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An haɗa synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kuma an yi amfani da shi don haɗa nau'ikan mahaɗan heterocyclic masu aiki sosai ta hanyar amsawarsa da nau'ikan nucleophiles na nitrogen daban-daban. Tsarin kowane mahaɗan heterocyclic da aka haɗa an yi shi sosai ta amfani da nazarin spectroscopic da elemental. Goma daga cikin sabbin mahaɗan heterocyclic guda goma sha uku sun nuna ingantaccen tasiri akan ƙwayoyin cuta masu jure wa magunguna da yawa (MRSA). Daga cikinsu, mahaɗan 6, 7, 10, 13b, da 14 sun nuna mafi girman aikin ƙwayoyin cuta tare da yankunan hanawa kusa da 4 cm. Duk da haka, nazarin ƙwayoyin cuta sun nuna cewa mahaɗan suna da alaƙa daban-daban ga furotin penicillin-binding 2a (PBP2a), babban abin da ke haifar da juriya ga MRSA. Wasu mahaɗan kamar 7, 10 da 14 sun nuna mafi girman alaƙa da kwanciyar hankali na hulɗa a wurin aiki na PBP2a idan aka kwatanta da ligand na quinazolinone mai haɗa crystallized. Sabanin haka, mahaɗan 6 da 13b suna da ƙananan maki na docking amma har yanzu suna nuna babban aikin ƙwayoyin cuta, inda mahaɗan 6 ke da mafi ƙarancin ƙimar MIC (9.7 μg/100 μL) da MBC (78.125 μg/100 μL). Binciken docking ya bayyana manyan hulɗar da suka haɗa da haɗin hydrogen da π-stacking, musamman tare da ragowar kamar Lys 273, Lys 316 da Arg 298, waɗanda aka gano suna hulɗa da haɗin gwiwa mai haɗaka a cikin tsarin lu'ulu'u na PBP2a. Waɗannan ragowar suna da mahimmanci ga aikin enzymatic na PBP2a. Waɗannan sakamakon sun nuna cewa mahaɗan da aka haɗa na iya zama magungunan hana MRSA masu alƙawarin, suna nuna mahimmancin haɗa docking na kwayoyin halitta tare da bioasys don gano masu tasiri na magani.
A cikin 'yan shekarun farko na wannan ƙarni, an fi mai da hankali kan ƙirƙirar sabbin hanyoyi masu sauƙi da hanyoyin haɗa sabbin hanyoyin heterocyclic tare da ayyukan ƙwayoyin cuta ta amfani da kayan farawa da ake samu cikin sauƙi.
Ana ɗaukar sassan Acrylonitrile a matsayin muhimman kayan farawa don haɗa tsarin heterocyclic masu ban mamaki saboda suna da sinadarai masu amsawa sosai. Bugu da ƙari, an yi amfani da abubuwan da aka samo daga 2-cyanoacryloyl chloride a cikin 'yan shekarun nan don haɓakawa da haɗa samfuran da ke da mahimmanci a fagen aikace-aikacen magunguna, kamar magunguna1,2,3, abubuwan da suka riga suka fara maganin HIV, antiviral, anticancer, antibacterial, antidepressant da antioxidants4,5,6,7,8,9,10. Kwanan nan, ingancin halitta na anthracene da abubuwan da aka samo daga gare shi, gami da maganin rigakafi, anticancer11,12, antibacterial13,14,15 da kaddarorin kashe kwari16,17, sun jawo hankali sosai18,19,20,21. An nuna mahaɗan antimicrobial waɗanda ke ɗauke da acrylonitrile da anthracene a cikin Hoto na 1 da 2.
A cewar Hukumar Lafiya ta Duniya (WHO) (2021), juriya ga ƙwayoyin cuta (AMR) barazana ce ga lafiya da ci gaba a duniya22,23,24,25. Ba za a iya warkar da marasa lafiya ba, wanda ke haifar da tsawaita zaman asibiti da buƙatar magunguna masu tsada, da kuma ƙaruwar mace-mace da nakasa. Rashin ingantattun magungunan kashe ƙwayoyin cuta sau da yawa yakan haifar da gazawar magani ga cututtuka daban-daban, musamman a lokacin chemotherapy da manyan tiyata.
A cewar rahoton Hukumar Lafiya ta Duniya na 2024, Staphylococcus aureus (MRSA) da E. coli masu juriya ga methicillin suna cikin jerin manyan cututtukan da suka fi muhimmanci. Dukansu ƙwayoyin cuta suna jure wa magungunan rigakafi da yawa, don haka suna wakiltar cututtuka da ke da wahalar magani da sarrafawa, kuma akwai buƙatar gaggawa don ƙirƙirar sabbin ƙwayoyin cuta masu tasiri don magance wannan matsalar. Anthracene da abubuwan da suka samo asali sanannu ne na ƙwayoyin cuta waɗanda za su iya aiki akan ƙwayoyin cuta na Gram-positive da Gram-negative. Manufar wannan binciken ita ce ƙirƙirar sabon samfurin da zai iya yaƙi da waɗannan ƙwayoyin cuta waɗanda ke da haɗari ga lafiya.
Hukumar Lafiya ta Duniya (WHO) ta ba da rahoton cewa yawancin ƙwayoyin cuta suna jure wa maganin rigakafi da yawa, ciki har da Staphylococcus aureus (MRSA) mai jure wa methicillin, wanda shine sanadin kamuwa da cuta a cikin al'umma da wuraren kiwon lafiya. An ruwaito cewa marasa lafiya da ke dauke da cututtukan MRSA suna da kashi 64% na mace-mace fiye da waɗanda ke dauke da cututtukan da ke jure wa magani. Bugu da ƙari, E. coli yana haifar da haɗari a duniya saboda layin kariya na ƙarshe akan Enterobacteriaceae mai jure wa carbapenem (watau, E. coli) shine colistin, amma an ruwaito ƙwayoyin cuta masu jure wa colistin kwanan nan a ƙasashe da dama. 22,23,24,25
Saboda haka, bisa ga Tsarin Aiki na Duniya na Hukumar Lafiya ta Duniya kan Juriyar Kwayoyin cuta26, akwai buƙatar gaggawa don gano da kuma haɗa sabbin magungunan kashe ƙwayoyin cuta. An nuna babban ƙarfin anthracene da acrylonitrile a matsayin magungunan kashe ƙwayoyin cuta27, antifungal28, anticancer29 da antioxidants30 a cikin takardu da yawa da aka buga. Dangane da wannan, za a iya cewa waɗannan abubuwan da aka samo asali suna da kyau don amfani da su don magance Staphylococcus aureus (MRSA) mai juriya ga methicillin.
Sharhin wallafe-wallafen da suka gabata ya motsa mu mu haɗa sabbin abubuwan da suka samo asali a cikin waɗannan azuzuwan. Saboda haka, wannan binciken yana da nufin haɓaka sabbin tsarin heterocyclic wanda ke ɗauke da ƙwayoyin anthracene da acrylonitrile, kimanta ingancinsu na ƙwayoyin cuta da ƙwayoyin cuta, da kuma bincika yiwuwar hulɗar ɗaurewa da furotin penicillin-binding 2a (PBP2a) ta hanyar haɗa ƙwayoyin cuta. Dangane da binciken da ya gabata, wannan binciken ya ci gaba da haɗawa, kimantawar halittu, da kuma nazarin lissafi na tsarin heterocyclic don gano wakilai masu juriya ga Staphylococcus aureus (MRSA) masu ƙarfi waɗanda ke da ƙarfin hana PBP2a31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Bincikenmu na yanzu ya mayar da hankali ne kan haɗakar da kuma kimanta ƙwayoyin cuta na sabbin mahaɗan heterocyclic waɗanda ke ɗauke da ƙwayoyin anthracene da acrylonitrile. An shirya 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 kuma an yi amfani da shi azaman tubalin gini don gina sabbin tsarin heterocyclic.
An tantance tsarin mahaɗin 4 ta amfani da bayanan spectral. Bakan 1H-NMR ya nuna kasancewar CH= a 9.26 ppm, bakan IR ya nuna kasancewar ƙungiyar carbonyl a 1737 cm−1 da ƙungiyar cyano a 2224 cm−1, kuma bakan 13CNMR shi ma ya tabbatar da tsarin da aka gabatar (duba sashen gwaji).
An cimma hadawar 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ta hanyar hydrolysis na ƙungiyoyin aromatic 250, 41, 42, 53 tare da maganin ethanolic sodium hydroxide (10%) don samar da acid 354, 45, 56, wanda aka yi wa magani da thionyl chloride a kan wankan ruwa don samar da acryloyl chloride derivative 4 a cikin yawan amfanin ƙasa mai yawa (88.5%), kamar yadda aka nuna a Hoto na 3.
Don ƙirƙirar sabbin mahaɗan heterocyclic tare da tasirin maganin kashe ƙwayoyin cuta da ake tsammani, an gudanar da martanin acyl chloride 4 tare da nau'ikan dinucleophiles daban-daban.
An yi wa acid chloride 4 magani da hydrazine hydrate a digiri 0 na tsawon awa ɗaya. Abin takaici, ba a sami pyrazolone 5 ba. Samfurin wani abu ne da aka samo daga acrylamide wanda aka tabbatar da tsarinsa ta hanyar bayanan spectral. Bakan IR ɗinsa ya nuna madaurin sha na C=O a 1720 cm−1, C≡N a 2228 cm−1 da NH a 3424 cm−1. Bakan 1H-NMR ya nuna siginar musayar singlet na olefin protons da NH protons a 9.3 ppm (duba Sashen Gwaji).
An yi amfani da moles guda biyu na acid chloride 4 da moles ɗaya na phenylhydrazine don samar da N-phenylacryloylhydrazine derivative 7 a cikin kyakkyawan yawan amfanin ƙasa (77%) (Hoto na 5). An tabbatar da tsarin 7 ta hanyar bayanan infrared spectroscopy, wanda ya nuna sha na ƙungiyoyin C=O guda biyu a 1691 da 1671 cm−1, sha na rukunin CN a 2222 cm−1 da sha na rukunin NH a 3245 cm−1, kuma bakan 1H-NMR ɗinsa ya nuna rukunin CH a 9.15 da 8.81 ppm da kuma NH proton a 10.88 ppm (duba sashen gwaji).
A cikin wannan binciken, an binciki martanin acyl chloride 4 tare da 1,3-dinucleophiles. Maganin acyl chloride 4 tare da 2-aminopyridine a cikin 1,4-dioxane tare da TEA a matsayin tushe a zafin ɗaki ya ba da acrylamide derivative 8 (Hoto na 5), ​​wanda aka gano tsarinsa ta amfani da bayanan spectral. IR spectra ya nuna madaurin sha na cyano a 2222 cm−1, NH a 3148 cm−1, da carbonyl a 1665 cm−1; 1H NMR spectra ya tabbatar da kasancewar olefin protons a 9.14 ppm (duba Sashen Gwaji).
Compound 4 yana yin aiki da thiourea don ba pyrimidinethione 9; compound 4 yana yin aiki da thiosemiccarbazide don ba da thiopyrazole derivative 10 (Hoto na 5). An tabbatar da tsarin mahadi 9 da 10 ta hanyar nazarin spectral da elemental (duba sashen gwaji).
An shirya Tetrazine-3-thiol 11 ta hanyar amsawar mahaɗin 4 tare da thiocarbazide a matsayin 1,4-dinucleophile (Hoto na 5), ​​kuma an tabbatar da tsarinsa ta hanyar spectroscopy da nazarin elemental. A cikin infrared spectrum, haɗin C=N ya bayyana a 1619 cm−1. A lokaci guda, 1H-NMR spectrum ɗinsa ya riƙe siginar faranti masu yawa na protons masu ƙanshi a 7.78–8.66 ppm da SH protons a 3.31 ppm (duba Sashen Gwaji).
Acryloyl chloride 4 yana yin aiki da 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, da ethanolamine a matsayin 1,4-dinucleophiles don samar da sabbin tsarin heterocyclic (13-16).
An tabbatar da tsarin waɗannan sabbin mahaɗan da aka haɗa ta hanyar nazarin spectral da elemental (duba sashen gwaji). An samo asalin 2-Hydroxyphenylacrylamide 17 ta hanyar amsawa da 2-aminophenol a matsayin dinucleophile (Hoto na 6), kuma an tabbatar da tsarinsa ta hanyar nazarin spectral da elemental. Tsarin infrared na mahaɗin 17 ya nuna cewa siginar C=O da C≡N sun bayyana a 1681 da 2226 cm−1, bi da bi. A halin yanzu, bakan 1H-NMR ɗinsa ya riƙe siginar singlet na olefin proton a 9.19 ppm, kuma OH proton ya bayyana a 9.82 ppm (duba sashen gwaji).
Amsar acid chloride 4 tare da nucleophile ɗaya (misali, ethylamine, 4-toluidine, da 4-methoxyaniline) a cikin dioxane a matsayin mai narkewa da kuma TEA a matsayin mai kara kuzari a zafin ɗaki ya samar da abubuwan da aka samo daga acrylamide mai launin kore 18, 19a, da 19b. Bayanan abubuwa da na gani na mahadi 18, 19a, da 19b sun tabbatar da tsarin waɗannan abubuwan da aka samo (duba Sashen Gwaji) (Hoto na 7).
Bayan tantance ayyukan ƙwayoyin cuta na mahaɗan roba daban-daban, an sami sakamako daban-daban kamar yadda aka nuna a cikin Tebur 1 da Hoto na 8 (duba fayil ɗin hoto). Duk mahaɗan da aka gwada sun nuna matakai daban-daban na hana ƙwayoyin cuta na Gram-positive MRSA, yayin da ƙwayoyin cuta na Gram-negative Escherichia coli suka nuna cikakken juriya ga dukkan mahaɗan. Ana iya raba mahaɗan da aka gwada zuwa rukuni uku bisa ga diamita na yankin hanawa akan MRSA. Rukunin farko shine mafi aiki kuma ya ƙunshi mahaɗan biyar (6, 7, 10, 13b da 14). Diamita na yankin hanawa na waɗannan mahaɗan ya kusa da 4 cm; mahaɗan da suka fi aiki a cikin wannan rukuni sune mahaɗan 6 da 13b. Rukunin na biyu yana aiki matsakaici kuma ya ƙunshi wasu mahaɗan biyar (11, 13a, 15, 18 da 19a). Yankin hanawa na waɗannan mahaɗan ya kasance daga 3.3 zuwa 3.65 cm, tare da mahaɗan 11 yana nuna mafi girman yankin hanawa na 3.65 ± 0.1 cm. A gefe guda kuma, rukunin ƙarshe ya ƙunshi mahadi uku (8, 17 da 19b) tare da mafi ƙarancin aikin ƙwayoyin cuta (ƙasa da 3 cm). Hoto na 9 yana nuna rarrabawar yankunan hanawa daban-daban.
Ƙarin bincike kan ayyukan ƙwayoyin cuta na mahaɗan da aka gwada ya haɗa da tantance MIC da MBC ga kowane mahaɗi. Sakamakon ya ɗan bambanta kaɗan (kamar yadda aka nuna a cikin Tebur 2, 3 da Hoto na 10 (duba fayil ɗin hoto)), tare da mahaɗan 7, 11, 13a da 15 a bayyane aka sake rarraba su a matsayin mafi kyawun mahaɗi. Suna da ƙimar MIC da MBC iri ɗaya mafi ƙanƙanta (39.06 μg/100 μL). Duk da cewa mahaɗan 7 da 8 suna da ƙimar MIC ƙasa (9.7 μg/100 μL), ƙimar MBC ɗinsu ta fi girma (78.125 μg/100 μL). Saboda haka, an ɗauke su da rauni fiye da mahaɗan da aka ambata a baya. Duk da haka, waɗannan mahaɗan guda shida sune mafi inganci daga cikin waɗanda aka gwada, saboda ƙimar MBC ɗinsu ta ƙasa da 100 μg/100 μL.
Haɗaka (10, 14, 18 da 19b) ba su da aiki sosai idan aka kwatanta da sauran haɗaɗɗun da aka gwada saboda ƙimar MBC ɗinsu ta kasance daga 156 zuwa 312 μg/100 μL. A gefe guda kuma, haɗaɗɗun (8, 17 da 19a) ba su da wani tasiri sosai domin suna da mafi girman ƙimar MBC (625, 625 da 1250 μg/100 μL, bi da bi).
A ƙarshe, bisa ga matakan haƙuri da aka nuna a Jadawali na 3, za a iya raba mahaɗan da aka gwada zuwa rukuni biyu bisa ga yanayin aikinsu: mahaɗan da ke da tasirin kashe ƙwayoyin cuta (7, 8, 10, 11, 13a, 15, 18, 19b) da mahaɗan da ke da tasirin kashe ƙwayoyin cuta (6, 13b, 14, 17, 19a). Daga cikinsu, an fi son mahaɗan 7, 11, 13a da 15, waɗanda ke nuna ayyukan kashe ƙwayoyin cuta a ƙaramin taro (39.06 μg/100 μL).
Goma daga cikin mahaɗan guda goma sha uku da aka gwada sun nuna yuwuwar yin maganin Staphylococcus aureus (MRSA) mai jure wa maganin rigakafi (methicillin-resistance antibiotics). Saboda haka, ana ba da shawarar a ƙara yin gwajin ƙwayoyin cuta masu jure wa maganin rigakafi (musamman ƙwayoyin cuta na gida da ke ɗauke da ƙwayoyin cuta masu cutarwa na Gram-positive da Gram-negative) da kuma yis ɗin da ke haifar da cututtuka, da kuma gwajin cytotoxic na kowane mahaɗan don tantance amincinsa.
An gudanar da nazarin ƙwayoyin halitta don tantance yuwuwar mahaɗan da aka haɗa a matsayin masu hana furotin mai ɗaure penicillin 2a (PBP2a) a cikin Staphylococcus aureus mai juriya ga methicillin (MRSA). PBP2a babban enzyme ne da ke da hannu a cikin biosynthesis na bangon ƙwayoyin cuta, kuma hana wannan enzyme yana tsoma baki ga samuwar bangon tantanin halitta, wanda a ƙarshe ke haifar da lysis na ƙwayoyin cuta da mutuwar tantanin halitta1. Sakamakon docking an jera su a cikin Jadawali na 4 kuma an bayyana su dalla-dalla a cikin fayil ɗin ƙarin bayanai, kuma sakamakon ya nuna cewa mahaɗan da yawa sun nuna ƙarfin ɗaurewa ga PBP2a, musamman mahimmin ragowar wurin aiki kamar Lys 273, Lys 316, da Arg 298. Hulɗar, gami da haɗin hydrogen da π-stacking, sun yi kama da na co-crystallized quinazolinone ligand (CCL), yana nuna yuwuwar waɗannan mahaɗan a matsayin masu hana ƙarfi.
Bayanan docking na kwayoyin halitta, tare da sauran sigogin lissafi, sun nuna cewa hana PBP2a shine babban hanyar da ke da alhakin ayyukan ƙwayoyin cuta da aka lura da su na waɗannan mahaɗan. Sakamakon docking da ƙimar matsakaicin karkacewar murabba'i (RMSD) sun ƙara bayyana kusanci da kwanciyar hankali na ɗaurewa, suna tallafawa wannan hasashe. Kamar yadda aka nuna a cikin Jadawali na 4, yayin da mahaɗan da yawa suka nuna kyakkyawar alaƙar ɗaurewa, wasu mahaɗan (misali, 7, 9, 10, da 14) suna da maki docking mafi girma fiye da ligand mai haɗin gwiwa, wanda ke nuna cewa suna iya samun hulɗa mai ƙarfi da ragowar wurin aiki na PBP2a. Duk da haka, mafi yawan mahaɗan bioactive 6 da 13b sun nuna ƙarancin maki docking (-5.98 da -5.63, bi da bi) idan aka kwatanta da sauran ligands. Wannan yana nuna cewa kodayake ana iya amfani da maki docking don annabta kusancin ɗaurewa, wasu abubuwa (misali, kwanciyar hankali na ligand da hulɗar kwayoyin halitta a cikin yanayin halittu) suma suna taka muhimmiyar rawa wajen tantance ayyukan ƙwayoyin cuta. Abin lura shi ne, ƙimar RMSD na duk mahaɗan da aka haɗa sun kasance ƙasa da 2 Å, wanda ke tabbatar da cewa yanayin docking ɗinsu ya yi daidai da tsarin ɗaurewar ligand mai haɗin gwiwa, wanda ke ƙara tallafawa ƙarfinsu a matsayin masu hana PBP2a masu ƙarfi.
Duk da cewa makin docking da ƙimar RMS suna ba da hasashen abubuwa masu mahimmanci, alaƙar da ke tsakanin waɗannan sakamakon docking da aikin ƙwayoyin cuta ba koyaushe take bayyana ba a kallon farko. Duk da cewa hana PBP2a yana da ƙarfi sosai a matsayin babban abin da ke tasiri ga ayyukan ƙwayoyin cuta, bambance-bambance da yawa suna nuna cewa wasu kaddarorin halittu suma suna taka muhimmiyar rawa. Haɗaɗɗun 6 da 13b sun nuna mafi girman aikin ƙwayoyin cuta, tare da diamita na yankin hanawa na 4 cm da mafi ƙarancin MIC (9.7 μg/100 μL) da MBC (78.125 μg/100 μL), duk da ƙarancin makin docking idan aka kwatanta da mahaɗan 7, 9, 10 da 14. Wannan yana nuna cewa kodayake hana PBP2a yana ba da gudummawa ga ayyukan ƙwayoyin cuta, abubuwa kamar narkewa, samuwar halittu da yanayin hulɗa a cikin yanayin ƙwayoyin cuta suma suna shafar aikin gabaɗaya. Hoto na 11 ya nuna yanayin docking ɗinsu, yana nuna cewa mahaɗan biyu, koda tare da ƙarancin makin ɗaurewa, har yanzu suna iya hulɗa da mahimman ragowar PBP2a, wanda zai iya daidaita hadaddun hanawa. Wannan ya nuna cewa yayin da docking na kwayoyin halitta ke ba da mahimman bayanai game da hana PBP2a, dole ne a yi la'akari da wasu abubuwan halitta don fahimtar tasirin antimicrobial na gaske na waɗannan mahaɗan.
Ta amfani da tsarin lu'ulu'u na PBP2a (PDB ID: 4CJN), an gina taswirar hulɗar 2D da 3D na mahaɗan da suka fi aiki 6 da 13b waɗanda aka haɗa da furotin mai ɗaure penicillin 2a (PBP2a) na Staphylococcus aureus mai juriya ga methicillin (MRSA). Waɗannan taswirorin suna kwatanta tsarin hulɗar waɗannan mahaɗan tare da ligand na quinazolinone mai haɗaka (CCL) da aka sake haɗawa, suna nuna mahimman hulɗar kamar haɗin hydrogen, π-stacking, da hulɗar ionic.
An lura da irin wannan tsari ga mahaɗin 7, wanda ya nuna babban maki na docking (-6.32) da kuma diamita irin wannan na hanawa (3.9 cm) zuwa mahaɗin 10. Duk da haka, MIC ɗinsa (39.08 μg/100 μL) da MBC (39.06 μg/100 μL) sun fi girma sosai, wanda ke nuna cewa yana buƙatar ƙarin yawan abubuwa don nuna tasirin maganin kashe ƙwayoyin cuta. Wannan yana nuna cewa kodayake mahaɗin 7 ya nuna ƙarfin haɗin gwiwa a cikin nazarin docking, abubuwa kamar bioavailability, ɗaukar ƙwayoyin halitta, ko wasu kaddarorin kimiyyar lissafi na iya iyakance tasirinsa na halitta. Duk da cewa mahaɗin 7 ya nuna halayen kashe ƙwayoyin cuta, bai yi tasiri sosai wajen hana haɓakar ƙwayoyin cuta ba idan aka kwatanta da mahaɗin 6 da 13b.
Compound 10 ya nuna bambanci mai ban mamaki tare da mafi girman maki na docking (-6.40), wanda ke nuna ƙarfin haɗin gwiwa ga PBP2a. Duk da haka, yankin diamita na hana shi (3.9 cm) ya yi daidai da compound 7, kuma MBC (312 μg/100 μL) ya fi mahadi 6, 7, da 13b girma sosai, wanda ke nuna raunin aikin kashe ƙwayoyin cuta. Wannan yana nuna cewa duk da kyawawan hasashen docking, compound 10 bai yi tasiri sosai ba wajen kashe MRSA saboda wasu abubuwan da ke iyakancewa kamar narkewa, kwanciyar hankali, ko rashin isasshen iskar membrane na ƙwayoyin cuta. Waɗannan sakamakon suna goyan bayan fahimtar cewa yayin da hana PBP2a ke taka muhimmiyar rawa a cikin ayyukan kashe ƙwayoyin cuta, bai bayyana cikakken bambance-bambancen ayyukan halittu da aka lura a tsakanin mahaɗan da aka gwada ba. Waɗannan bambance-bambancen suna nuna cewa ana buƙatar ƙarin nazarin gwaji da zurfin kimantawar halittu don fayyace hanyoyin kashe ƙwayoyin cuta da ke tattare da su gaba ɗaya.
Sakamakon docking na kwayoyin halitta a cikin Jadawali na 4 da Fayil ɗin Bayanai na Ƙarin Bayani ya nuna alaƙar da ke tsakanin makin docking da aikin ƙwayoyin cuta. Duk da cewa mahaɗan 6 da 13b suna da ƙananan makin docking fiye da mahaɗan 7, 9, 10, da 14, suna nuna mafi girman aikin antimicrobial. Taswirar hulɗarsu (wanda aka nuna a Hoto na 11) sun nuna cewa duk da ƙananan makin da ke ɗaure su, har yanzu suna samar da mahimman haɗin hydrogen da hulɗar π-stacking tare da mahimman ragowar PBP2a waɗanda za su iya daidaita hadaddun enzyme-inhibitor ta hanyar da ta dace da ilimin halitta. Duk da ƙarancin makin docking na 6 da 13b, haɓaka aikin ƙwayoyin cuta yana nuna cewa ya kamata a yi la'akari da wasu halaye kamar narkewa, kwanciyar hankali, da ɗaukar ƙwayoyin halitta tare da bayanan docking lokacin tantance yuwuwar hanawa. Wannan yana nuna mahimmancin haɗa nazarin docking tare da nazarin ƙwayoyin cuta na gwaji don tantance yuwuwar warkewa ta sabbin mahaɗan daidai.
Waɗannan sakamakon sun nuna cewa yayin da toshewar ƙwayoyin halitta kayan aiki ne mai ƙarfi don hasashen kusancin ɗaurewa da gano hanyoyin hanawa, bai kamata a dogara da shi kaɗai don tantance ingancin ƙwayoyin cuta ba. Bayanan ƙwayoyin halitta sun nuna cewa hana PBP2a muhimmin abu ne da ke tasiri ga ayyukan ƙwayoyin cuta, amma canje-canje a cikin ayyukan halittu sun nuna cewa dole ne a inganta wasu kaddarorin physicochemical da pharmacokinetic don haɓaka ingancin magani. Nazarin gaba ya kamata ya mayar da hankali kan inganta tsarin sinadarai na mahadi 7 da 10 don inganta samuwar halittu da ɗaukar ƙwayoyin halitta, tabbatar da cewa an fassara hulɗar docking mai ƙarfi zuwa ainihin aikin ƙwayoyin cuta. Ƙarin karatu, gami da ƙarin gwaje-gwajen bio da nazarin dangantaka tsakanin tsari da aiki (SAR), zai zama mahimmanci don ƙara fahimtarmu game da yadda waɗannan mahaɗan ke aiki azaman masu hana PBP2a da kuma haɓaka ingantattun magungunan ƙwayoyin cuta.
Magungunan da aka haɗa daga 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 sun nuna matakai daban-daban na aikin ƙwayoyin cuta, tare da wasu sinadarai da dama da suka nuna babban hana Staphylococcus aureus (MRSA) mai jure wa methicillin. Binciken alaƙar aiki da tsari (SAR) ya nuna muhimman fasalulluka na tsarin da ke ƙarƙashin tasirin ƙwayoyin cuta na waɗannan mahadi.
Kasancewar ƙungiyoyin acrylonitrile da anthracene ya tabbatar da cewa yana da matuƙar muhimmanci wajen haɓaka ayyukan ƙwayoyin cuta. Ƙungiyar nitrile mai yawan amsawa a cikin acrylonitrile yana da mahimmanci don sauƙaƙe hulɗa da sunadaran ƙwayoyin cuta, ta haka yana ba da gudummawa ga halayen ƙwayoyin cuta na mahaɗin. Haɗaɗɗun da ke ɗauke da acrylonitrile da anthracene sun nuna tasirin ƙwayoyin cuta masu ƙarfi. Ƙamshin ƙungiyar anthracene ya ƙara daidaita waɗannan mahaɗan, yana iya haɓaka ayyukansu na halitta.
Gabatar da zoben heterocyclic ya inganta tasirin maganin kashe ƙwayoyin cuta na wasu abubuwan da aka samo asali. Musamman ma, benzothiazole derivative 13b da acrylhydrazide derivative 6 sun nuna mafi girman aikin maganin kashe ƙwayoyin cuta tare da yankin hanawa na kimanin cm 4. Waɗannan abubuwan da aka samo asali na heterocyclic sun nuna ƙarin tasirin halittu masu mahimmanci, wanda ke nuna cewa tsarin heterocyclic yana taka muhimmiyar rawa a cikin tasirin maganin kashe ƙwayoyin cuta. Haka nan, pyrimidinethione a cikin mahaɗin 9, thiopyrazole a cikin mahaɗin 10, da zoben tetrazine a cikin mahaɗin 11 sun ba da gudummawa ga kaddarorin maganin kashe ƙwayoyin cuta na mahaɗin, wanda hakan ya ƙara nuna mahimmancin gyaran heterocyclic.
Daga cikin mahaɗan da aka haɗa, 6 da 13b sun yi fice saboda kyawawan ayyukansu na hana ƙwayoyin cuta. Mafi ƙarancin yawan hana ƙwayoyin cuta (MIC) na mahaɗan 6 shine 9.7 μg/100 μL, kuma mafi ƙarancin yawan kashe ƙwayoyin cuta (MBC) shine 78.125 μg/100 μL, wanda ke nuna kyakkyawan ikonsa na share Staphylococcus aureus mai jure wa methicillin (MRSA). Hakazalika, mahaɗan 13b yana da yankin hanawa na 4 cm da ƙarancin ƙimar MIC da MBC, wanda ke tabbatar da ƙarfin aikin ƙwayoyin cuta. Waɗannan sakamakon suna nuna mahimman rawar da ƙungiyoyin aiki na acrylohydrazide da benzothiazole ke takawa wajen tantance tasirin waɗannan mahaɗan.
Sabanin haka, mahadi 7, 10, da 14 sun nuna matsakaicin aikin kashe ƙwayoyin cuta tare da yankunan hanawa daga 3.65 zuwa 3.9 cm. Waɗannan mahaɗan suna buƙatar ƙarin yawan abubuwa don kashe ƙwayoyin cuta gaba ɗaya, kamar yadda ƙimar MIC da MBC mai yawa ke nunawa. Duk da cewa waɗannan mahaɗan ba su da ƙarfi kamar mahaɗan 6 da 13b, har yanzu sun nuna babban ƙarfin kashe ƙwayoyin cuta, yana nuna cewa haɗakar ƙwayoyin acrylonitrile da anthracene cikin zoben heterocyclic yana taimakawa ga tasirin maganin kashe ƙwayoyin cuta.
Sinadaran suna da hanyoyi daban-daban na aiki, wasu suna nuna halayen kashe ƙwayoyin cuta wasu kuma suna nuna tasirin bacteriostatic. Sinadaran 7, 11, 13a, da 15 suna kashe ƙwayoyin cuta kuma suna buƙatar ƙananan yawan don kashe ƙwayoyin cuta gaba ɗaya. Sabanin haka, sinadarai 6, 13b, da 14 suna da bacteriostatic kuma suna iya hana haɓakar ƙwayoyin cuta a ƙananan yawan, amma suna buƙatar babban yawan don kashe ƙwayoyin cuta gaba ɗaya.
Gabaɗaya, nazarin dangantakar tsari da aiki ya nuna mahimmancin gabatar da ƙwayoyin acrylonitrile da anthracene da tsarin heterocyclic don cimma babban aikin ƙwayoyin cuta. Waɗannan sakamakon sun nuna cewa inganta waɗannan sassan tsarin da kuma bincika ƙarin gyare-gyare don inganta narkewa da kuma iyawar membrane na iya haifar da haɓaka magungunan anti-MRSA mafi inganci.
An tsarkake dukkan sinadaran da abubuwan da ke narkewa kuma an busar da su ta amfani da hanyoyin da aka saba (El Gomhouria, Egypt). An tantance wuraren narkewa ta amfani da na'urar GallenKamp electronic melt point kuma an bayar da rahotonsu ba tare da gyara ba. An yi rikodin infrared (IR) spectra (cm⁻1) a Sashen Kimiyya, Faculty of Science, Jami'ar Ain Shams ta amfani da potassium bromide (KBr) pellets akan Thermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, Amurka).
An sami spectra na 1H NMR a 300 MHz ta amfani da na'urar auna GEMINI NMR (GEMINI Manufacturing & Engineering, Anaheim, CA, Amurka) da kuma na'urar auna BRUKER 300 MHz NMR (BRUKER Manufacturing & Engineering, Inc.). An yi amfani da Tetramethylsilane (TMS) a matsayin ma'aunin ciki tare da deuterated dimethyl sulfoxide (DMSO-d₆). An yi ma'aunin NMR a Faculty of Science, Jami'ar Cairo, Giza, Masar. An yi nazarin Elemental (CHN) ta amfani da Perkin-Elmer 2400 Elemental Analyzer kuma sakamakon da aka samu ya yi daidai da ƙimar da aka ƙididdige.
An dumama cakuda acid 3 (5 mmol) da thionyl chloride (5 ml) a cikin ruwan wanka a zafin 65 °C na tsawon awanni 4. An cire sinadarin thionyl chloride da ya wuce kima ta hanyar tacewa a ƙarƙashin ƙarancin matsin lamba. An tattara jan ƙarfe da aka samu kuma an yi amfani da shi ba tare da ƙarin tsarkakewa ba. Wurin narkewa: 200-202 °C, yawan amfani: 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. Mai nazari. An ƙididdige don C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. An samo: C, 74.41; H, 3.34; N, 4.66%.
A zafin 0°C, an narkar da 4 (2 mmol, 0.7 g) a cikin dioxane mai hana ruwa (20 ml) sannan aka ƙara hydrazine hydrate (2 mmol, 0.16 ml, 80%) a hankali sannan aka juya na tsawon awa 1. An tattara sinadarin da aka haƙa ta hanyar tacewa sannan aka sake mayar da shi daga ethanol don samar da sinadarin 6.
Kwayar lu'ulu'u kore, wurin narkewa 190-192℃, yawan amfanin ƙasa 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, mai musanya), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Ƙimar da aka ƙididdige don C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. An samo: C, 84.01; H, 4.38; N, 8.05%.
A narke 4 (2 mmol, 0.7 g) a cikin 20 ml na maganin dioxane mai hana ruwa (wanda ke ɗauke da ɗigon triethylamine kaɗan), a ƙara phenylhydrazine/2-aminopyridine (2 mmol) a gauraya a zafin ɗaki na tsawon awanni 1 da 2, bi da bi. A zuba cakudawar a cikin kankara ko ruwa a yi acidify da acid mai narkewar hydrochloric acid. A tace sinadarin da aka raba sannan a sake yin recrystallize daga ethanol don samun 7 sannan a sake yin recrystallize daga benzene don samun 8.
Kwayar lu'ulu'u kore, wurin narkewa 160-162℃, yawan amfanin ƙasa 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, mai musanya), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Ƙimar da aka ƙididdige don C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. An samo: C, 81.96; H, 3.91; N, 8.91%.
An narkar da 4 (2 mmol, 0.7 g) a cikin 20 ml na maganin dioxane mai hana ruwa (wanda ke ɗauke da ɗigon triethylamine kaɗan), an ƙara 2-aminopyridine (2 mmol, 0.25 g) sannan aka juya cakuda a zafin ɗaki na tsawon awanni 2. An zuba cakudawar amsawar a cikin ruwan ƙanƙara kuma an ƙara masa acid mai narkewa da hydrochloric acid. An tace ruwan da ya haifar sannan aka sake mayar da shi daga benzene, yana ba da lu'ulu'u kore na 8 tare da wurin narkewa na 146-148 °C da yawan amfanin ƙasa na 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, mai musanya), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); An ƙididdige don C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. An samo: C, 78.93; H, 3.97; N, 12.36%.
An narkar da mahadi 4 (2 mmol, 0.7 g) a cikin 20 ml na busasshen dioxane (wanda ke ɗauke da ɗigon triethylamine da 2 mmol na thiourea/semicarbazide) sannan aka dumama shi a ƙarƙashin reflux na tsawon awanni 2. An fitar da sinadarin a cikin vacuo. An sake sake haɗa ragowar daga dioxane don samar da cakuda.