworeka obushoboorozi bw’ebirungo ebi nk’ebirikuzibira eby’amaani.
Ebihandiiko by‘okutaho molekyu, hamwe n‘ebindi bihandiiko by‘okubara, bikagira ngu okuzibira PBP2a n‘omuringo mukuru ogurikujunanizibwa aha mirimo y‘okurwanisa obukooko obureebirwe ey‘ebirungo ebi. Obubonero bw‘okutaho n‘emihendo y‘okutaana kw‘omuzi (RMSD) bukagaruka bwayoreka obuzaare bw‘okuhamira hamwe n‘okugumaho, kushagika enteekateeka egi. Nk‘oku kirikworekwa omu kipande kya 4, n‘obu ebirungo bitari bimwe na bimwe byabaire nibyoreka obuzaare burungi bw‘okukwatira hamwe, ebirungo ebimwe (nk‘eky‘okureeberaho, 7, 9, 10, na 14) bikaba biine obubonero bw‘okukwatira hamwe bw‘ahaiguru kukira co-crystallized ligand, ekirikworeka ngu nibibaasa kugira enkoragana y‘amaani n‘ebisigarira by‘omwanya ogurikukora ogwa PBP2a. Kwonka, ebirungo ebirikukirayo kukora eby‘amagara 6 na 13b bikooreka obubonero bw‘okuteerana obukye (-5.98 na -5.63, buri kimwe) waagyeragyeranisa n‘ebindi bihingwa. Eki nikimanyisa ngu n‘obu obubonero bw‘okuteerana buraabe nibubaasa kukoresibwa kuteebereza aha nkoragana y‘okuteerana, ebindi (nk‘okugumaho kw‘ebicweka by‘omubiri n‘enkoragana y‘ebicweka by‘omubiri omu mbeera y‘ebihangirwe) nabyo nibikora omurimo muhango omu kumanya emirimo y‘okurwanisa obukooko. Ekikuru, emihendo ya RMSD y‘ebirungo byona ebyakozirwe ekaba eri ahansi ya 2 Å, ekirikuhamya ngu emitwarize yaabo y‘okuteerana neekwatagana n‘omutindo gw‘okuteerana kw‘ekicweka ky‘omubiri ekirikuteerana (co-crystallized ligand), ekirikwongyera kushagika obushoboorozi bwabyo nk‘ebirikuzibira PBP2a eby‘amaani.
N‘obu obubonero bw‘okutaho n‘emihendo ya RMS buraabe nibuha okuteebereza kw‘omugasho, akakwate akari ahagati y‘ebirugire omu kutaho ebi n‘emirimo y‘okurwanisa obukooko tiburikureebeka gye omu kubanza. N‘obu okuzibira PBP2a kuraabe nikushagikwa munonga nk‘enshonga nkuru erikuteganisa emirimo y‘okurwanisa obukooko, entaaniso nyingi nizooreka ngu ebindi bihangirwe by‘amagara nabyo nibikora omurimo muhango. Ebirungo 6 na 13b byorekire emirimo y‘okurwanisa obukooko oburikukirayo, byombi biine oburaingwa bw‘ekicweka ky‘okuzibira oburaingwa bwa cm 4 n‘emihendo ya MIC (9.7 μg/100 μL) na MBC (78.125 μg/100 μL) eri ahansi munonga, n‘obu obubonero bwabyo bw‘okutaho obukooko buri ahansi waagyeragyeranisa n‘ebirungo ebi, al94th, 7. Okuzibira PBP2a nikuhwera omu mirimo y‘okurwanisa obukooko, enshonga nk‘okushohoza, okutunga ebiriisa n‘okuhinduka kw‘okukoragana omu mbeera ya bacteria nabyo nibikwata aha mirimo yoona. Ekishushani 11 nikyoreka oku barikuteerana, ekirikworeka ngu ebirungo byombi, n‘obu biraabe biine obubonero bukye bw‘okukwatira hamwe, nibibaasa kukwatagana n‘ebisigarira bikuru bya PBP2a, ekirikubaasa kuhamya ekizibu ky‘okuzibira. Eki nikyoreka ngu n‘obu okutaho molekyu kurikuha okumanya okukuru aha kuzibira PBP2a, ebindi bintu by‘ebihangirwe biine kuteekateekwaho kwetegyereza gye ebirikuruga omu nkora y‘okurwanisa obukooko obu omu nsi eyaabuzima.
Okukozesa omutindo gw‘ekibiriiti kya PBP2a (PDB ID: 4CJN), maapu z‘okukoragana za 2D na 3D z‘ebirungo ebirikukirayo kukora 6 na 13b ebiine puroteyini erikukwatira hamwe penisilini 2a (PBP2a) ey‘obukooko obutarikubaasa kukwatwa methicillin (MRSA) zikaba zikozirwe. Maapu ezi nizigyeragyeranisa emiringo y‘okukoragana kw‘ebirungo ebi n‘enkoragana y‘ekirungo kya quinazolinone (CCL) ekigarukiremu kukwatiraine, erikworeka enkoragana ekuru nk‘okuteerana kwa haidrojeni, π-okuteerana, n‘enkoragana ya ionic.
Enkora niyo emwe ekareebekyera aha kirungo kya 7, ekyayorekire obubonero bw‘okutaho obubonero bw‘ahaiguru munonga (-6.32) n‘oburaingwa bw‘ekicweka ky‘okuzibira ekirikushushana (3.9 cm) n‘ekirungo kya 10. Kwonka, MIC yaakyo (39.08 μg/100 μL) na MBC (39.06 it μL) zikaba ziri ahaiguru munonga, nizetenga munonga μg/100. kworeka obukooko oburikurwanisa obukooko. Eki nikimanyisa ngu n‘obu ekirungo kya 7 kiraabe kyorekire akakwate k‘amaani omu kucondooza aha kukwatira hamwe, enshonga nk‘okutunga ebiriisa, okutwara obutafaari, nari ebindi bihingwa n‘eby‘obuhangwa nibibaasa kukyendeeza aha burungi bwakyo omu by‘amagara. N’obu ekirungo kya 7 kiraabe kyorekire ngu nikibaasa kwita obukooko, kikaba kitarikukora gye omu kuzibira obukooko kukura waagyeragyeranisa n’ekirungo kya 6 na 13b.
Ekirungo kya 10 kikooreka entaaniso y‘amaani n‘obubonero bw‘okuteerana oburikukirayo (-6.40), ekirikworeka akakwate k‘amaani ak‘okukwatiraine na PBP2a. Kwonka, zoni yaayo ey’okuzibira diamita (3.9 cm) ekaba neegyeragyeranisibwa n’ekirungo 7, kandi MBC yaayo (312 μg/100 μL) ekaba eri ahaiguru munonga kukira ekirungo 6, 7, na 13b, ekirikworeka ngu emirimo y’okurwanisa obukooko ekaba eine amaani makye. Eki nikimanyisa ngu n‘obu okuteebereza kurungi kw‘okuteerana, ekirungo 10 kikaba kitarikukora gye omu kwita MRSA ahabw‘ebindi ebirikuzibira nk‘okushohoza, okugumaho, nari okutabaasa kuraba gye kw‘omubiri gw‘obukooko. Ebirugiremu ebi nibishagika okwetegyereza ngu n‘obu okuzibira PBP2a kuraabe nikukora omurimo muhango omu mirimo y‘okurwanisa obukooko, tikurikushoboorora gye entaaniso omu mirimo y‘ebihangirwe ebireebirwe omu birungo ebyakyeberwa. Entaaniso ezi nizooreka ngu okweyongyera kweshwijuma kw‘okugyezesa n‘okushwijuma eby‘amagara okuri omu bwijwire nibyetengyesa kushoboorora gye emiringo y‘okurwanisa obukooko oburikwejumbamu.
Ebirugire omu kukwatira hamwe kwa molekyu omu kipande kya kana na Fayiro y‘ebihandiiko by‘okwongyeraho nibyoreka akakwate kagumire ahagati y‘obubonero bw‘okukwatira hamwe n‘emirimo y‘okurwanisa obukooko. N‘obu ebirungo 6 na 13b biraabe biine obubonero bw‘okutaho obukooko obukye kukira ebirungo 7, 9, 10, na 14, nibyoreka emirimo y‘okurwanisa obukooko oburikukirayo. Maapu zaabo z‘okukoragana (ezirikworekwa omu kishushani 11) nizooreka ngu n‘obu baraabe baine obubonero bw‘ahansi bw‘okukwatira hamwe, nibakikora enkoragana z‘amaani eza haidrojeni n‘enkoragana ya π-stacking n‘ebisigarira ebikuru bya PBP2a ebirikubaasa kuhamya enzyme-inhibitor complex omu muringo gw‘omugasho omu by‘amagara. N‘obu obubonero bw‘okutaho 6 na 13b buraabe buri bukye, emirimo yaabo ey‘okurwanisa obukooko oburikwongyerwamu amaani neeyoreka ngu ebindi nk‘okushohoza, okugumaho, n‘okutwara obutafaari biine kuteekateekwaho omu kukwatanisa n‘ebihandiiko by‘okutaho baaba nibashwijuma obushoboorozi bw‘okuzibira. Eki nikyoreka obukuru bw‘okugaita okucondooza kw‘okuta aha mwaro n‘okucondooza kw‘okugyezesa okurikurwanisa obukooko kubaasa kukyebera gye obushoboorozi bw‘okujanjaba obw‘ebirungo bisya.
Ebirugiremu ebi nibyoreka ngu n‘obu okuteerana kw‘ebicweka by‘omubiri (molecular docking) kuri ekikwato ky‘amaani eky‘okuteebereza okutaana kw‘okukwatira hamwe n‘okumanya emiringo erikubaasa kuzibira, tikiine kwesigamira kyonka kubaasa kumanya oburungi bw‘okurwanisa obukooko. Ebihandiiko bya molekyu nibyoreka ngu okuzibira PBP2a n‘enshonga nkuru erikuteganisa emirimo y‘okurwanisa obukooko, kwonka empindahinduka omu mirimo y‘ebihangirwe nibyoreka ngu ebindi birungi by‘omubiri n‘eby‘emibazi biine kubonezibwa kubaasa kutunguura oburungi bw‘okujanjaba. Okucondooza okw‘omumaisho kushemerire kuta omutima aha kutunguura omutindo gw‘eby‘obuhangwa gw‘ebirungo 7 na 10 kutunguura okubaasa kw‘ebintu ebiine amagara n‘okutwara obutafaari, kureeba ngu enkoragana z‘amaani z‘okuteerana zihindurwa omu mirimo y‘okurwanisa obukooko eyaabuzima. Ebindi bihandiiko, obariiremu ebindi bikyebezo by‘amagara n‘okucondooza aha nkoragana y‘eby‘obuhangwa n‘emirimo (SAR), nibiija kuba bikuru munonga kwongyera aha kwetegyereza kwaitu oku ebirungo ebi birikukora nk‘ebirikuzibira PBP2a n‘okukora emibazi y‘okurwanisa obukooko oburikureeta endwara.
Ebirungo ebyakozirwe kuruga omu 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 byorekire emirimo y‘okurwanisa obukooko obutarikushushana, n‘ebirungo bitari bimwe na bimwe nibyoreka okuzibira kw‘amaani obukooko oburikurwanisa obukooko oburikureeta endwara (MRSA). Okushwijuma enkoragana y‘enkora n‘emirimo (SAR) kukashohoza ebintu bikuru eby‘enkora ebiri ahansi y‘oburungi bw‘okurwanisa obukooko obu obw‘ebirungo ebi.
Okubaho kw’ebicweka byombi ebya acrylonitrile na anthracene kukahamibwa kuba bikuru omu kwongyera aha mirimo y’okurwanisa obukooko. Ekibiina kya nitrile ekirikukora munonga omu acrylonitrile nikyetengyesa kwongyera aha nkoragana n’ebiriisa bya bacteria, obwo nikihwera omu kureetaho obutwa bw’okurwanisa obukooko oburikureeta endwara. Ebirungo ebirimu acrylonitrile na anthracene bigumire nibyoreka amaani g‘okurwanisa obukooko. Oburungi bw’ekibiina kya anthracene bukayongyera kuhamya ebirungo ebi, ekirikubaasa kwongyera aha mirimo yaabyo ey’ebihangirwe.
Okutaho empeta za heterocyclic kikatunguura munonga obushoboorozi bw’okurwanisa obukooko oburikuruga omu bihingwa ebitari bimwe na bimwe. Okukira munonga, ekirungo kya benzothiazole 13b n’ekirungo kya acrylhydrazide 6 byorekire emirimo y’okurwanisa obukooko oburikukirayo n’omwanya gw’okuzibira ogurikwingana sentimita 4. Ebirugire omu heterocyclic ebi bikooreka ebirugire omu bihangirwe ebiine amagara ebikuru munonga, ekirikworeka ngu omutindo gwa heterocyclic nigukora omurimo muhango omu birugire omu kurwanisa obukooko. Nikyo kimwe, pyrimidinethione omu kirungo kya 9, thiopyrazole omu kirungo kya 10, na tetrazine ring omu kirungo kya 11 bikahwera omu kureetaho obutwa bw’okurwanisa obukooko oburikureeta endwara, ekirikwongyera kworeka obukuru bw’okuhindura omu nkora ya heterocyclic.
Omuri ebyo ebikozirwe, 6 na 13b nibyo byabaire nibikora gye munonga omu kurwanisa obukooko. Ekirungo ky‘okuzibira (MIC) ky‘ekirungo 6 kikaba kiri 9.7 μg/100 μL, kandi ekirungo ky‘okuzibira obukooko (MBC) kikaba kiri 78.125 μg/100 μL, ekirikworeka obushoboorozi bwakyo burungi bw‘okukyebera obukooko obutarikukwatwa methicillin (MRSA). Omu muringo nigwo gumwe, ekirungo 13b kikaba kiine omwanya gw’okuzibira ogwa cm 4 n’emihendo y’ahansi ya MIC na MBC, ekirikuhamya ngu kiine amaani g’okurwanisa obukooko. Ebirugiremu ebi nibyoreka emirimo mikuru y‘ebicweka by‘emirimo bya acrylohydrazide na benzothiazole omu kumanya oburungi bw‘ebihangirwe ebi.
Okutaana n‘ekyo, ebirungo 7, 10, na 14 byorekire emirimo y‘okurwanisa obukooko ey‘omutindo gw‘ahaiguru n‘ebicweka by‘okuzibira kuruga ahari 3.65 kuhika ahari 3.9 cm. Ebirungo ebi bikaba nibyetenga ebiriisa bingi kubaasa kwita kimwe obukooko obu, nk’oku kirikworekwa omu mihendo yaabyo ey’ahaiguru munonga eya MIC na MBC. N’obu ebirungo ebi biraabe byabaire bitarikukora munonga kukira ebirungo 6 na 13b, bikaguma nibyoreka obushoboorozi bw’okurwanisa obukooko oburikureeta endwara, ekirikumanyisa ngu okutaho ebicweka bya acrylonitrile na anthracene omu mpeta ya heterocyclic nikihwera omu kureetaho okurwanisa obukooko oburikureeta endwara.
Ebirungo ebi biine emiringo y’okukora etari emwe n’emwe, ebimwe nibyoreka obushoboorozi bw’okwita obukooko kandi ebindi nibyoreka obushoboorozi bw’okuzibira obukooko. Ebirungo 7, 11, 13a, na 15 nibiita obukooko kandi nibyetenga okuteebwamu ebiriisa bikye kubaasa kwita obukooko bwona. Okutaana n’ekyo, ebirungo 6, 13b, na 14 nibizibira obukooko kandi nibibaasa kuzibira obukooko kukura omu bwingi bukye, kwonka nibyetenga obukooko bwingi kwita obukooko bwona.
Okutwarira hamwe, okweshwijuma kw‘enkoragana y‘enkora n‘emirimo nikworeka obukuru bw‘okutaho ebicweka bya acrylonitrile na anthracene n‘enkora za heterocyclic kubaasa kutunga emirimo y‘amaani ey‘okurwanisa obukooko. Ebirugiremu ebi nibyoreka ngu okutunguura ebicweka ebi eby‘omubiri n‘okucondooza aha kuhindura okundi kubaasa kutunguura okushohoza n‘okutaaha omu nkora y‘okusheeshasheesha nikibaasa kureetera okukora emibazi y‘okurwanisa MRSA erikukora gye.
Ebirikukoresibwa n’ebirikusheesheka byona bikashemezibwa kandi byayomezibwa barikukoresa enkora ezitebeekanisiibwe (El Gomhouria, Egypt). Ebicweka by‘okusheenya bikamanyirwa aha kukozesa ekyoma ky‘okusheenya eky‘ebyoma ekya GallenKamp kandi nibigambwaho hatariho kushoboorora. Ebishushani by’omushana (cm−1) bikahandiikwa omu kitongore ky’eby’obuhangwa, ekitongore kya sayansi, yunivasite ya Ain Shams barikukoresa obujuma bwa potassium bromide (KBr) aha kipimo ky’eby’obuhangwa (Thermo Fisher Scientific, Waltham, MA, USA).
Ebishushani bya 1H NMR bikatunga aha 300 MHz barikukoresa ekikwato kya GEMINI NMR (ekitongore kya GEMINI eky’okukora n’okukora, Anaheim, CA, USA) n’ekikwato kya BRUKER 300 MHz (ekitongore kya BRUKER eky’okukora n’okukora, Inc.). Tetramethylsilane (TMS) ekakoresibwa nk‘omutindo gw‘omunda n‘ekirungo ky‘okukyebera (DMSO-d6). Okupima kwa NMR kukakorwa aha kitongore kya sayansi, Yunivasite ya Cairo, Giza, Misri. Okushwijuma eby‘okurya (CHN) kukakorwa barikukoresa ekikwato kya Perkin-Elmer 2400 Elemental Analyzer kandi ebyarugamu nibihikaana gye n‘emihendo ebariirwe.
Omutaano gwa asidi 3 (5 mmol) na thionyl chloride (5 ml) gukaheebwa omuriro omu kyombeko ky’amaizi aha 65 °C kumara eshaaha 4. Thionyl chloride eyongyeireho ekaihwaho omu kugisheenya ahansi y’okukyendeeza aha nkora. Ekintu ekigumire ekirikutukura ekyarugiremu kikatorotoorwaho kandi kyakoresibwa hatariho kugaruka kushemezibwa. Okusheenya: 200-202 °C, okurugamu: 88.5%. 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, okuhindura kw‘eby‘okurya ebitarikushushana). 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); Omubiri (ESI) m/z [M + H]+: 291.73111. Omucondoozi. Okubara kwa C18H10ClNO (291,73): C, 74,11; H, 3.46; N, 4.80. Ebishangirwe: C, 74.41; H, 3.34; N, ebicweka 4.66 ahari igana.
Aha 0°C, 4 (2 mmol, 0.7 g) zikashohozibwa omu dioxane etaine maizi (miriyoni 20) kandi amaizi g’okunywa (2 mmol, miriyoni 0.16, 80%) zikateebwamu amatondo n’amatondo kandi zikasheesheka kumara eshaaha 1. Ekintu ekigumire ekyashohoziibwe kikatorotoorwa omu kushenyuka kandi kyagaruka kyahinduka ekibiriiti kuruga omu ethanol kuha ekirungo 6.
Ebishushani bya kinyasi, ebirikusheenya 190-192°C, nibireeta 69.36%; 1720 (C=O), 1621 (C=N) cm-1. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.3 (br s, H, NH, ebirikuhindurwa), 7.69-8.51 (m, 18H, ebitarikushushana), 9.16 (s, 1H, CH=), 8.54 (s, CH= 1H, 1H); Omuhendo ogubariirwe ogwa C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Ebishangirwe: C, 84.01; H, 4.38; N, ebicweka 8.05 ahari igana.
(2 mmol, 0.7 g) omu miriyoni 20 z‘omubazi gwa dioxane ogutarimu maizi (ogurimu amatondo makye g‘ekirungo kya triethylamine), otemu phenylhydrazine/2-aminopyridine (2 mmol) kandi oshukyemu aha bwire bw‘obwire bw‘ekishengye kumara eshaaha 1 na 2, nk‘oku biri. Shuka omutaano gw’okugarukamu omu barafu nari omu maizi kandi okore asidi n’asidi y’amaizi erimu amaizi. Sefa ekigumire ekitaanisiibweho kandi ogarukye okihindure ekirungo kuruga omu ethanol otungye 7 kandi ogarukye okihindure ekirungo kuruga omu benzene otungye 8.
Ebicupuri bya kinyasi, ebirikusheenya 160-162°C, nibireeta 77%; IR (KBr, ν, cm-1): 3245 (NH), 2222 (C≡N), 1691 (C=O), 1671 (C=O) cm-1. 10.88 (s, 1H, NH, ebirikuhindurwa), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, 2); Omuhendo ogubariirwe ogwa C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Ebishangirwe: C, 81.96; H, 3.91; N, ebicweka 8.91 ahari igana.
4 (2 mmol, 0.7 g) ekateebwa omu miriyoni 20 z’omubazi gwa dioxane ogutarimu maizi (ogurimu amatondo makye g’ekirungo kya triethylamine), 2-aminopyridine (2 mmol, 0.25 g) ekateebwamu kandi omutaano gwateebwa omu bwire bw’obutagatsi bw’omu kishengye kumara eshaaha 2 h. Omutaano gw’okugarukamu gukashukwa omu maizi g’orubaare kandi gwateebwamu asidi n’asidi y’amaizi erikwetwa diluted hydrochloric acid. Ekicweka ekyahangirwe kikasendwa kandi kyagaruka kyahindurwa ekibiriiti kuruga omu benzene, kyaha ekibiriiti kya kinyasi kya 8 ekiine obutafaari bw’okusheenya 146-148 °C kandi kyarugamu 82.5%; 3148 (NH), 2222 (C≡N), 1665 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ (ppm): 8.78 (s, H, NH, ebirikuhindurwa), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, okuhindura kw‘eby‘okurya); Ebibariirwe ahabwa C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Ebishangirwe: C, 78.93; H, 3.97; N, ebicweka 12.36 ahari igana.
Ekirungo kya 4 (2 mmol, 0.7 g) kikashohozibwa omu miriyoni 20 z’amaizi g’omubiri (egarimu amatondo makye g’amaizi g’omubiri (triethylamine) na mmol 2 z’amaizi g’omubiri) kandi kyateebwa omu muriro ahansi y’okugaruka omu nkora kumara eshaaha 2. Ekirungo kikaba kifuka omu mwanya ogutarimu kintu kyona. Ebisigaireho bikagaruka byahindurwa ekibiriiti kuruga omu dioxane kuha omutaano.