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Synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 inapangidwa ndipo inagwiritsidwa ntchito popanga mitundu yosiyanasiyana ya mankhwala opangidwa ndi heterocyclic pogwiritsa ntchito momwe imagwirira ntchito ndi ma nucleophiles osiyanasiyana a nayitrogeni. Kapangidwe ka mankhwala aliwonse opangidwa ndi heterocyclic kanafotokozedwa bwino pogwiritsa ntchito spectroscopic ndi elemental analysis. Khumi mwa mankhwala atsopano khumi ndi atatu a heterocyclic anasonyeza kuti amagwira ntchito bwino polimbana ndi mabakiteriya ambiri osagwiritsa ntchito mankhwala (MRSA). Pakati pawo, mankhwala 6, 7, 10, 13b, ndi 14 anasonyeza kuti ali ndi mphamvu yolimbana ndi mabakiteriya ambiri okhala ndi malo oletsa pafupifupi 4 cm. Komabe, kafukufuku wokhudza ma molecular docking adawonetsa kuti mankhwalawo anali ndi ma affinity osiyanasiyana omangira ku penicillin-binding protein 2a (PBP2a), cholinga chachikulu cha kukana kwa MRSA. Mankhwala ena monga 7, 10 ndi 14 anasonyeza kuti ali ndi mphamvu yomangira komanso kukhazikika kwa mgwirizano pamalo ogwirira ntchito a PBP2a poyerekeza ndi co-crystallized quinazolinone ligand. Mosiyana ndi zimenezi, mankhwala 6 ndi 13b anali ndi ma docking scores otsika koma anali ndi mphamvu yowononga mabakiteriya, ndipo mankhwala 6 anali ndi MIC yotsika kwambiri (9.7 μg/100 μL) ndi MBC (78.125 μg/100 μL). Kusanthula kwa docking kunavumbula kuyanjana kwakukulu kuphatikizapo hydrogen bonding ndi π-stacking, makamaka ndi zotsalira monga Lys 273, Lys 316 ndi Arg 298, zomwe zinadziwika kuti zimagwirizana ndi co-crystallized ligand mu kapangidwe ka kristalo ka PBP2a. Zotsalira izi ndizofunikira kwambiri pa ntchito ya enzymatic ya PBP2a. Zotsatirazi zikusonyeza kuti mankhwala opangidwawo akhoza kukhala ngati mankhwala oteteza ku MRSA, zomwe zikuwonetsa kufunika kophatikiza ma molecular docking ndi bioassays kuti adziwe mankhwala othandiza.
M'zaka zoyambirira za m'ma 1900, kafukufuku anali makamaka pakupanga njira zatsopano komanso zosavuta zopangira machitidwe angapo atsopano okhala ndi mphamvu yolimbana ndi majeremusi pogwiritsa ntchito zinthu zoyambira zomwe zilipo mosavuta.
Ma Acrylonitrile moieties amaonedwa ngati zinthu zofunika kwambiri poyambira kupanga machitidwe ambiri odabwitsa a heterocyclic chifukwa ndi mankhwala ogwirizana kwambiri. Kuphatikiza apo, ma derivatives a 2-cyanoacryloyl chloride akhala akugwiritsidwa ntchito kwambiri m'zaka zaposachedwa popanga ndi kupanga zinthu zofunika kwambiri pantchito zamankhwala, monga mankhwala ophatikizana1,2,3, omwe amatsogolera ku anti-HIV, antiviral, anticancer, antibacterial, antidepressant ndi antioxidant4,5,6,7,8,9,10. Posachedwapa, mphamvu ya anthracene ndi ma derivatives ake, kuphatikiza ma antibiotic awo, anticancer11,12, antibacterial13,14,15 ndi mankhwala ophera tizilombo16,17, akope chidwi cha anthu ambiri18,19,20,21. Ma antibiotic okhala ndi ma acrylonitrile ndi ma anthracene akuwonetsedwa mu Zithunzi 1 ndi 2.
Malinga ndi bungwe la World Health Organization (WHO) (2021), kukana maantibayotiki (AMR) ndi chiwopsezo cha padziko lonse pa thanzi ndi chitukuko22,23,24,25. Odwala sangachiritsidwe, zomwe zimapangitsa kuti azikhala nthawi yayitali kuchipatala komanso kufunika kwa mankhwala okwera mtengo, komanso kuwonjezeka kwa imfa ndi kulumala. Kusowa kwa mankhwala othandiza maantibayotiki nthawi zambiri kumabweretsa kulephera kwa chithandizo cha matenda osiyanasiyana, makamaka panthawi ya chemotherapy ndi opaleshoni yayikulu.
Malinga ndi lipoti la World Health Organization la 2024, Staphylococcus aureus (MRSA) ndi E. coli zomwe sizili ndi methicillin zili m'gulu la tizilombo toyambitsa matenda tomwe timafunika kwambiri. Mabakiteriya onsewa ndi osagonjetsedwa ndi maantibayotiki ambiri, choncho akuyimira matenda omwe ndi ovuta kuchiza ndi kuwongolera, ndipo pakufunika kwambiri kupanga mankhwala atsopano komanso ogwira mtima ophera tizilombo toyambitsa matenda kuti athetse vutoli. Anthracene ndi mankhwala opangidwa kuchokera ku mankhwalawa ndi mankhwala odziwika bwino ophera tizilombo omwe amatha kugwira ntchito pa mabakiteriya onse a Gram-positive ndi Gram-negative. Cholinga cha kafukufukuyu ndikupanga mankhwala atsopano omwe angathe kuthana ndi tizilombo toyambitsa matenda omwe ndi oopsa pa thanzi.
Bungwe la World Health Organization (WHO) linanena kuti tizilombo toyambitsa matenda tambiri tomwe timayambitsidwa ndi mabakiteriya sitingathe kuchiritsidwa ndi maantibayotiki ambiri, kuphatikizapo Staphylococcus aureus (MRSA) yosagonjetsedwa ndi methicillin, yomwe imayambitsa matenda m'dera komanso m'malo azaumoyo. Odwala omwe ali ndi matenda a MRSA akuti ali ndi chiwerengero cha imfa chokwera ndi 64% kuposa omwe ali ndi matenda omwe amayambitsidwa ndi mankhwala. Kuphatikiza apo, E. coli ili pachiwopsezo padziko lonse lapansi chifukwa chitetezo chomaliza ku Enterobacteriaceae yosagonjetsedwa ndi carbapenem (monga E. coli) ndi colistin, koma mabakiteriya omwe sakhudzidwa ndi colistin apezeka posachedwapa m'maiko angapo. 22,23,24,25
Chifukwa chake, malinga ndi World Health Organization Global Action Plan on Antimicrobial Resistance26, pakufunika kwambiri kuti papezeke ndi kupanga mankhwala atsopano ophera tizilombo toyambitsa matenda. Kuthekera kwakukulu kwa anthracene ndi acrylonitrile monga antibacterial27, antifungal28, anticancer29 ndi antioxidant30 kwawonetsedwa m'mapepala ambiri ofalitsidwa. Pachifukwa ichi, tinganene kuti mankhwala opangidwa ndi mankhwalawa ndi abwino kugwiritsidwa ntchito motsutsana ndi Staphylococcus aureus (MRSA) yokana methicillin.
Ndemanga zakale za mabuku zinatilimbikitsa kupanga zinthu zatsopano zomwe zimapezeka m'magulu awa. Chifukwa chake, kafukufukuyu cholinga chake chinali kupanga machitidwe atsopano a heterocyclic okhala ndi anthracene ndi acrylonitrile, kuwunika mphamvu zawo zotsutsana ndi maantibayotiki ndi mabakiteriya, ndikufufuza momwe angagwirizanitsire ntchito ndi penicillin-binding protein 2a (PBP2a) pogwiritsa ntchito molecular docking. Potengera maphunziro am'mbuyomu, kafukufukuyu adapitiliza kupanga, kuwunika kwa zamoyo, komanso kusanthula kwa makompyuta a heterocyclic systems kuti adziwe mankhwala abwino a antimethicillin-resistant Staphylococcus aureus (MRSA) omwe ali ndi mphamvu zoletsa PBP2a31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Kafukufuku wathu wapano akuyang'ana kwambiri pa kapangidwe ndi kuwunika kwa maantibayotiki a mankhwala atsopano a heterocyclic okhala ndi anthracene ndi acrylonitrile. 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 idakonzedwa ndikugwiritsidwa ntchito ngati chomangira chomangira machitidwe atsopano a heterocyclic.
Kapangidwe ka compound 4 kanapezeka pogwiritsa ntchito deta ya spectral. 1H-NMR spectrum inasonyeza kukhalapo kwa CH= pa 9.26 ppm, IR spectrum inasonyeza kukhalapo kwa gulu la carbonyl pa 1737 cm−1 ndi gulu la cyano pa 2224 cm−1, ndipo 13CNMR spectrum inatsimikiziranso kapangidwe komwe kaperekedwa (onani gawo la Experimental).
Kupanga kwa 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kunachitika mwa hydrolysis ya magulu a aromatic 250, 41, 42, 53 ndi ethanolic sodium hydroxide solution (10%) kuti apereke ma acid 354, 45, 56, omwe kenako adathiridwa ndi thionyl chloride mu bafa lamadzi kuti apereke acryloyl chloride derivative 4 yochuluka (88.5%), monga momwe zasonyezedwera pa Chithunzi 3.
Kuti apange mankhwala atsopano a heterocyclic omwe ali ndi mphamvu yolimbana ndi mabakiteriya yomwe imayembekezeredwa, acyl chloride 4 ndi ma dinucleophiles osiyanasiyana adachitika.
Asidi chloride 4 inapatsidwa hydrazine hydrate pa 0° kwa ola limodzi. Mwatsoka, pyrazolone 5 sinapezeke. Chogulitsacho chinali chochokera ku acrylamide chomwe kapangidwe kake kanatsimikiziridwa ndi deta ya spectral. IR spectrum yake inawonetsa magulu oyamwa a C=O pa 1720 cm−1, C≡N pa 2228 cm−1 ndi NH pa 3424 cm−1. 1H-NMR spectrum inawonetsa chizindikiro cha kusinthana kwa ma protoni a olefin ndi ma protoni a NH pa 9.3 ppm (onani Gawo Loyesera).
Ma mole awiri a asidi chloride 4 adayankhidwa ndi mole imodzi ya phenylhydrazine kuti apereke N-phenylacryloylhydrazine derivative 7 yopindulitsa (77%) (Chithunzi 5). Kapangidwe ka 7 kanatsimikiziridwa ndi deta ya infrared spectroscopy, yomwe inasonyeza kuyamwa kwa magulu awiri a C=O pa 1691 ndi 1671 cm−1, kuyamwa kwa gulu la CN pa 2222 cm−1 ndi kuyamwa kwa gulu la NH pa 3245 cm−1, ndipo 1H-NMR spectrum yake inasonyeza gulu la CH pa 9.15 ndi 8.81 ppm ndi NH proton pa 10.88 ppm (onani gawo la Experimental).
Mu kafukufukuyu, momwe acyl chloride 4 imagwirira ntchito ndi 1,3-dinucleophiles idafufuzidwa. Chithandizo cha acyl chloride 4 ndi 2-aminopyridine mu 1,4-dioxane ndi TEA ngati maziko kutentha kwa chipinda chinapereka acrylamide derivative 8 (Chithunzi 5), kapangidwe kake kamene kanazindikirika pogwiritsa ntchito deta ya spectral. Ma IR spectra adawonetsa ma absorption bands a cyano stretching pa 2222 cm−1, NH pa 3148 cm−1, ndi carbonyl pa 1665 cm−1; Ma 1H NMR spectra adatsimikizira kukhalapo kwa olefin protons pa 9.14 ppm (onani Gawo Loyesera).
Kapangidwe ka mankhwala 4 kamakumana ndi thiourea kuti apereke pyrimidinethione 9; kapangidwe ka mankhwala 4 kamakumana ndi thiosemicarbazide kuti apereke thiopyrazole derivative 10 (Chithunzi 5). Kapangidwe ka mankhwala 9 ndi 10 kanatsimikiziridwa ndi kusanthula kwa spectral ndi elemental (onani gawo la Experimental).
Tetrazine-3-thiol 11 inakonzedwa pogwiritsa ntchito njira ya compound 4 ndi thiocarbazide ngati 1,4-dinucleophile (Chithunzi 5), ndipo kapangidwe kake kanatsimikiziridwa ndi spectroscopy ndi elemental analysis. Mu infrared spectrum, C=N bond inaonekera pa 1619 cm−1. Nthawi yomweyo, 1H-NMR spectrum yake inasunga zizindikiro zambiri za aromatic protons pa 7.78–8.66 ppm ndi SH protons pa 3.31 ppm (onani Gawo Loyesera).
Acryloyl chloride 4 imakumana ndi 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, ndi ethanolamine monga 1,4-dinucleophiles kuti ipange machitidwe atsopano a heterocyclic (13-16).
Kapangidwe ka mankhwala atsopanowa opangidwa kumene adatsimikiziridwa ndi kusanthula kwa spectral ndi elemental (onani gawo la Experimental). 2-Hydroxyphenylacrylamide derivative 17 idapezeka mwa kuchitapo kanthu ndi 2-aminophenol ngati dinucleophile (Chithunzi 6), ndipo kapangidwe kake kanatsimikiziridwa ndi kusanthula kwa spectral ndi elemental. Ma infrared spectrum a compound 17 adawonetsa kuti zizindikiro za C=O ndi C≡N zidawonekera pa 1681 ndi 2226 cm−1, motsatana. Pakadali pano, 1H-NMR spectrum yake idasunga chizindikiro cha singlet cha olefin proton pa 9.19 ppm, ndipo OH proton idawonekera pa 9.82 ppm (onani gawo la Experimental).
Mmene asidi chloride 4 amachitira ndi nucleophile imodzi (monga ethylamine, 4-toluidine, ndi 4-methoxyaniline) mu dioxane ngati solvent ndi TEA ngati chothandizira kutentha kwa chipinda chinapereka zobiriwira za crystalline acrylamide derivatives 18, 19a, ndi 19b. Deta ya elemental ndi spectral ya mankhwala 18, 19a, ndi 19b inatsimikizira kapangidwe ka zotumphukira izi (onani Gawo Loyesera) (Chithunzi 7).
Pambuyo pofufuza mphamvu ya mankhwala ophera tizilombo toyambitsa matenda a mankhwala osiyanasiyana opangidwa, zotsatira zosiyanasiyana zinapezeka monga momwe zasonyezedwera mu Table 1 ndi Chithunzi 8 (onani fayilo ya chithunzi). Mankhwala onse oyesedwa adawonetsa madigiri osiyanasiyana oletsa motsutsana ndi bacterium MRSA ya Gram-positive, pomwe bacterium Escherichia coli ya Gram-negative idawonetsa kukana kwathunthu kwa mankhwala onse. Mankhwala oyesedwawo akhoza kugawidwa m'magulu atatu kutengera kukula kwa dera loletsa motsutsana ndi MRSA. Gulu loyamba linali logwira ntchito kwambiri ndipo linali ndi mankhwala asanu (6, 7, 10, 13b ndi 14). M'lifupi mwa dera loletsa la mankhwala awa linali pafupi ndi 4 cm; mankhwala omwe amagwira ntchito kwambiri m'gululi anali mankhwala 6 ndi 13b. Gulu lachiwiri linali logwira ntchito pang'ono ndipo linali ndi mankhwala ena asanu (11, 13a, 15, 18 ndi 19a). Malo oletsa a mankhwala awa anali kuyambira 3.3 mpaka 3.65 cm, pomwe gulu 11 likuwonetsa dera lalikulu kwambiri loletsa la 3.65 ± 0.1 cm. Kumbali ina, gulu lomaliza linali ndi mankhwala atatu (8, 17 ndi 19b) omwe ali ndi mphamvu yochepa kwambiri yolimbana ndi majeremusi (osakwana 3 cm). Chithunzi 9 chikuwonetsa kufalikira kwa madera osiyanasiyana oletsa.
Kufufuza kwina kwa ntchito ya maantibayotiki ya mankhwala oyesedwa kunaphatikizapo kudziwa MIC ndi MBC pa mankhwala aliwonse. Zotsatira zake zinasiyana pang'ono (monga momwe zasonyezedwera mu Matebulo 2, 3 ndi Chithunzi 10 (onani fayilo ya chithunzi)), ndipo mankhwala 7, 11, 13a ndi 15 akuoneka kuti asinthidwa kukhala mankhwala abwino kwambiri. Anali ndi MIC ndi MBC zomwezo (39.06 μg/100 μL). Ngakhale kuti mankhwala 7 ndi 8 anali ndi MIC zochepa (9.7 μg/100 μL), MBC zawo zinali zapamwamba (78.125 μg/100 μL). Chifukwa chake, amaonedwa kuti ndi ofooka kuposa mankhwala omwe atchulidwa kale. Komabe, mankhwala asanu ndi limodzi awa anali ogwira mtima kwambiri mwa omwe adayesedwa, chifukwa MBC zawo zinali pansi pa 100 μg/100 μL.
Ma compounds (10, 14, 18 ndi 19b) sanali kugwira ntchito kwenikweni poyerekeza ndi ma compounds ena omwe adayesedwa chifukwa ma MBC values ​​awo anali pakati pa 156 ndi 312 μg/100 μL. Kumbali inayi, ma compounds (8, 17 ndi 19a) anali otsika kwambiri chifukwa anali ndi ma MBC values ​​​​apamwamba kwambiri (625, 625 ndi 1250 μg/100 μL, motsatana).
Pomaliza, malinga ndi kuchuluka kwa kulekerera komwe kwawonetsedwa mu Table 3, mankhwala oyesedwawa akhoza kugawidwa m'magulu awiri kutengera momwe amagwirira ntchito: mankhwala okhala ndi mphamvu yopha mabakiteriya (7, 8, 10, 11, 13a, 15, 18, 19b) ndi mankhwala okhala ndi mphamvu yopha mabakiteriya (6, 13b, 14, 17, 19a). Pakati pawo, mankhwala 7, 11, 13a ndi 15 ndi omwe amakondedwa, omwe amasonyeza mphamvu yopha anthu pamlingo wochepa kwambiri (39.06 μg/100 μL).
Mankhwala khumi mwa khumi ndi atatu omwe adayesedwa adawonetsa kuthekera kolimbana ndi Staphylococcus aureus (MRSA) yokana mankhwala opha tizilombo toyambitsa matenda (makamaka tizilombo tating'onoting'ono tomwe timakhala ndi mabakiteriya a Gram-positive ndi Gram-negative) ndi yisiti yoyambitsa matenda ikulimbikitsidwa, komanso kuyesa mankhwala opha tizilombo toyambitsa matenda a cytotoxic a mankhwala aliwonse kuti awone ngati ali otetezeka.
Kafukufuku wokhudza mamolekyulu a mamolekyulu anachitika kuti awone mphamvu ya mankhwala opangidwa ngati oletsa puloteni yomangira penicillin 2a (PBP2a) mu Staphylococcus aureus (MRSA) yolimbana ndi methicillin. PBP2a ndi enzyme yofunika kwambiri yomwe imakhudzidwa ndi kupanga makoma a makoma a mabakiteriya, ndipo kuletsa kwa enzyme iyi kumasokoneza mapangidwe a makoma a ma cell, zomwe zimapangitsa kuti mabakiteriya ayambe kugwira ntchito komanso kufa kwa ma cell1. Zotsatira za docking zalembedwa mu Table 4 ndipo zafotokozedwa mwatsatanetsatane mu fayilo yowonjezera, ndipo zotsatira zake zikuwonetsa kuti mankhwala angapo adawonetsa mgwirizano wamphamvu wa PBP2a, makamaka ma residues ofunikira monga Lys 273, Lys 316, ndi Arg 298. Kuyanjana, kuphatikiza hydrogen bonding ndi π-stacking, kunali kofanana kwambiri ndi kwa co-crystallized quinazolinone ligand (CCL), zomwe zikusonyeza kuthekera kwa mankhwala awa ngati oletsa amphamvu.
Deta ya ma molekyulu, pamodzi ndi magawo ena owerengera, inanena mwamphamvu kuti kuletsa kwa PBP2a ndiye njira yofunika kwambiri yomwe imayang'anira ntchito yolimbana ndi mabakiteriya yomwe yawonedwa ya ma compounds awa. Ma docking scores ndi root mean square deviation (RMSD) values ​​​​zinawonetsanso mgwirizano wabwino ndi kukhazikika, zomwe zikuthandizira lingaliro ili. Monga momwe zasonyezedwera mu Table 4, ngakhale ma compounds angapo adawonetsa mgwirizano wabwino wolumikizana, ma compounds ena (monga, 7, 9, 10, ndi 14) anali ndi ma docking scores apamwamba kuposa co-crystallized ligand, zomwe zikusonyeza kuti akhoza kukhala ndi kuyanjana kwamphamvu ndi zotsalira za malo ogwirira ntchito za PBP2a. Komabe, ma compounds omwe amagwira ntchito kwambiri 6 ndi 13b adawonetsa ma docking scores otsika pang'ono (-5.98 ndi -5.63, motsatana) poyerekeza ndi ma ligands ena. Izi zikusonyeza kuti ngakhale ma docking scores angagwiritsidwe ntchito kulosera mgwirizano wolumikizana, zinthu zina (monga kukhazikika kwa ligand ndi kuyanjana kwa ma molekyulu m'chilengedwe chachilengedwe) zimathandizanso kwambiri pakuzindikira ntchito yolimbana ndi mabakiteriya. Chochititsa chidwi n'chakuti, ma RMSD values ​​​​a mankhwala onse opangidwa anali pansi pa 2 Å, kutsimikizira kuti mawonekedwe awo a docking akugwirizana ndi kapangidwe kake kogwirizana ndi kapangidwe ka ligand yolumikizidwa ndi crystallized, zomwe zimathandizanso kuthekera kwawo ngati zoletsa zamphamvu za PBP2a.
Ngakhale kuti zigoli za docking ndi ma RMS values ​​​​zimapatsa maulosi ofunikira, mgwirizano pakati pa zotsatira za docking ndi ntchito yolimbana ndi maantibayotiki nthawi zambiri sumveka bwino poyamba. Ngakhale kuti PBP2a inhibition imathandizidwa kwambiri ngati chinthu chofunikira chomwe chimakhudza ntchito yolimbana ndi maantibayotiki, kusiyana kosiyanasiyana kukusonyeza kuti zinthu zina zamoyo zimathandizanso kwambiri. Ma compounds 6 ndi 13b adawonetsa ntchito yayikulu kwambiri yolimbana ndi maantibayotiki, yokhala ndi mainchesi 4 cm m'mimba mwake komanso MIC yotsika kwambiri (9.7 μg/100 μL) ndi MBC (78.125 μg/100 μL), ngakhale kuti ali ndi zigoli zochepa za docking poyerekeza ndi ma compounds 7, 9, 10 ndi 14. Izi zikusonyeza kuti ngakhale PBP2a inhibition imathandizira pa ntchito yolimbana ndi maantibayotiki, zinthu monga kusungunuka, bioavailability ndi mphamvu zolumikizirana m'malo ozungulira mabakiteriya zimakhudzanso ntchito yonse. Chithunzi 11 chikuwonetsa momwe ma docking poses awo amakhalira, zomwe zikusonyeza kuti ma compounds onsewa, ngakhale ali ndi zigoli zochepa zomangira, amathabe kuyanjana ndi zotsalira zazikulu za PBP2a, zomwe zingathe kukhazikika pa choletsa choletsa. Izi zikusonyeza kuti ngakhale kuti kuyika ma molecular docking kumapereka chidziwitso chofunikira pa kuletsa kwa PBP2a, zinthu zina zamoyo ziyenera kuganiziridwa kuti zimvetsetse bwino zotsatira zenizeni za mankhwala awa.
Pogwiritsa ntchito kapangidwe ka kristalo ka PBP2a (PDB ID: 4CJN), mapu a 2D ndi 3D olumikizirana a mankhwala ogwira ntchito kwambiri 6 ndi 13b olumikizidwa ndi penicillin-binding protein 2a (PBP2a) ya methicillin-resistant Staphylococcus aureus (MRSA) adapangidwa. Mamapu awa amayerekeza machitidwe olumikizirana a mankhwala awa ndi re-docked co-crystallized quinazolinone ligand (CCL), kuwonetsa kuyanjana kofunikira monga hydrogen bonding, π-stacking, ndi ionic interactions.
Chitsanzo chofananacho chinawonedwa pa compound 7, yomwe inawonetsa kuchuluka kwa docking score (-6.32) ndi mulifupi wofanana wa inhibition zone (3.9 cm) ndi compound 10. Komabe, MIC yake (39.08 μg/100 μL) ndi MBC (39.06 μg/100 μL) zinali zapamwamba kwambiri, zomwe zikusonyeza kuti imafunikira kuchuluka kwakukulu kuti iwonetse mphamvu ya antibacterial. Izi zikusonyeza kuti ngakhale compound 7 inawonetsa kugwirizana kwamphamvu mu maphunziro a docking, zinthu monga bioavailability, cell uptake, kapena zina zomwe zimapangitsa kuti physicochemical igwire bwino ntchito zitha kuchepetsa mphamvu yake yachilengedwe. Ngakhale compound 7 inawonetsa mphamvu ya bactericidal, sinali yothandiza kwambiri poletsa kukula kwa mabakiteriya poyerekeza ndi compound 6 ndi 13b.
Compound 10 inasonyeza kusiyana kwakukulu ndi chiŵerengero chapamwamba kwambiri cha docking (-6.40), kusonyeza kugwirizana kwakukulu kwa PBP2a. Komabe, dera lake la diameter yoletsa (3.9 cm) linali lofanana ndi compound 7, ndipo MBC yake (312 μg/100 μL) inali yayikulu kwambiri kuposa compound 6, 7, ndi 13b, kusonyeza mphamvu yofooka ya mabakiteriya. Izi zikusonyeza kuti ngakhale kuti malonjezo abwino a docking, compound 10 sinali yothandiza kwambiri kupha MRSA chifukwa cha zinthu zina zolepheretsa monga kusungunuka, kukhazikika, kapena kulephera kulowa bwino kwa nembanemba ya bakiteriya. Zotsatirazi zikuthandizira kumvetsetsa kuti ngakhale kuti PBP2a yoletsa imagwira ntchito yofunika kwambiri pa ntchito yoletsa mabakiteriya, sikufotokoza bwino kusiyana kwa ntchito ya zamoyo zomwe zawonedwa pakati pa mankhwala omwe ayesedwa. Kusiyana kumeneku kukusonyeza kuti kusanthula kwina koyesera ndi kuwunika kwakuya kwa zamoyo ndikofunikira kuti timvetse bwino njira zoletsa mabakiteriya zomwe zimakhudzidwa.
Kuyika mamolekyulu mu Gome 4 ndi Fayilo Yowonjezera ya Deta ikuwonetsa ubale wovuta pakati pa zigoli za docking ndi ntchito yolimbana ndi maantibayotiki. Ngakhale kuti ma compounds 6 ndi 13b ali ndi zigoli zochepa za docking kuposa ma compounds 7, 9, 10, ndi 14, amasonyeza ntchito yayikulu kwambiri yolimbana ndi maantibayotiki. Mapu awo ogwirizana (omwe akuwonetsedwa pa Chithunzi 11) akuwonetsa kuti ngakhale kuti ali ndi zigoli zochepa zomangira, amapangabe ma hydrogen bonds ndi π-stacking interactions ndi ma key residues a PBP2a omwe amatha kukhazikika pa enzyme-inhibitor complex mwanjira yopindulitsa ya biologically. Ngakhale kuti pali zigoli zochepa za docking za 6 ndi 13b, ntchito yawo yowonjezereka yolimbana ndi maantibayotiki ikusonyeza kuti zinthu zina monga kusungunuka, kukhazikika, ndi kutengedwa kwa maselo ziyenera kuganiziridwa pamodzi ndi deta ya docking poyesa mphamvu ya inhibitor. Izi zikuwonetsa kufunika kophatikiza maphunziro a docking ndi kusanthula kwa antimicrobial koyesera kuti muwone molondola mphamvu ya mankhwala atsopano.
Zotsatirazi zikuwonetsa kuti ngakhale kuti kuyika ma molecular docking ndi chida champhamvu cholosera mgwirizano womangirira ndi kuzindikira njira zomwe zingatheke zoletsa, sikuyenera kudaliridwa kokha kuti kudziwike mphamvu ya maantibayotiki. Deta ya ma molecular ikusonyeza kuti kuletsa kwa PBP2a ndi chinthu chofunikira kwambiri chomwe chimakhudza ntchito ya maantibayotiki, koma kusintha kwa ntchito ya zamoyo kukuwonetsa kuti zinthu zina za physicochemical ndi pharmacokinetic ziyenera kukonzedwanso kuti ziwonjezere mphamvu ya mankhwala. Maphunziro amtsogolo ayenera kuyang'ana kwambiri pakukonza kapangidwe ka mankhwala a mankhwala 7 ndi 10 kuti akonze kupezeka kwa bioavailability ndi kuyamwa kwa maselo, kuonetsetsa kuti kuyanjana kwamphamvu kwa docking kumasinthidwa kukhala ntchito yeniyeni ya maantibayotiki. Maphunziro ena, kuphatikizapo kusanthula kwina kwa bioassays ndi kusanthula kwa ubale wa kapangidwe ndi ntchito (SAR), adzakhala ofunikira kwambiri kuti timvetsetse momwe ma compounds awa amagwirira ntchito ngati zoletsa za PBP2a ndikupanga ma antibayotiki ogwira ntchito bwino.
Mankhwala opangidwa kuchokera ku 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 anali ndi mphamvu zosiyanasiyana zothana ndi majeremusi, ndipo mankhwala angapo amasonyeza kuletsa kwakukulu kwa Staphylococcus aureus (MRSA) yokana methicillin. Kusanthula kwa ubale wa kapangidwe kake (SAR) kunavumbula zinthu zofunika kwambiri zomwe zimapangitsa kuti mankhwalawa akhale ndi mphamvu zothana ndi majeremusi.
Kupezeka kwa magulu a acrylonitrile ndi anthracene kwakhala kofunikira kwambiri pakulimbikitsa ntchito yolimbana ndi mabakiteriya. Gulu la nitrile lomwe limagwira ntchito kwambiri mu acrylonitrile ndilofunikira kuti lithandizire kuyanjana ndi mapuloteni a mabakiteriya, motero limathandizira kukhala ndi mphamvu zothana ndi mabakiteriya. Mafakitale okhala ndi acrylonitrile ndi anthracene nthawi zonse amasonyeza mphamvu zothana ndi mabakiteriya. Kununkhira kwa gulu la anthracene kunapangitsa kuti mafakitalewa akhale olimba, zomwe mwina zinawonjezera ntchito yawo yachilengedwe.
Kuyambitsa mphete za heterocyclic kunathandiza kwambiri kuti mankhwala angapo opangidwa kuchokera ku benzothiazole agwire bwino ntchito. Makamaka, benzothiazole derivative 13b ndi acrylhydrazide derivative 6 zinawonetsa mphamvu yayikulu kwambiri yolimbana ndi mabakiteriya yokhala ndi malo oletsa pafupifupi 4 cm. Mankhwalawa opangidwa kuchokera ku heterocyclic derivatives adawonetsa zotsatira zazikulu zamoyo, zomwe zikusonyeza kuti kapangidwe ka heterocyclic kamagwira ntchito yofunika kwambiri pa zotsatira za antibacterial. Momwemonso, pyrimidinethione mu compound 9, thiopyrazole mu compound 10, ndi tetrazine ring mu compound 11 zinathandizira pakupanga mabakiteriya a mankhwalawo, zomwe zikuwonetsanso kufunika kwa kusintha kwa heterocyclic.
Pakati pa mankhwala opangidwa, 6 ndi 13b adadziwika ndi ntchito zawo zabwino kwambiri zothana ndi mabakiteriya. Kuchuluka kochepa koletsa (MIC) kwa mankhwala 6 kunali 9.7 μg/100 μL, ndipo kuchuluka kochepa koletsa mabakiteriya (MBC) kunali 78.125 μg/100 μL, zomwe zikuwonetsa kuthekera kwake kwabwino kochotsa Staphylococcus aureus (MRSA) yolimbana ndi methicillin. Mofananamo, mankhwala 13b anali ndi malo oletsa a 4 cm ndi otsika a MIC ndi MBC, kutsimikizira mphamvu yake yolimbana ndi mabakiteriya. Zotsatirazi zikuwonetsa ntchito zazikulu za magulu ogwira ntchito a acrylohydrazide ndi benzothiazole podziwa mphamvu ya mankhwala awa.
Mosiyana ndi zimenezi, mankhwala 7, 10, ndi 14 anali ndi mphamvu yochepetsera mabakiteriya ndipo anali ndi malo oletsa mabakiteriya kuyambira 3.65 mpaka 3.9 cm. Mankhwalawa ankafunika kuchuluka kwa mabakiteriya kuti aphe mabakiteriya onse, monga momwe zimasonyezedwera ndi kuchuluka kwawo kwakukulu kwa MIC ndi MBC. Ngakhale kuti mankhwalawa sanali amphamvu kwambiri poyerekeza ndi mankhwala 6 ndi 13b, anali ndi mphamvu yochepetsera mabakiteriya, zomwe zikusonyeza kuti kulowetsedwa kwa acrylonitrile ndi anthracene mu heterocyclic ring kumathandiza kuti azitha kupha mabakiteriya.
Mankhwalawa ali ndi njira zosiyanasiyana zogwirira ntchito, ena ali ndi mphamvu zopha mabakiteriya ndipo ena ali ndi mphamvu zopha mabakiteriya. Mankhwala 7, 11, 13a, ndi 15 ndi opha mabakiteriya ndipo amafuna kuchuluka kochepa kuti aphe mabakiteriya kwathunthu. Mosiyana ndi zimenezi, mankhwala 6, 13b, ndi 14 ndi opha mabakiteriya ndipo amatha kuletsa kukula kwa mabakiteriya pa kuchuluka kochepa, koma amafunika kuchuluka kwakukulu kuti aphe mabakiteriya kwathunthu.
Ponseponse, kusanthula ubale wa kapangidwe ndi ntchito kukuwonetsa kufunika koyambitsa acrylonitrile ndi anthracene moieties ndi mapangidwe a heterocyclic kuti akwaniritse ntchito yofunika kwambiri yolimbana ndi mabakiteriya. Zotsatirazi zikusonyeza kuti kukonza bwino kapangidwe ka zinthuzi ndi kufufuza zosintha zina kuti ziwongolere kusungunuka ndi kulowa kwa nembanemba kungayambitse kupanga mankhwala othandiza kwambiri oletsa MRSA.
Ma reagents ndi zosungunulira zonse zinayeretsedwa ndi kuumitsidwa pogwiritsa ntchito njira zokhazikika (El Gomhouria, Egypt). Malo osungunuka anapezeka pogwiritsa ntchito chipangizo cha GallenKamp electronic melting point ndipo ananenedwa popanda kukonzedwa. Ma infrared (IR) spectra (cm⁻1) analembedwa ku Dipatimenti ya Chemistry, Faculty of Science, Ain Shams University pogwiritsa ntchito ma potassium bromide (KBr) pellets pa Thermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
Ma spectra a 1H NMR adapezeka pa 300 MHz pogwiritsa ntchito GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) ndi BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.). Tetramethylsilane (TMS) idagwiritsidwa ntchito ngati muyezo wamkati wokhala ndi deuterated dimethyl sulfoxide (DMSO-d₆). Kuyeza kwa NMR kudachitika ku Faculty of Science, Cairo University, Giza, Egypt. Kusanthula kwa elemental (CHN) kudachitika pogwiritsa ntchito Perkin-Elmer 2400 Elemental Analyzer ndipo zotsatira zomwe zapezeka zikugwirizana bwino ndi zomwe zawerengedwa.
Chisakanizo cha asidi 3 (5 mmol) ndi thionyl chloride (5 ml) chinatenthedwa mu bafa la madzi pa 65 °C kwa maola 4. Thionyl chloride yochulukirapo inachotsedwa mwa kusungunuka pansi pa kupsinjika kochepa. Cholimba chofiira chomwe chinatulukacho chinasonkhanitsidwa ndikugwiritsidwa ntchito popanda kuyeretsa kwina. Malo osungunuka: 200-202 °C, phindu: 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. Katswiri. Anawerengera C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Yapezeka: C, 74.41; H, 3.34; N, 4.66%.
Pa 0°C, 4 (2 mmol, 0.7 g) inasungunuka mu anhydrous dioxane (20 ml) ndipo hydrazine hydrate (2 mmol, 0.16 ml, 80%) inawonjezedwa pang'onopang'ono ndikusakanikirana kwa ola limodzi. Cholimba chomwe chinasungunuka chinasonkhanitsidwa mwa kusefedwa ndikusinthidwanso kuchokera ku ethanol kuti chipereke mankhwala 6.
Makristalo obiriwira, malo osungunuka 190-192℃, amatulutsa 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, yosinthika), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Mtengo wowerengedwa wa C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Yapezeka: C, 84.01; H, 4.38; N, 8.05%.
Sungunulani 4 (2 mmol, 0.7 g) mu 20 ml ya yankho la anhydrous dioxane (lomwe lili ndi madontho ochepa a triethylamine), onjezerani phenylhydrazine/2-aminopyridine (2 mmol) ndikusakaniza kutentha kwa chipinda kwa ola limodzi ndi awiri, motsatana. Thirani chisakanizo cha reaction mu ayezi kapena madzi ndikuwonjezera acidity ndi hydrochloric acid wosungunuka. Sefani cholimba cholekanitsidwa ndikubwezeretsanso kuchokera ku ethanol kuti mupeze 7 ndikubwezeretsanso kuchokera ku benzene kuti mupeze 8.
Makristalo obiriwira, malo osungunuka 160-162℃, amatulutsa 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, yosinthika), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Mtengo wowerengedwa wa C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Wopezeka: C, 81.96; H, 3.91; N, 8.91%.
4 (2 mmol, 0.7 g) inasungunuka mu 20 ml ya yankho la anhydrous dioxane (lomwe lili ndi madontho ochepa a triethylamine), 2-aminopyridine (2 mmol, 0.25 g) inawonjezedwa ndipo chisakanizocho chinasakanizidwa kutentha kwa chipinda kwa maola awiri. Chisakanizocho chinathiridwa m'madzi oundana ndipo chinathiridwa ndi asidi wa hydrochloric acid wochepetsedwa. Mpweya wopangidwawo unasefedwa ndikubwezeretsedwanso kuchokera ku benzene, zomwe zinapereka makhiristo obiriwira a 8 okhala ndi malo osungunuka a 146-148 °C ndi phindu la 82.5%; infrared spectrum (KBr) ν: 3148 (NH), 2222 (C≡N), 1665 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ (ppm): 8.78 (s, H, NH, yosinthika), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); Kuwerengedwa kwa C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Kupezeka: C, 78.93; H, 3.97; N, 12.36%.
Chosakaniza 4 (2 mmol, 0.7 g) chinasungunuka mu 20 ml ya dioxane youma (yomwe ili ndi madontho ochepa a triethylamine ndi 2 mmol ya thiourea/semicarbazide) ndipo chinatenthedwa pansi pa reflux kwa maola awiri. Chosungunuliracho chinasanduka nthunzi mu vacuo. Zotsalirazo zinabwezeretsedwanso kuchokera ku dioxane kuti zipereke chisakanizo.