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Synton 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yi endliwile naswona yi tirhisiwile ku endla swihlanganisi swo hambana swa heterocyclic leswi tirhaka swinene hi ku tirhisa ku cinca ka yona na ti nucleophiles to hambana ta nitrogen. Xivumbeko xa nkatsakanyo wun’wana na wun’wana wa heterocyclic lowu endliweke xi hlawuriwile hi ku hetiseka hi ku tirhisa nxopaxopo wa spectroscopic na elemental. Khume eka khume nharhu wa ti novhele ta ti heterocyclic compounds ti kombisile ku tirha loku khutazaka eka tibakteriya leti lwisanaka na mirhi yo tala (MRSA). Exikarhi ka swona, ti compounds 6, 7, 10, 13b, na 14 ti kombisile ntirho wale henhla swinene wa antibacterial na ti inhibition zones ekusuhi na 4 cm. Hambiswiritano, tidyondzo ta molecular docking ti paluxile leswaku ti compounds a ti ri na ti binding affinities to hambana eka penicillin-binding protein 2a (PBP2a), xikongomelo xa nkoka xa ku lwisana na MRSA. Ti compounds tin’wana tofana na 7, 10 na 14 ti kombisile bonding affinity yale henhla xikan’we naku tshamiseka ka interaction eka ndzhawu leyi tirhaka ya PBP2a loko ku pimanyisiwa na co-crystallized quinazolinone ligand. Kuhambana na sweswo, ti compounds 6 na 13b atiri na swikoweto swale hansi swa docking kambe tahari na ntirho lowukulu wa antibacterial, laha compound 6 ayi ri na mimpimo yale hansi swinene ya MIC (9.7 μg/100 μL) na MBC (78.125 μg/100 μL). Nxopaxopo wa docking wu paluxe ku tirhisana ka nkoka ku katsa na hydrogen bonding na π-stacking, ngopfu ngopfu na masalela yofana na Lys 273, Lys 316 na Arg 298, lawa ya tivekaka tani hi lawa ya tirhisanaka na co-crystallized ligand eka xivumbeko xa crystal xa PBP2a. Masalela lawa yana nkoka eka ntirho wa enzymatic wa PBP2a. Mimbuyelo leyi yi ringanyeta leswaku swihlanganisi leswi endliweke swi nga tirha tanihi mirhi leyi tshembisaka ya anti-MRSA, leswi kombisaka nkoka wo hlanganisa molecular docking na bioassays ku kuma vahlawuriwa va vutshunguri lava tirhaka.
Eka malembe yosungula ya lembe xidzana leri, matshalatshala ya ndzavisiso ya kongomisiwile ngopfu eka ku tumbuluxa maendlelo yantshwa, yo olova na maendlelo ya ku hlanganisiwa ka ti heterocyclic systems to hlaya ta vutumbuluxi letingana ntirho wa antimicrobial hiku tirhisa switirhisiwa swosungula leswi kumekaka hiku olova.
Ti acrylonitrile moieties ti tekiwa tani hi switirhisiwa swa nkoka swosungula eka ku endliwa ka ti heterocyclic systems totala to hlamarisa hikuva i ti compounds leti tirhaka swinene. Ku tlula kwalaho, swiaki swa 2-cyanoacryloyl chloride swi tirhisiwile ngopfu eka malembe ya sweswinyana eka ku tumbuluxiwa na ku hlanganisiwa ka swikumiwa swa nkoka swinene eka xiyenge xa ​​switirhisiwa swa mirhi, ku fana na switirhisiwa swa le xikarhi swa mirhi1,2,3, swirhange swa anti-HIV, antiviral, anticancer, antibacterial, antidepressant na antioxidant agents4,5,6,7,8,9,10. Sweswinyana, ku tirha kahle ka biological ka anthracene na switirhisiwa swa yona, ku katsa na swidlaya-switsongwatsongwana, anticancer11,12, antibacterial13,14,15 na swivumbeko swa swidlaya-switsotswana16,17, swi koke nyingiso lowukulu18,19,20,21. Swihlanganisi swa antimicrobial leswingana swiphemu swa acrylonitrile na anthracene swikombisiwile eka Swifaniso 1 na 2.
Hi ku ya hi Nhlangano wa Rihanyo wa Misava (WHO) (2021), ku lwisana na switsongwatsongwana (AMR) i nxungeto wa misava hinkwayo eka rihanyo na nhluvukiso22,23,24,25. Vavabyi a va nge tshunguriwi, leswi endlaka leswaku va tshama nkarhi wo leha exibedlhele ni xilaveko xa mirhi yo durha swinene, swin’we ni ku andza ka ku fa ni vulema. Ku pfumaleka ka swidlaya-switsongwatsongwana leswi tirhaka hakanyingi swi endla leswaku vutshunguri byi tsandzeka eka mavabyi yo hambana-hambana, ngopfu-ngopfu hi nkarhi wa vutshunguri bya tikhemikhali ni vuhandzuri lebyikulu.
Hi ku ya hi xiviko xa World Health Organization 2024, Staphylococcus aureus (MRSA) leyi lwisanaka na methicillin na E. coli swi katsiwile eka nxaxamelo wa switsongwatsongwana leswi rhangisaka emahlweni. Tibakteriya leti hatimbirhi ti lwisana ni swidlaya-switsongwatsongwana swo tala, hikwalaho ti yimela mavabyi lama tikaka ku ma tshungula ni ku ma lawula, naswona ku ni xilaveko xa xihatla xo endla swiaki leswintshwa ni leswi tirhaka swa swidlaya-switsongwatsongwana leswaku ku lulamisiwa xiphiqo lexi. Anthracene na switirhisiwa swa yona i swidlaya switsongwatsongwana leswi tivekaka leswinga tirha eka ti bacteria ta Gram-positive na Gram-negative. Xikongomelo xa ndzavisiso lowu i ku hlanganisa xitirhisiwa lexintshwa lexi nga lwisanaka na switsongwatsongwana leswi leswi nga na khombo eka rihanyo.
Nhlangano wa Rihanyo wa Misava Hinkwayo (WHO) wu vika leswaku switsongwatsongwana swo tala swa tibakteriya a swi lwisana ni swidlaya-switsongwatsongwana swo tala, ku katsa ni Staphylococcus aureus (MRSA) leyi lwisanaka ni methicillin, ku nga xivangelo lexi tolovelekeke xa ku tluleriwa emigangeni ni le tindhawini ta nhlayiso wa rihanyo. Vavabyi lava nga na mavabyi ya MRSA va vikiwa ku va na 64% wa mpimo wa le henhla wa ku fa ku tlula lava nga na mavabyi lama nga na vuvabyi bya mirhi. Ku engetela kwalano, E. coli yi tisa khombo ra misava hinkwayo hikuva layini yohetelela ya nsirhelelo eka Enterobacteriaceae leyi lwisanaka na carbapenem (i.e., E. coli) i colistin, kambe ti bacteria leti lwisanaka na colistin ti vikiwile sweswinyana eka matiko yo hlaya. 22,23,24,25
Hikwalaho, hi ku ya hi Pulani ya Matirhelo ya Misava Hinkwayo ya Nhlangano wa Rihanyo wa Misava Hinkwayo eka ku Lwisana na Switsongwatsongwana26, ku na xilaveko xa xihatla xa ku tshuburiwa na ku hlanganisiwa ka swidlaya-switsongwatsongwana leswintshwa. Vuswikoti lebyikulu bya anthracene na acrylonitrile tanihi switirhisiwa swa antibacterial27, antifungal28, anticancer29 na antioxidant30 byi kombisiwile eka maphepha yo tala lama kandziyisiweke. Eka mhaka leyi, swinga vuriwa leswaku switirhisiwa leswi i ti candidates ta kahle eka kutirhisiwa eka methicillin-resistant Staphylococcus aureus (MRSA).
Nxopaxopo wa matsalwa wa khale wu hi susumetele ku hlanganisa switirhisiwa leswintshwa leswi humaka eka titlilasi leti. Hikokwalaho, dyondzo ya sweswi a yi kongomisiwile ku tumbuluxa tisisiteme ta novhele ta heterocyclic leti nga na swiphemu swa anthracene na acrylonitrile, ku kambela ku tirha ka tona ka antimicrobial na antibacterial, na ku lavisisa ku tirhisana ka tona loku nga vaka kona ka ku boha na penicillin-binding protein 2a (PBP2a) hi ku docking molecular. Hi ku aka eka tidyondzo ta khale, dyondzo ya sweswi yi yise emahlweni ku hlanganisiwa, ku kamberiwa ka biological, na nxopaxopo wa xibalo wa tisisiteme ta heterocyclic ku kuma switirhisiwa leswi tshembisaka swa antimethicillin-resistant Staphylococcus aureus (MRSA) leswi nga na matimba ya PBP2a inhibitory ntirho31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Vulavisisi bya hina bya sweswi byi kongomisa eka ku hlanganisiwa na ku kamberiwa ka antimicrobial ka novhele ya ti heterocyclic compounds leti nga na swiphemu swa anthracene na acrylonitrile. 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 yi lulamisiwile no tirhisiwa tani hi xiaki xo aka eka ku akiwa ka tisisiteme ta novhele ta heterocyclic.
Xivumbeko xa compound 4 xikumiwile hiku tirhisa spectral data. 1H-NMR spectrum yi kombisile vukona bya CH= eka 9.26 ppm, IR spectrum yi kombisile vukona bya ntlawa wa carbonyl eka 1737 cm−1 na ntlawa wa cyano eka 2224 cm−1, naswona 13CNMR spectrum yitlhele yi tiyisisa xivumbeko lexi ringanyetiweke (vona xiyenge xa ​​Experimental).
Ku endliwa ka 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 swi endliwile hi hydrolysis ya mintlawa ya aromatic 250, 41, 42, 53 hi ethanolic sodium hydroxide solution (10%) ku nyika ti acids 354, 45, 56, leti endzhaku ti tshunguriweke hi thionyl chloride eka bath ya mati ku nyika acryloyl chloride derivative 4 eka mbuyelo wale henhla (88.5%), tani hileswi swikombisiweke eka Xifaniso xa 3.
Ku tumbuluxa ti heterocyclic compounds tintshwa letingana matimba lawa ya languteriweke ya antibacterial, ku endliwa ka reaction ya acyl chloride 4 na ti dinucleophiles to hambana hambana.
Acid chloride 4 yi cheriwile hi hydrazine hydrate eka 0° kuringana awara yin’we. Khombo ra kona, pyrazolone 5 a yi kumeki. Xiendliwa lexi akuri xiaki xa acrylamide lexi xivumbeko xa xona xi tiyisisiweke hi data ya spectral. IR spectrum ya yona yi kombisile ti absorption bands ta C=O eka 1720 cm−1, C≡N eka 2228 cm−1 na NH eka 3424 cm−1. Xiphemu xa 1H-NMR xi kombisile xikombiso xa exchange singlet xa ti olefin protons na ti NH protons eka 9.3 ppm (vona Xiyenge xa ​​Experimental).
Ti moles timbirhi ta acid chloride 4 ti endliwile na mole yin’we ya phenylhydrazine kuva tinyika N-phenylacryloylhydrazine derivative 7 eka mbuyelo wa kahle (77%) (Xifaniso 5). Xivumbeko xa 7 xi tiyisisiwile hi data ya infrared spectroscopy, leyi kombiseke ku amukeriwa ka mintlawa yimbirhi ya C=O eka 1691 na 1671 cm−1, ku amukeriwa ka ntlawa wa CN eka 2222 cm−1 na ku amukeriwa ka ntlawa wa NH eka 3245 cm−1, naswona spectrum ya yona ya 1H-NMR yi kombisile ntlawa wa CH eka 9.15 na 8.81 ppm na NH proton eka 10.88 ppm (vona xiyenge xa ​​Experimental).
Eka ndzavisiso lowu, ku lavisisiwile ku cinca ka acyl chloride 4 na 1,3-dinucleophiles. Ku tshunguriwa ka acyl chloride 4 hi 2-aminopyridine eka 1,4-dioxane na TEA tani hi base eka mahiselo ya kamara swi nyikile acrylamide derivative 8 (Xifaniso 5), xivumbeko xa yona xi tiviwile hiku tirhisa spectral data. IR spectra yi kombisile ti absorption bands ta cyano leyi ololokeke eka 2222 cm−1, NH eka 3148 cm−1, na carbonyl eka 1665 cm−1; 1H NMR spectra yi tiyisisile vukona bya ti olefin protons eka 9.14 ppm (vona Xiyenge xa ​​Experimental).
Nkatsakanyo wa 4 wu endla nhluvuko na thiourea ku nyika pyrimidinethione 9; nkatsakanyo wa 4 wu endla nhluvuko na thiosemicarbazide ku nyika thiopyrazole derivative 10 (Xifaniso 5). Swivumbeko swa swihlanganisi swa 9 na 10 swi tiyisisiwile hi nxopaxopo wa spectral na elemental (vona xiyenge xa ​​Experimental).
Tetrazine-3-thiol 11 yi lulamisiwile hiku cinca cinca ka compound 4 na thiocarbazide tani hi 1,4-dinucleophile (Xifaniso 5), naswona xivumbeko xa yona xi tiyisisiwile hi spectroscopy na elemental analysis. Eka spectrum ya infrared, C=N bond yi humelerile eka 1619 cm−1. Hi nkarhi lowu fanaka, spectrum ya yona ya 1H-NMR yi hlayise swikombiso swa multiplate swa ti aromatic protons eka 7.78–8.66 ppm na SH protons eka 3.31 ppm (vona Xiyenge xa ​​Experimental).
Acryloyl chloride 4 yi tirhisana na 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, na ethanolamine tani hi 1,4-dinucleophiles ku vumba tisisiteme tintshwa ta heterocyclic (13–16).
Swivumbeko swa swihlanganisi leswi swintshwa leswi endliweke swi tiyisisiwile hi nxopaxopo wa spectral na elemental (vona xiyenge xa ​​Experimental). 2-Hydroxyphenylacrylamide derivative 17 yi kumiwile hi ku endla reaction na 2-aminophenol tani hi dinucleophile (Xifaniso 6), naswona xivumbeko xa yona xi tiyisisiwile hi spectral na elemental analysis. Infrared spectrum ya compound 17 yi kombisile leswaku swikombiso swa C=O na C≡N swi humelerile eka 1681 na 2226 cm−1, hi ku landzelelana. Hi nkarhi wolowo, spectrum ya yona ya 1H-NMR yi hlayise xikombiso xa singlet xa proton ya olefin eka 9.19 ppm, naswona proton ya OH yi humelerile eka 9.82 ppm (vona xiyenge xa ​​Experimental).
Ku cinca ka acid chloride 4 na nucleophile yin’we (xikombiso, ethylamine, 4-toluidine, na 4-methoxyaniline) eka dioxane tani hi solvent na TEA tani hi catalyst eka mahiselo ya kamara swi nyikile green crystalline acrylamide derivatives 18, 19a, na 19b. Data ya elemente na spectral ya ti compounds 18, 19a, na 19b yi tiyisisile swivumbeko swa swiaki leswi (vona Xiyenge xa ​​Experimental) (Xifaniso 7).
Endzhaku ko kambela ntirho wa antimicrobial wa swihlanganisi swohambana hambana swa synthetic, mbuyelo wohambana wukumeke tani hileswi swikombisiweke eka Tafula ra 1 na Xifaniso xa 8 (vona fayili ya xifaniso). Ti compounds hinkwato leti kamberiweke ti kombisile ti degree to hambana ta ku sivela eka Gram-positive bacterium MRSA, kasi Gram-negative bacterium Escherichia coli yi kombisile ku lwisana loku heleleke eka ti compounds hinkwato. Ti compounds leti kamberiweke tinga avanyisiwa hi swiyenge swinharhu kuya hi diameter ya inhibition zone eka MRSA. Xiyenge xo sungula a xi tirha ngopfu naswona a xi ri na swihlanganisi swa ntlhanu (6, 7, 10, 13b na 14). Diameter ya inhibition zone ya ti compounds leti ayi ri ekusuhi na 4 cm; swihlanganisi leswi tirhaka ngopfu eka xiyenge lexi a ku ri swihlanganisi swa 6 na 13b. Xiyenge xa ​​vumbirhi a xi tirha hi ku ringanela naswona a xi ri na swihlanganisi swin’wana swa ntlhanu (11, 13a, 15, 18 na 19a). Ndzhawu ya inhibition ya ti compounds leti ayi sukela eka 3.3 kuya eka 3.65 cm, laha compound 11 yikombisa ndzhawu leyikulu swinene ya inhibition ya 3.65 ± 0.1 cm. Hi tlhelo rin’wana, ntlawa wohetelela awuri na ti compounds tinharhu (8, 17 na 19b) letingana ntirho wale hansi swinene wa antimicrobial (ehansi ka 3 cm). Xifaniso xa 9 xi kombisa ku hangalaka ka tindzhawu to hambana ta ku sivela.
Vulavisisi byin’wana bya ntirho wa antimicrobial wa ti compounds leti kamberiweke byi katsa ku kumiwa ka MIC na MBC eka compound yin’wana na yin’wana. Mimbuyelo yi hambanile nyana (hilaha swi kombisiweke hakona eka Tithebulu ta 2, 3 na Xifaniso xa 10 (vona fayili ya xifaniso)), laha swihlanganisi swa 7, 11, 13a na 15 swi vonakaka swi hlayisiwile nakambe tanihi swihlanganisi leswinene. Va vile na mimpimo yale hansi ya MIC na MBC leyi fanaka (39.06 μg/100 μL). Hambi leswi ti compounds ta 7 na 8 a ti ri na mimpimo ya le hansi ya MIC (9.7 μg/100 μL), mimpimo ya tona ya MBC a yi ri ehenhla (78.125 μg/100 μL). Hikwalaho, a ti tekiwa ti tsanile ku tlula swihlanganisi leswi boxiweke eku sunguleni. Hambiswiritano, swihlanganisi leswi swa tsevu aswi tirha swinene eka leswi kamberiweke, tani hileswi mimpimo ya swona ya MBC ayi ri ehansi ka 100 μg/100 μL.
Ti compounds (10, 14, 18 na 19b) ati tirhi ngopfu loko ti pimanyisiwa na ti compounds tin’wana leti kamberiweke tani hileswi mimpimo ya tona ya MBC ayi sukela eka 156 kuya eka 312 μg/100 μL. Hi tlhelo rin’wana, ti compounds (8, 17 na 19a) ati tshembisa ngopfu tani hileswi atiri na mimpimo yale henhla ya MBC (625, 625 na 1250 μg/100 μL, hiku landzelelana).
Eku heteleleni, kuya hi swiyimo swa ku tiyisela leswi kombisiweke eka Tafula ra 3, swihlanganisi leswi kamberiweke swinga avanyisiwa hi swiyenge swimbirhi kuya hi ndlela ya swona yo tirha: swihlanganisi leswingana mbuyelo wo dlaya tibakteriya (7, 8, 10, 11, 13a, 15, 18, 19b) na swihlanganisi leswingana mbuyelo wo lwisana na tibakteriya (6, 13b, 14, 17, 19a). Exikarhi ka swona, ti compounds 7, 11, 13a na 15 ta tsakeriwa, leti kombisaka ntirho wo dlaya eka nhlayo yale hansi swinene (39.06 μg/100 μL).
Khume eka khume-nharhu wa swihlanganisi leswi kamberiweke swi kombisile vuswikoti byo lwisana na Staphylococcus aureus (MRSA) leyi lwisanaka na methicillin leyi lwisanaka na swidlaya-switsongwatsongwana. Hikokwalaho, ku kamberiwa kun’wana na ti pathogens leti lwisanaka na antibiotic swinene (ngopfu ngopfu ti local isolates leti funengetaka ti pathogenic Gram-positive na Gram-negative bacteria) na ti pathogenic yeasts swa hlohleteriwa, xikan’we na ku kamberiwa ka cytotoxic ka compound yin’wana na yin’wana ku kambela vuhlayiseki bya yona.
Tidyondzo ta molecular docking ti endliwile ku kambela vuswikoti bya swihlanganisi leswi endliweke tani hi swisivela swa penicillin-binding protein 2a (PBP2a) eka methicillin-resistant Staphylococcus aureus (MRSA). PBP2a i enzyme ya nkoka leyi katsekaka eka biosynthesis ya rirhangu ra tisele ta tibakteriya, naswona ku sivela enzyme leyi swi kavanyeta ku tumbuluxiwa ka rirhangu ra tisele, eku heteleleni swi yisa eka lysis ya tibakteriya na ku fa ka tisele1. Mimbuyelo ya docking yi xaxametiwile eka Tafula ra 4 naswona yi hlamuseriwile hi vuxokoxoko eka fayili ya data yo engetela, naswona mbuyelo wu kombisa leswaku ti compounds to hlaya ti kombisile ku boha loku tiyeke eka PBP2a, ngopfu ngopfu masalela ya ndzhawu leyi tirhaka ya nkoka yo fana na Lys 273, Lys 316, na Arg 298. Ku tirhisana, ku katsa na ku boha ka hayidirojeni na π-stacking, a swi fana swinene na swa co-crystallized quinazolinone ligand (CCL), leswi kombisaka vuswikoti bya swihlanganisi leswi tani hi swisivela swa matimba.
Data ya molecular docking, xikan’we na ti parameter tin’wana ta xibalo, yi ringanyete swinene leswaku PBP2a inhibition akuri endlelo ra nkoka leri nga na vutihlamuleri eka ntirho lowu xiyiweke wa antibacterial wa ti compounds leti. Swikoweto swa docking na mimpimo ya root mean square deviation (RMSD) swi tlhele swi paluxa ku boha affinity na ku tshamiseka, leswi seketelaka xiringanyeto lexi. Tani hilaha swikombisiweke hakona eka Tafula ra 4, loko ti compounds to hlaya ti kombisile ku boha lokunene, ti compounds tin’wana (xikombiso, 7, 9, 10, na 14) atiri na swikoweto swale henhla swa docking kutlula co-crystallized ligand, leswi kombisaka leswaku tingava na vuhlanganisi byo tiya na masalela ya ndzhawu leyi tirhaka ya PBP2a. Hambiswiritano, ti bioactive compounds 6 na 13b ti kombisile ti docking scores tale hansi nyana (-5.98 na -5.63, hiku landzelelana) loko ku pimanyisiwa na ti ligands tin’wana. Leswi swikomba leswaku hambi leswi ti docking scores tinga tirhisiwaka ku vhumbha binding affinity, swin’wana (xikombiso, ligand stability xikan’we na molecular interactions eka ndzhawu ya biological) na swona swina xiave xa nkoka eka ku kumisisa ntirho wa antibacterial. Lexi xiyekaka, mimpimo ya RMSD ya ti compounds hinkwato leti endliweke ayiri ehansi ka 2 Å, leswi tiyisisaka leswaku ti docking poses ta tona ti fambelana hi xivumbeko na binding conformation ya co-crystallized ligand, leswi yaka emahlweni swi seketela vuswikoti bya tona tani hi ti PBP2a inhibitors ta matimba.
Hambi leswi swikoweto swa docking na mimpimo ya RMS swi nyikaka vuprofeta bya nkoka, ku yelana exikarhi ka mbuyelo lowu wa docking na ntirho wa antimicrobial a hi minkarhi hinkwayo swi nga erivaleni loko u swi languta ro sungula. Hambi leswi ku sivela ka PBP2a ku seketeriwaka swinene tani hi nchumu wa nkoka lowu khumbhaka ntirho wa antimicrobial, ku hambana ko hlayanyana ku ringanyeta leswaku swivumbeko swin’wana swa biological na swona swi tlanga xiave xa nkoka. Ti compounds 6 na 13b ti kombisile ntirho wale henhla swinene wa antimicrobial, laha havumbirhi bya tona ti inhibition zone diameter ya 4 cm xikan’we na mimpimo yale hansi swinene ya MIC (9.7 μg/100 μL) na MBC (78.125 μg/100 μL), hambi leswi ti docking scores ta tona tale hansi loko ku pimanyisiwa na ti compounds 7, 9, 10 na 14. Leswi swikomba leswaku hambi leswi PBP2a ku sivela swi hoxa xandla eka ntirho wa antimicrobial, swilo swofana na solubility, bioavailability xikan’we na interaction dynamics eka ndzhawu ya ti bacteria na swona swikucetela ntirho hinkwawo. Xifaniso xa 11 xi kombisa swiyimo swa tona swa docking, leswi kombisaka leswaku ti compounds leti hatimbirhi, hambi kuri na swikoweto swa le hansi swa ku boha, ta ha kota ku tirhisana na masalela ya nkoka ya PBP2a, leswi nga ha tiyisisaka inhibition complex. Leswi swi kombisa leswaku hambi leswi molecular docking yi nyikaka vutivi bya nkoka eka ku sivela ka PBP2a, swilo swin’wana swa biological swifanele ku tekeriwa enhlokweni kuva switwisisa hiku hetiseka mbuyelo wa xiviri wa antimicrobial wa ti compounds leti.
Hiku tirhisa xivumbeko xa crystal xa PBP2a (PDB ID: 4CJN), mimepe ya vuhlanganisi bya 2D na 3D ya ti compounds leti tirhaka swinene 6 na 13b leti dockiweke na penicillin-binding protein 2a (PBP2a) ya methicillin-resistant Staphylococcus aureus (MRSA) yi akiwile. Mepe lowu wu pimanisa swivumbeko swa ku tirhisana ka swihlanganisi leswi na re-docked co-crystallized quinazolinone ligand (CCL), leswi kombisaka ku tirhisana ka nkoka ku fana na ku hlanganisiwa ka hayidirojeni, π-stacking, na ku tirhisana ka ionic.
Xivumbeko lexi fanaka xi voniwile eka compound 7, leyi kombiseke docking score yale henhla swinene (-6.32) xikan’we na inhibition zone diameter leyi fanaka (3.9 cm) kuya eka compound 10. Hambiswiritano, MIC ya yona (39.08 μg/100 μL) na MBC (39.06 μg/100 μL) ayiri e henhla swinene, leswi kombaka leswaku yilava nhlayo yale henhla kuva yi kombisa mbuyelo wa antibacterial. Leswi swikomba leswaku hambi leswi compound 7 yi kombiseke ku boha loku tiyeke eka tidyondzo ta docking, swilo swofana na bioavailability, cellular uptake, kumbe swin’wana swa physicochemical properties swinga hunguta ku tirha ka yona ka biological. Hambi leswi compound 7 yi kombiseke swivumbeko swa bactericidal, ayi tirhi ngopfu eka ku sivela kukula ka ti bacteria loko ku pimanyisiwa na compounds 6 na 13b.
Compound 10 yi kombisile ku hambana lokukulu swinene na docking score yale henhla (-6.40), leswi kombisaka strong binding affinity eka PBP2a. Hambiswiritano, zone ya yona ya inhibition diameter (3.9 cm) ayi ringanisiwa na compound 7, naswona MBC ya yona (312 μg/100 μL) ayi tlakukile swinene kutlula compounds 6, 7, na 13b, leswi kombaka ntirho wo dlaya tibakteriya lowu tsaneke. Leswi swikomba leswaku hambi leswi ku nga na vuprofeta bya kahle bya docking, compound 10 ayi tirhi ngopfu eka ku dlaya MRSA hikokwalaho ka swin’wana leswi sivelaka kufana na solubility, stability, kumbe ku nga ngheni kahle ka membrane ya bacteria. Mimbuyelo leyi yi seketela ku twisisa leswaku hambi leswi ku sivela ka PBP2a ku tlangaka xiave xa nkoka eka ntirho wa antibacterial, a swi hlamuseli hi ku hetiseka ku hambana eka ntirho wa biological lowu voniweke exikarhi ka swihlanganisi leswi kamberiweke. Ku hambana loku ku ringanyeta leswaku minxopaxopo yin’wana ya swikambelo na ku kamberiwa loku dzikeke ka biological swa laveka ku paluxa hi ku hetiseka tindlela ta antibacterial leti katsekaka.
Mimbuyelo ya ku dokiwa ka timolekhuli eka Tafula ra 4 na Fayili ya Datha yo Engetela yi kombisa vuxaka lebyi rharhanganeke exikarhi ka swikoweto swa docking na ntirho wa antimicrobial. Hambi leswi ti compounds 6 na 13b tingana ti docking scores tale hansi kutlula ti compounds 7, 9, 10, na 14, ti kombisa ntirho wale henhla swinene wa antimicrobial. Mepe wa vona wa ku tirhisana (lowu kombisiweke eka Xifaniso xa 11) wu kombisa leswaku hambi leswi swikoweto swa vona swa le hansi swa ku boha, va ha vumba swihlanganisi swa nkoka swa hayidirojeni na ku tirhisana ka π-stacking na masalela ya nkoka ya PBP2a lawa ya nga tiyisisaka enzyme-inhibitor complex hi ndlela leyi pfunaka hi tlhelo ra biological. Hambi leswi swikoweto swale hansi swa docking swa 6 na 13b, ntirho wa tona lowu antswisiweke wa antimicrobial wu ringanyeta leswaku swivumbeko swin’wana swofana na solubility, stability, na cellular uptake swifanele ku tekeriwa enhlokweni xikan’we na data ya docking loko ku kamberiwa vuswikoti bya inhibitor. Leswi swi kombisa nkoka wo hlanganisa tidyondzo ta docking na experimental antimicrobial analysis ku kambela kahle vuswikoti bya vutshunguri bya ti compounds tintshwa.
Mimbuyelo leyi yi kombisa leswaku hambi leswi molecular docking yinga xitirhisiwa xa matimba xo vhumbha ku boha affinity xikan’we naku kuma tindlela letinga kona ta ku sivela, aswifanelanga ku tshembiwa ntsena ku kumisisa ku tirha kahle ka antimicrobial. Data ya molekyuli yi ringanyeta leswaku ku sivela ka PBP2a i nchumu wa nkoka lowu khumbhaka ntirho wa antimicrobial, kambe ku cinca eka ntirho wa biological swi ringanyeta leswaku swivumbeko swin’wana swa physicochemical na pharmacokinetic swi fanele ku antswisiwa ku ndlandlamuxa ku tirha kahle ka vutshunguri. Tidyondzo ta nkarhi lowu taka tifanele ku kongomisa eka ku antswisa xivumbeko xa tikhemikhali ta ti compounds 7 na 10 ku antswisa bioavailability xikan’we naku amukeriwa ka ti cellular, ku tiyisisa leswaku ku tirhisana ka docking yo tiya ku hundzuluxeriwa eka ntirho wa xiviri wa antimicrobial. Tidyondzo tin’wana, ku katsa na ti bioassays to engetela na nxopaxopo wa vuxaka bya xivumbeko-ntirho (SAR), swi ta va swa nkoka swinene ku yisa emahlweni ku twisisa ka hina ka ndlela leyi swihlanganisi leswi swi tirhaka ha yona tanihi swisivela swa PBP2a na ku tumbuluxa switirhisiwa swa antimicrobial leswi tirhaka swinene.
Ti compounds leti endliweke kusuka eka 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ti kombisile ti degree to hambana ta ntirho wa antimicrobial, laha ti compounds to hlaya ti kombisaka ku sivela lokukulu ka methicillin-resistant Staphylococcus aureus (MRSA). Nxopaxopo wa vuxaka bya xivumbeko-ntirho (SAR) wu paluxe swihlawulekisi swa nkoka swa xivumbeko leswi nga ehansi ka ku tirha kahle ka antimicrobial ka swihlanganisi leswi.
Kuva kona ka mintlawa ya acrylonitrile na anthracene switikombise swiri swa nkoka swinene eka ku ndlandlamuxa ntirho wa antimicrobial. Ntlawa wa nitrile lowu hlamulaka swinene eka acrylonitrile wa laveka ku olovisa ku tirhisana na ti protein ta ti bacteria, xisweswo wu hoxa xandla eka swivumbeko swa antimicrobial swa compound. Ti compounds letingana acrylonitrile na anthracene ti tshama tiri karhi ti kombisa mbuyelo wo tiya wa antimicrobial. Ku nun’hwela ka ntlawa wa anthracene switlhele swi tiyisisa ti compounds leti, leswinga antswisa ntirho wa tona wa biological.
Ku nghenisiwa ka ti heterocyclic rings swi antswise swinene ku tirha kahle ka antibacterial ka switirhisiwa swo hlaya leswi humaka eka swona. Ngopfu ngopfu, benzothiazole derivative 13b na acrylhydrazide derivative 6 swikombe ntirho wale henhla swinene wa antibacterial na ndzhawu yo sivela ya kwalomu ka 4 cm. Ti heterocyclic derivatives leti ti kombisile switandzhaku swa nkoka swinene swa biological, leswi kombaka leswaku xivumbeko xa heterocyclic xi tlanga xiave xa nkoka eka switandzhaku swa antibacterial. Hilaha ku fanaka, pyrimidinethione eka nkatsakanyo wa 9, thiopyrazole eka nkatsakanyo wa 10, na tetrazine ring eka nkatsakanyo wa 11 swi hoxe xandla eka swivumbeko swa antibacterial swa swihlanganisi, leswi yaka emahlweni swi kombisa nkoka wa ku cinca ka heterocyclic.
Exikarhi ka ti compounds leti endliweke, 6 na 13b ti humelerile hi mintirho ya tona ya kahle swinene ya antibacterial. Nhlayo yale hansi ya inhibitory (MIC) ya compound 6 akuri 9.7 μg/100 μL, naswona nhlayo yale hansi ya bactericidal (MBC) akuri 78.125 μg/100 μL, leswi kombisaka vuswikoti bya yona bya kahle swinene byo basisa methicillin-resistant Staphylococcus aureus (MRSA). Hilaha ku fanaka, compound 13b ayiri na ndzhawu yo sivela ya 4 cm na mimpimo yale hansi ya MIC na MBC, leswi tiyisisaka ntirho wa yona wa matimba wa antibacterial. Mimbuyelo leyi yi kombisa mintirho ya nkoka ya mintlawa ya ntirho ya acrylohydrazide na benzothiazole eka ku kumisisa bioefficacy ya swihlanganisi leswi.
Kuhambana na sweswo, ti compounds 7, 10, na 14 ti kombisile ntirho wo ringanela wa antibacterial na ti inhibition zones kusuka eka 3.65 kuya eka 3.9 cm. Ti compounds leti ati lava nhlayo yale henhla kuva ti dlaya ti bacteria hiku hetiseka, tani hileswi swikombisiweke hi mimpimo ya tona yale henhla swinene ya MIC na MBC. Hambi leswi swihlanganisi leswi aswinga tirhi ngopfu kutlula swihlanganisi swa 6 na 13b, swahari na vuswikoti lebyikulu bya antibacterial, leswi kombaka leswaku ku nghenisiwa ka swiphemu swa acrylonitrile na anthracene eka ring ya heterocyclic swi hoxa xandla eka mbuyelo wa swona wa antibacterial.
Ti compounds tina tindlela tohambana hambana ta ntirho, tin’wana ti kombisa swivumbeko swa bactericidal kasi tin’wana ti kombisa mbuyelo wa bacteriostatic. Swihlanganisi swa 7, 11, 13a na 15 swi dlaya tibakteriya naswona swi lava mpimo wa le hansi leswaku swi dlaya tibakteriya hi ku helela. Kuhambana na sweswo, ti compounds 6, 13b na 14 ti bacteriostatic naswona tinga sivela kukula ka ti bacteria eka nhlayo yale hansi, kambe ti lava nhlayo yale henhla kuva ti dlaya ti bacteria hiku hetiseka.
Hiku angarhela, nxopaxopo wa vuxaka bya xivumbeko-ntirho wu kombisa nkoka wo nghenisa swiphemu swa acrylonitrile na anthracene na swivumbeko swa heterocyclic ku fikelela ntirho lowukulu wa antibacterial. Mimbuyelo leyi yi ringanyeta leswaku ku antswisiwa ka swiphemu leswi swa xivumbeko na ku lavisisa ku cinca kun’wana ku antswisa ku n’oka na ku nghenelela ka membrane swi nga yisa eka ku tumbuluxiwa ka mirhi leyi tirhaka swinene ya anti-MRSA.
Ti reagents hinkwato nati solvents ti basisiwile naku omisiwa hiku tirhisa maendlelo ya ntolovelo (El Gomhouria, Egypt). Tindhawu to n’oka tikumiwile hiku tirhisa xitirhisiwa xa GallenKamp electronic melting point apparatus naswona ti vikiwa handle ko lulamisiwa. Ti spectra ta infrared (IR) (cm−1) ti rhekhodiwile eka Ndzawulo ya Tikhemikhali, Faculty of Science, Ain Shams University hiku tirhisa ti pellets ta potassium bromide (KBr) eka Thermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
1H NMR spectra yi kumiwile eka 300 MHz hiku tirhisa GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) na BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.). Tetramethylsilane (TMS) yitirhisiwile tani hi standard yale ndzeni na deuterated dimethyl sulfoxide (DMSO-d3). Ku pimiwa ka NMR ku endliwile eFaculty of Science, Yunivhesiti ya Cairo, Giza, Egypt. Nxopaxopo wa elemente (CHN) wu endliwile hiku tirhisa Perkin-Elmer 2400 Elemental Analyzer naswona mbuyelo lowu kumiweke wu pfumelelana kahle na mimpimo leyi hlayiweke.
Nkatsakanyo wa acid 3 (5 mmol) na thionyl chloride (5 ml) wu hisiwa eka bath ya mati eka 65 °C kuringana 4 h. Thionyl chloride leyi tlulaka mpimo yi susiwile hi distillation ehansi ka ntshikelelo lowu hungutiweke. Xiphemu xo tshwuka lexi humeleleke xi hlengeletiwile kutani xi tirhisiwa handle ko basisiwa kun’wana. Nhlayo ya ku n’oka: 200-202 °C, mbuyelo: 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, ku endliwa ka swilo leswi nga ni nun’hwelo wa 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. Muhlahluvi. Ku hlayiwile eka C18H10ClNO (291.73): C, 74.11; H, 3,46, naswona 3,46; N, 4,80. Ku kumiwile: C, 74,41; H, 3,34, naswona 3,34; N, 4.66%.
Eka 0°C, 4 (2 mmol, 0.7 g) yi pfanganisiwile na anhydrous dioxane (20 ml) naswona hydrazine hydrate (2 mmol, 0.16 ml, 80%) yi cheriwile hi mathonsi kutani yi hlanganisiwa kuringana 1 h. Xiphemu lexi tiyeke lexi khulukaka xi hlengeletiwile hiku sefa kutani xi recrystallized kusuka eka ethanol kuva xinyika compound 6.
Ti crystals ta rihlaza, melting point 190-192°C, ti humesa 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, ku cincana), 7,69-8,51 (m, 18H, heteroaromatic), 9,16 (s, 1H, CH=), 8,54 (s, 1H, CH=); Nhlayo leyi hlayiweke ya C33H21N3O (475.53): C, 83.35; H, 4,45, naswona 4,45; N, 8,84. Ku kumiwile: C, 84,01; H, 4,38, naswona 4,38; N, 8,05%.
N’okisa 4 (2 mmol, 0.7 g) eka 20 ml ya anhydrous dioxane solution (leyingana mathonsi nyana ya triethylamine), chela phenylhydrazine/2-aminopyridine (2 mmol) kutani u hlanganisa eka mahiselo ya kamara kuringana 1 na 2 h, hiku landzelelana. Chela nkatsakanyo wa reaction eka ayisi kumbe mati kutani u acidify hi dilute hydrochloric acid. Sefa solid leyi hambanisiweke kutani u recrystallize kusuka eka ethanol kuva u kuma 7 kutani u recrystallize kusuka eka benzene kuva u kuma 8.
Ti crystals ta rihlaza, melting point 160-162°C, ti humesa 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, ku cincana), 9,15 (s, 1H, CH=), 8,81 (s, 1H, CH=), 6.78-8,58 (m, 23H, heteroaromatic); Nhlayo leyi hlayiweke ya C42H26N4O2 (618.68): C, 81.54; H, 4,24, naswona 4,24; N, 9.06. Ku kumiwile: C, 81,96; H, 3,91, naswona 3,91; N, 8.91%.
4 (2 mmol, 0.7 g) yi pfanganisiwile na 20 ml ya anhydrous dioxane solution (leyi nga na mathonsi nyana ya triethylamine), 2-aminopyridine (2 mmol, 0.25 g) yi cheriwile naswona nkatsakanyo wu hlanganisiwile eka mahiselo ya kamara kuringana 2 h. Nkatsakanyo wa reaction wu cheriwile eka mati ya ayisi kutani wu acidified hi dilute hydrochloric acid. Precipitate leyi vumbiweke yi sefiwile kutani yi recrystallized kusuka eka benzene, leswinga nyika ti crystals ta rihlaza ta 8 letingana melting point ya 146-148 °C xikan’we na mbuyelo wa 82.5%; spektrum ya infrared (KBr) ν: 3148 (NH), 2222 (C≡N), 1665 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ (ppm): 8.78 (s, H, NH, ku cincana), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); Ku hlayiwile eka C23H15N3O (348.38): C, 79.07; H, 4,33, naswona 4,33; N, 12.03. Ku kumiwile: C, 78,93; H, 3,97, naswona 3,97; N, 12,36%.
Compound 4 (2 mmol, 0.7 g) yi pfanganisiwile na 20 ml ya dioxane yo oma (leyi nga na mathonsi nyana ya triethylamine na 2 mmol ya thiourea/semicarbazide) kutani yi hisiwa ehansi ka reflux kuringana 2 h. Solvent yi pfaleriwile eka vacuum. Masalela ya recrystallized kusuka eka dioxane kuva ya nyika nkatsakanyo.