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Cov synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 tau tsim thiab siv los tsim ntau yam khoom sib xyaw heterocyclic uas muaj zog heev los ntawm nws cov tshuaj tiv thaiv nrog ntau yam nitrogen nucleophiles. Cov qauv ntawm txhua yam khoom sib xyaw heterocyclic tau piav qhia txog kev siv spectroscopic thiab elemental analysis. Kaum ntawm kaum peb yam khoom sib xyaw heterocyclic tshiab tau qhia txog kev ua haujlwm zoo tiv thaiv cov kab mob multidrug-resistant bacteria (MRSA). Ntawm lawv, cov khoom sib xyaw 6, 7, 10, 13b, thiab 14 tau qhia txog kev ua haujlwm antibacterial siab tshaj plaws nrog thaj chaw inhibition ze li 4 cm. Txawm li cas los xij, kev tshawb fawb molecular docking tau qhia tias cov khoom sib xyaw muaj kev sib txuas sib txawv rau penicillin-binding protein 2a (PBP2a), lub hom phiaj tseem ceeb rau kev tiv thaiv MRSA. Qee cov khoom sib xyaw xws li 7, 10 thiab 14 tau qhia txog kev sib txuas siab dua thiab kev sib cuam tshuam ruaj khov ntawm qhov chaw ua haujlwm ntawm PBP2a piv rau cov co-crystallized quinazolinone ligand. Qhov sib piv, cov tshuaj 6 thiab 13b muaj cov qhab nia docking qis dua tab sis tseem ua rau pom cov tshuaj tua kab mob tseem ceeb, nrog rau cov tshuaj 6 muaj cov nqi MIC qis tshaj plaws (9.7 μg / 100 μL) thiab MBC (78.125 μg / 100 μL). Kev tshuaj xyuas docking tau qhia txog kev sib cuam tshuam tseem ceeb suav nrog hydrogen bonding thiab π-stacking, tshwj xeeb tshaj yog nrog cov residues xws li Lys 273, Lys 316 thiab Arg 298, uas tau txheeb xyuas tias cuam tshuam nrog cov co-crystallized ligand hauv cov qauv siv lead ua ntawm PBP2a. Cov residues no yog qhov tseem ceeb rau kev ua haujlwm enzymatic ntawm PBP2a. Cov txiaj ntsig no qhia tau hais tias cov tshuaj synthesized yuav ua haujlwm ua cov tshuaj tiv thaiv MRSA cog lus, qhia txog qhov tseem ceeb ntawm kev sib xyaw ua ke molecular docking nrog bioassays los txheeb xyuas cov neeg sib tw kho mob zoo.
Nyob rau ob peb xyoos thawj zaug ntawm lub xyoo pua no, kev tshawb fawb tau tsom mus rau kev tsim cov txheej txheem tshiab, yooj yim thiab cov txheej txheem rau kev tsim ntau lub tshuab heterocyclic tshiab nrog kev ua haujlwm antimicrobial siv cov ntaub ntawv pib yooj yim.
Acrylonitrile moieties raug suav hais tias yog cov khoom siv pib tseem ceeb rau kev tsim ntau lub cev heterocyclic zoo kawg vim tias lawv yog cov tshuaj uas muaj zog heev. Ntxiv mus, 2-cyanoacryloyl chloride derivatives tau siv dav hauv xyoo tas los no rau kev tsim thiab tsim cov khoom tseem ceeb hauv kev siv tshuaj, xws li cov tshuaj nruab nrab1,2,3, cov khoom ua ntej ntawm anti-HIV, antiviral, anticancer, antibacterial, antidepressant thiab antioxidant agents4,5,6,7,8,9,10. Tsis ntev los no, kev ua haujlwm ntawm anthracene thiab nws cov derivatives, suav nrog lawv cov tshuaj tua kab mob, anticancer11,12, antibacterial13,14,15 thiab cov khoom tua kab16,17, tau nyiam ntau qhov kev saib xyuas18,19,20,21. Cov tshuaj tua kab mob uas muaj acrylonitrile thiab anthracene moieties tau qhia hauv Daim Duab 1 thiab 2.
Raws li Lub Koom Haum Kev Noj Qab Haus Huv Ntiaj Teb (WHO) (2021), kev tiv thaiv kab mob (AMR) yog qhov kev hem thawj thoob ntiaj teb rau kev noj qab haus huv thiab kev loj hlob22,23,24,25. Cov neeg mob tsis tuaj yeem kho tau, ua rau nyob hauv tsev kho mob ntev dua thiab xav tau cov tshuaj kim dua, nrog rau kev tuag thiab kev tsis taus ntxiv. Qhov tsis muaj cov tshuaj tua kab mob zoo feem ntau ua rau kev kho mob tsis ua tiav rau ntau yam kab mob, tshwj xeeb tshaj yog thaum lub sijhawm kho mob chemotherapy thiab phais loj.
Raws li daim ntawv tshaj tawm ntawm Lub Koom Haum Kev Noj Qab Haus Huv Ntiaj Teb xyoo 2024, cov kab mob Staphylococcus aureus (MRSA) thiab E. coli uas tiv taus methicillin suav nrog hauv daim ntawv teev cov kab mob tseem ceeb. Ob hom kab mob no tiv taus ntau yam tshuaj tua kab mob, yog li lawv sawv cev rau cov kab mob uas nyuaj kho thiab tswj, thiab muaj qhov xav tau ceev ceev los tsim cov tshuaj tua kab mob tshiab thiab zoo los daws qhov teeb meem no. Anthracene thiab nws cov derivatives yog cov tshuaj tua kab mob paub zoo uas tuaj yeem ua haujlwm rau ob qho tib si Gram-positive thiab Gram-negative bacteria. Lub hom phiaj ntawm txoj kev tshawb fawb no yog los tsim cov derivative tshiab uas tuaj yeem tawm tsam cov kab mob no uas txaus ntshai rau kev noj qab haus huv.
Lub Koom Haum Kev Noj Qab Haus Huv Ntiaj Teb (WHO) tau tshaj tawm tias ntau tus kab mob bacterial pathogens tiv taus ntau yam tshuaj tua kab mob, suav nrog methicillin-resistant Staphylococcus aureus (MRSA), uas yog ib qho ua rau muaj kev kis kab mob hauv zej zog thiab chaw kho mob. Cov neeg mob uas muaj tus kab mob MRSA tau tshaj tawm tias muaj tus nqi tuag siab dua 64% dua li cov neeg uas muaj tus kab mob uas cuam tshuam nrog tshuaj. Tsis tas li ntawd, E. coli muaj kev pheej hmoo thoob ntiaj teb vim tias kab kawg ntawm kev tiv thaiv tawm tsam carbapenem-resistant Enterobacteriaceae (piv txwv li, E. coli) yog colistin, tab sis cov kab mob uas tiv taus colistin tau tshaj tawm tsis ntev los no hauv ntau lub tebchaws. 22, 23, 24, 25
Yog li ntawd, raws li Lub Koom Haum Ntiaj Teb Kev Noj Qab Haus Huv Txoj Kev Npaj Ua Haujlwm Thoob Ntiaj Teb rau Kev Tiv Thaiv Kab Mob26, muaj qhov xav tau ceev ceev rau kev tshawb pom thiab kev tsim cov tshuaj tua kab mob tshiab. Lub peev xwm loj ntawm anthracene thiab acrylonitrile ua cov tshuaj tua kab mob27, antifungal28, anticancer29 thiab antioxidant30 tau raug hais txog hauv ntau daim ntawv tshaj tawm. Hauv qhov no, nws tuaj yeem hais tias cov derivatives no yog cov neeg sib tw zoo rau kev siv tawm tsam methicillin-resistant Staphylococcus aureus (MRSA).
Cov kev tshuaj xyuas cov ntaub ntawv yav dhau los tau txhawb kom peb tsim cov khoom siv tshiab hauv cov chav kawm no. Yog li ntawd, kev tshawb fawb tam sim no tsom mus rau kev tsim cov kab ke heterocyclic tshiab uas muaj anthracene thiab acrylonitrile moieties, ntsuas lawv cov tshuaj tua kab mob thiab cov tshuaj tua kab mob, thiab tshawb nrhiav lawv cov kev sib cuam tshuam nrog penicillin-binding protein 2a (PBP2a) los ntawm molecular docking. Los ntawm kev tshawb fawb yav dhau los, kev tshawb fawb tam sim no txuas ntxiv kev tsim, kev ntsuam xyuas kab mob, thiab kev tshuaj xyuas kev suav ntawm cov kab ke heterocyclic los txheeb xyuas cov neeg sawv cev antimethicillin-resistant Staphylococcus aureus (MRSA) uas muaj zog PBP2a inhibitory activity31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Peb cov kev tshawb fawb tam sim no tsom mus rau kev tsim thiab kev soj ntsuam cov tshuaj tua kab mob ntawm cov tshuaj heterocyclic tshiab uas muaj cov tshuaj anthracene thiab acrylonitrile moieties. 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 tau npaj thiab siv ua lub hauv paus rau kev tsim cov kab ke heterocyclic tshiab.
Cov qauv ntawm cov tshuaj 4 tau txiav txim siab siv cov ntaub ntawv spectral. Lub spectrum 1H-NMR qhia tau tias muaj CH = ntawm 9.26 ppm, lub spectrum IR qhia tau tias muaj ib pawg carbonyl ntawm 1737 cm−1 thiab ib pawg cyano ntawm 2224 cm−1, thiab lub spectrum 13CNMR kuj tau lees paub cov qauv uas tau hais tseg (saib ntu Experimental).
Kev tsim cov 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 tau ua tiav los ntawm kev hydrolysis ntawm cov pab pawg aromatic 250, 41, 42, 53 nrog cov kua ethanolic sodium hydroxide (10%) kom muab cov kua qaub 354, 45, 56, uas tom qab ntawd tau kho nrog thionyl chloride ntawm lub dab dej kom muab acryloyl chloride derivative 4 hauv cov txiaj ntsig siab (88.5%), raws li qhia hauv Daim Duab 3.
Txhawm rau tsim cov tshuaj heterocyclic tshiab nrog cov txiaj ntsig antibacterial xav tau, cov tshuaj tiv thaiv ntawm acyl chloride 4 nrog ntau yam dinucleophiles tau ua tiav.
Cov kua qaub chloride 4 tau kho nrog hydrazine hydrate ntawm 0 ° rau ib teev. Hmoov tsis zoo, pyrazolone 5 tsis tau txais. Cov khoom yog ib qho acrylamide derivative uas nws cov qauv tau lees paub los ntawm cov ntaub ntawv spectral. Nws cov IR spectrum qhia txog cov kab nqus ntawm C = O ntawm 1720 cm−1, C≡N ntawm 2228 cm−1 thiab NH ntawm 3424 cm−1. Lub spectrum 1H-NMR tau qhia txog lub teeb liab pauv ntawm olefin protons thiab NH protons ntawm 9.3 ppm (saib seem Experimental).
Ob lub moles ntawm acid chloride 4 tau raug tshuaj nrog ib lub mole ntawm phenylhydrazine kom tau N-phenylacryloylhydrazine derivative 7 hauv cov txiaj ntsig zoo (77%) (Daim Duab 5). Cov qauv ntawm 7 tau lees paub los ntawm cov ntaub ntawv infrared spectroscopy, uas qhia txog kev nqus ntawm ob pawg C = O ntawm 1691 thiab 1671 cm−1, kev nqus ntawm pawg CN ntawm 2222 cm−1 thiab kev nqus ntawm pawg NH ntawm 3245 cm−1, thiab nws cov spectrum 1H-NMR qhia txog pawg CH ntawm 9.15 thiab 8.81 ppm thiab NH proton ntawm 10.88 ppm (saib ntu Experimental).
Hauv txoj kev tshawb no, qhov kev tshuaj tiv thaiv ntawm acyl chloride 4 nrog 1,3-dinucleophiles tau raug tshawb xyuas. Kev kho mob ntawm acyl chloride 4 nrog 2-aminopyridine hauv 1,4-dioxane nrog TEA ua lub hauv paus ntawm chav tsev kub tau muab acrylamide derivative 8 (Daim Duab 5), cov qauv uas tau txheeb xyuas siv cov ntaub ntawv spectral. IR spectra qhia txog cov kab nqus ntawm cyano ncab ntawm 2222 cm−1, NH ntawm 3148 cm−1, thiab carbonyl ntawm 1665 cm−1; 1H NMR spectra tau lees paub qhov muaj olefin protons ntawm 9.14 ppm (saib seem Experimental).
Cov tshuaj 4 ua rau thiourea ua pyrimidinethione 9; cov tshuaj 4 ua rau thiosemicarbazide ua thiopyrazole derivative 10 (Daim Duab 5). Cov qauv ntawm cov tshuaj 9 thiab 10 tau lees paub los ntawm kev tshuaj xyuas spectral thiab elemental (saib ntu Experimental).
Tetrazine-3-thiol 11 tau npaj los ntawm kev sib xyaw ntawm cov tshuaj 4 nrog thiocarbazide ua 1,4-dinucleophile (Daim Duab 5), thiab nws cov qauv tau lees paub los ntawm spectroscopy thiab kev tshuaj xyuas elemental. Hauv infrared spectrum, C = N bond tau tshwm sim ntawm 1619 cm - 1. Tib lub sijhawm, nws cov 1H-NMR spectrum khaws cov cim ntau ntawm cov protons aromatic ntawm 7.78-8.66 ppm thiab SH protons ntawm 3.31 ppm (saib Experimental Section).
Acryloyl chloride 4 reacts nrog 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, thiab ethanolamine ua 1,4-dinucleophiles los tsim cov kab ke heterocyclic tshiab (13–16).
Cov qauv ntawm cov tshuaj sib xyaw ua ke tshiab no tau lees paub los ntawm kev tshuaj xyuas spectral thiab elemental (saib ntu Experimental). 2-Hydroxyphenylacrylamide derivative 17 tau txais los ntawm kev sib xyaw nrog 2-aminophenol ua dinucleophile (Daim Duab 6), thiab nws cov qauv tau lees paub los ntawm kev tshuaj xyuas spectral thiab elemental. Lub spectrum infrared ntawm compound 17 qhia tau tias cov teeb liab C = O thiab C≡N tau tshwm sim ntawm 1681 thiab 2226 cm−1, feem. Lub caij no, nws cov spectrum 1H-NMR khaws cov teeb liab ntawm olefin proton ntawm 9.19 ppm, thiab OH proton tau tshwm sim ntawm 9.82 ppm (saib ntu Experimental).
Qhov kev sib xyaw ntawm acid chloride 4 nrog ib qho nucleophile (piv txwv li, ethylamine, 4-toluidine, thiab 4-methoxyaniline) hauv dioxane ua cov kuab tshuaj thiab TEA ua cov tshuaj catalyst ntawm chav tsev kub tau muab cov crystalline acrylamide derivatives ntsuab 18, 19a, thiab 19b. Cov ntaub ntawv elemental thiab spectral ntawm cov tshuaj 18, 19a, thiab 19b tau lees paub cov qauv ntawm cov derivatives no (saib ntu Experimental) (Daim Duab 7).
Tom qab tshuaj xyuas cov tshuaj tua kab mob ntawm ntau yam tshuaj sib xyaw ua ke, cov txiaj ntsig sib txawv tau txais raws li pom hauv Rooj 1 thiab Daim Duab 8 (saib cov ntaub ntawv duab). Tag nrho cov tshuaj sib xyaw ua ke tau qhia txog qib sib txawv ntawm kev tiv thaiv tiv thaiv cov kab mob Gram-positive MRSA, thaum cov kab mob Gram-negative Escherichia coli tau qhia txog kev tiv thaiv tag nrho rau txhua yam tshuaj sib xyaw ua ke. Cov tshuaj sib xyaw ua ke tau muab faib ua peb pawg raws li txoj kab uas hla ntawm thaj chaw tiv thaiv tiv thaiv MRSA. Pawg thawj zaug yog qhov nquag tshaj plaws thiab muaj tsib yam tshuaj sib xyaw ua ke (6, 7, 10, 13b thiab 14). Txoj kab uas hla ntawm thaj chaw tiv thaiv ntawm cov tshuaj sib xyaw ua ke no ze li ntawm 4 cm; cov tshuaj sib xyaw ua ke tshaj plaws hauv pawg no yog cov tshuaj sib xyaw ua ke 6 thiab 13b. Pawg thib ob yog qhov nquag nruab nrab thiab muaj tsib yam tshuaj sib xyaw ua ke (11, 13a, 15, 18 thiab 19a). Thaj chaw tiv thaiv ntawm cov tshuaj sib xyaw ua ke no yog txij li 3.3 txog 3.65 cm, nrog rau cov tshuaj sib xyaw ua ke 11 qhia txog thaj chaw tiv thaiv loj tshaj plaws ntawm 3.65 ± 0.1 cm. Ntawm qhov tod tes, pawg kawg muaj peb lub tshuaj (8, 17 thiab 19b) nrog cov tshuaj tua kab mob qis tshaj plaws (tsawg dua 3 cm). Daim duab 9 qhia txog kev faib tawm ntawm cov cheeb tsam txwv tsis pub sib txawv.
Kev tshawb nrhiav ntxiv txog kev ua haujlwm tiv thaiv kab mob ntawm cov tshuaj uas tau sim suav nrog kev txiav txim siab ntawm MIC thiab MBC rau txhua yam tshuaj. Cov txiaj ntsig tau hloov pauv me ntsis (raws li pom hauv Cov Lus Qhia 2, 3 thiab Daim Duab 10 (saib cov ntaub ntawv duab)), nrog rau cov tshuaj 7, 11, 13a thiab 15 zoo li tau raug cais tawm ua cov tshuaj zoo tshaj plaws. Lawv muaj cov nqi MIC thiab MBC qis tshaj plaws (39.06 μg / 100 μL). Txawm hais tias cov tshuaj 7 thiab 8 muaj cov nqi MIC qis dua (9.7 μg / 100 μL), lawv cov nqi MBC siab dua (78.125 μg / 100 μL). Yog li ntawd, lawv tau suav tias tsis muaj zog dua li cov tshuaj uas tau hais ua ntej. Txawm li cas los xij, rau cov tshuaj no yog cov tshuaj zoo tshaj plaws ntawm cov uas tau sim, vim tias lawv cov nqi MBC qis dua 100 μg / 100 μL.
Cov tshuaj sib xyaw (10, 14, 18 thiab 19b) tsis tshua muaj zog piv rau lwm cov tshuaj sib xyaw uas tau sim vim lawv cov nqi MBC yog txij li 156 txog 312 μg / 100 μL. Ntawm qhov tod tes, cov tshuaj sib xyaw (8, 17 thiab 19a) yog cov uas tsis tshua muaj kev cia siab vim lawv muaj cov nqi MBC siab tshaj plaws (625, 625 thiab 1250 μg / 100 μL, feem).
Thaum kawg, raws li qib kev kam rau siab uas tau qhia hauv Rooj 3, cov tshuaj uas tau sim tuaj yeem muab faib ua ob pawg raws li lawv txoj kev ua haujlwm: cov tshuaj uas muaj cov nyhuv tua kab mob (7, 8, 10, 11, 13a, 15, 18, 19b) thiab cov tshuaj uas muaj cov nyhuv tua kab mob (6, 13b, 14, 17, 19a). Ntawm lawv, cov tshuaj 7, 11, 13a thiab 15 yog cov uas nyiam dua, uas ua rau muaj kev tua kab mob ntawm qhov concentration qis heev (39.06 μg/100 μL).
Kaum ntawm kaum peb yam khoom uas tau sim qhia tau tias muaj peev xwm tiv thaiv kab mob Staphylococcus aureus (MRSA) uas tiv taus tshuaj tua kab mob (methicillin). Yog li ntawd, kev tshuaj xyuas ntxiv nrog cov kab mob uas tiv taus tshuaj tua kab mob (tshwj xeeb tshaj yog cov kab mob hauv zos uas muaj cov kab mob Gram-positive thiab Gram-negative) thiab cov poov xab uas ua rau mob raug pom zoo, nrog rau kev kuaj cytotoxic ntawm txhua yam khoom los ntsuas nws txoj kev nyab xeeb.
Cov kev tshawb fawb txog kev sib txuas ntawm cov molecular tau ua los ntsuam xyuas lub peev xwm ntawm cov tshuaj synthesized ua cov tshuaj inhibitors ntawm penicillin-binding protein 2a (PBP2a) hauv methicillin-resistant Staphylococcus aureus (MRSA). PBP2a yog ib qho enzyme tseem ceeb uas koom nrog cov kab mob cell phab ntsa biosynthesis, thiab kev txwv tsis pub cov enzyme no cuam tshuam rau kev tsim cell phab ntsa, thaum kawg ua rau cov kab mob lysis thiab cell tuag1. Cov txiaj ntsig docking tau teev nyob rau hauv Rooj 4 thiab piav qhia ntxiv hauv cov ntaub ntawv ntxiv, thiab cov txiaj ntsig qhia tau tias ntau cov tshuaj tau pom tias muaj kev sib txuas zoo rau PBP2a, tshwj xeeb tshaj yog cov khoom seem tseem ceeb xws li Lys 273, Lys 316, thiab Arg 298. Kev sib cuam tshuam, suav nrog hydrogen bonding thiab π-stacking, zoo ib yam li cov ntawm co-crystallized quinazolinone ligand (CCL), qhia txog lub peev xwm ntawm cov tshuaj no ua cov tshuaj inhibitors muaj zog.
Cov ntaub ntawv molecular docking, nrog rau lwm cov kev suav lej, tau hais tias PBP2a inhibition yog lub hauv paus tseem ceeb uas ua rau pom kev ua haujlwm antibacterial ntawm cov tshuaj no. Cov qhab nia docking thiab cov hauv paus ntsiab lus square deviation (RMSD) tus nqi ntxiv qhia txog kev sib txuas thiab kev ruaj khov, txhawb nqa qhov kev xav no. Raws li pom hauv Rooj 4, thaum ntau cov tshuaj tau qhia txog kev sib txuas zoo, qee cov tshuaj (piv txwv li, 7, 9, 10, thiab 14) muaj cov qhab nia docking siab dua li cov co-crystallized ligand, qhia tias lawv yuav muaj kev sib cuam tshuam zoo dua nrog cov chaw ua haujlwm ntawm PBP2a. Txawm li cas los xij, cov tshuaj bioactive feem ntau 6 thiab 13b tau qhia cov qhab nia docking qis dua me ntsis (-5.98 thiab -5.63, feem) piv rau lwm cov ligands. Qhov no qhia tau hais tias txawm hais tias cov qhab nia docking tuaj yeem siv los kwv yees kev sib txuas, lwm yam (piv txwv li, ligand stability thiab kev sib cuam tshuam molecular hauv ib puag ncig biological) kuj ua lub luag haujlwm tseem ceeb hauv kev txiav txim siab txog kev ua haujlwm antibacterial. Qhov tseem ceeb, cov nqi RMSD ntawm txhua cov tshuaj synthesized yog qis dua 2 Å, lees paub tias lawv cov docking poses yog cov qauv sib xws nrog cov qauv khi ntawm cov co-crystallized ligand, txhawb nqa lawv lub peev xwm ua cov tshuaj PBP2a inhibitors muaj zog.
Txawm hais tias cov qhab nia docking thiab RMS tus nqi muab cov lus kwv yees muaj txiaj ntsig, qhov kev sib raug zoo ntawm cov txiaj ntsig docking no thiab kev ua haujlwm antimicrobial tsis yog ib txwm meej thaum xub thawj siab. Txawm hais tias PBP2a inhibition tau txhawb nqa zoo li qhov tseem ceeb uas cuam tshuam rau kev ua haujlwm antimicrobial, ntau qhov sib txawv qhia tias lwm yam khoom siv biological kuj ua lub luag haujlwm tseem ceeb. Cov tshuaj sib xyaw 6 thiab 13b tau qhia txog kev ua haujlwm antimicrobial siab tshaj plaws, nrog rau ob qho tib si thaj chaw inhibition txoj kab uas hla ntawm 4 cm thiab MIC qis tshaj plaws (9.7 μg / 100 μL) thiab MBC (78.125 μg / 100 μL) tus nqi, txawm tias lawv cov qhab nia docking qis dua piv rau cov tshuaj sib xyaw 7, 9, 10 thiab 14. Qhov no qhia tau hais tias txawm hais tias PBP2a inhibition pab txhawb rau kev ua haujlwm antimicrobial, cov yam xws li solubility, bioavailability thiab kev sib cuam tshuam dynamics hauv cov kab mob ib puag ncig kuj cuam tshuam rau tag nrho cov haujlwm. Daim duab 11 qhia lawv cov docking poses, qhia tias ob qho tib si sib xyaw, txawm tias muaj cov qhab nia qis qis, tseem tuaj yeem cuam tshuam nrog cov khoom seem tseem ceeb ntawm PBP2a, uas tuaj yeem ua kom lub zog inhibition ruaj khov. Qhov no qhia tau hais tias thaum lub sijhawm molecular docking muab kev nkag siab tseem ceeb rau PBP2a inhibition, lwm yam kev mob nkeeg yuav tsum tau txiav txim siab kom nkag siab tag nrho cov teebmeem antimicrobial hauv lub ntiaj teb tiag tiag ntawm cov tshuaj no.
Siv cov qauv siv lead ua ntawm PBP2a (PDB ID: 4CJN), 2D thiab 3D daim ntawv qhia kev sib cuam tshuam ntawm cov tshuaj sib xyaw ua ke 6 thiab 13b uas muaj penicillin-binding protein 2a (PBP2a) ntawm methicillin-resistant Staphylococcus aureus (MRSA) tau tsim. Cov ntawv qhia no piv cov qauv kev sib cuam tshuam ntawm cov tshuaj sib xyaw ua ke nrog cov quinazolinone ligand (CCL) uas tau rov kho dua tshiab, qhia txog kev sib cuam tshuam tseem ceeb xws li hydrogen bonding, π-stacking, thiab ionic interactions.
Ib qho qauv zoo sib xws tau pom rau cov tshuaj 7, uas qhia tau tias qhov qhab nia docking siab dua (-6.32) thiab qhov cheeb tsam inhibition zoo sib xws (3.9 cm) rau cov tshuaj 10. Txawm li cas los xij, nws MIC (39.08 μg / 100 μL) thiab MBC (39.06 μg / 100 μL) siab dua, qhia tau tias nws xav tau cov concentration siab dua kom pom cov nyhuv antibacterial. Qhov no qhia tau hais tias txawm hais tias cov tshuaj 7 tau qhia txog kev sib raug zoo hauv kev tshawb fawb docking, cov yam xws li bioavailability, cellular uptake, lossis lwm yam khoom physicochemical yuav txwv nws cov txiaj ntsig biological. Txawm hais tias cov tshuaj 7 tau qhia txog cov khoom bactericidal, nws tsis tshua muaj txiaj ntsig hauv kev tiv thaiv cov kab mob loj hlob piv rau cov tshuaj 6 thiab 13b.
Cov Tshuaj 10 tau qhia txog qhov sib txawv ntau dua nrog qhov qhab nia docking siab tshaj plaws (-6.40), qhia txog kev sib txuas lus zoo rau PBP2a. Txawm li cas los xij, nws thaj tsam ntawm txoj kab uas hla inhibition (3.9 cm) yog sib piv rau cov tshuaj 7, thiab nws cov MBC (312 μg/100 μL) siab dua li cov tshuaj 6, 7, thiab 13b, qhia txog kev ua haujlwm bactericidal tsis muaj zog. Qhov no qhia tau hais tias txawm hais tias muaj kev kwv yees zoo txog docking, cov tshuaj 10 tsis tshua muaj txiaj ntsig hauv kev tua MRSA vim muaj lwm yam kev txwv xws li kev yaj, kev ruaj khov, lossis kev nkag mus tsis zoo ntawm daim nyias nyias ntawm cov kab mob. Cov txiaj ntsig no txhawb nqa kev nkag siab tias thaum PBP2a inhibition ua lub luag haujlwm tseem ceeb hauv kev ua haujlwm antibacterial, nws tsis piav qhia tag nrho qhov sib txawv ntawm kev ua haujlwm biological pom ntawm cov tshuaj kuaj. Cov kev sib txawv no qhia tau hais tias yuav tsum muaj kev tshuaj xyuas kev sim ntxiv thiab kev ntsuam xyuas biological tob tob kom piav qhia tag nrho cov txheej txheem antibacterial koom nrog.
Cov txiaj ntsig ntawm kev sib txuas ntawm cov molecular hauv Rooj 4 thiab Cov Ntaub Ntawv Ntxiv qhia txog kev sib raug zoo ntawm cov qhab nia docking thiab kev ua haujlwm tiv thaiv kab mob. Txawm hais tias cov tshuaj 6 thiab 13b muaj cov qhab nia docking qis dua li cov tshuaj 7, 9, 10, thiab 14, lawv qhia txog kev ua haujlwm tiv thaiv kab mob siab tshaj plaws. Lawv cov ntawv qhia kev sib cuam tshuam (qhia hauv Daim Duab 11) qhia tias txawm tias lawv cov qhab nia khi qis dua, lawv tseem tsim cov hydrogen bonds tseem ceeb thiab π-stacking kev sib cuam tshuam nrog cov seem tseem ceeb ntawm PBP2a uas tuaj yeem ua kom lub enzyme-inhibitor complex ruaj khov hauv txoj kev muaj txiaj ntsig zoo rau lub cev. Txawm hais tias cov qhab nia docking qis ntawm 6 thiab 13b, lawv cov kev ua haujlwm tiv thaiv kab mob zoo dua qhia tias lwm yam khoom xws li solubility, kev ruaj khov, thiab kev nqus ntawm tes yuav tsum tau txiav txim siab ua ke nrog cov ntaub ntawv docking thaum ntsuas lub peev xwm inhibitor. Qhov no qhia txog qhov tseem ceeb ntawm kev sib xyaw ua ke ntawm kev tshawb fawb docking nrog kev tshuaj ntsuam xyuas kev tiv thaiv kab mob kom ntsuas qhov tseeb ntawm lub peev xwm kho mob ntawm cov tshuaj tshiab.
Cov txiaj ntsig no qhia tau hais tias thaum molecular docking yog ib qho cuab yeej muaj zog rau kev kwv yees qhov sib txuas thiab txheeb xyuas cov txheej txheem ntawm kev txwv, nws yuav tsum tsis txhob cia siab rau nws ib leeg los txiav txim siab txog kev ua haujlwm ntawm cov tshuaj tua kab mob. Cov ntaub ntawv molecular qhia tias PBP2a inhibition yog ib qho tseem ceeb uas cuam tshuam rau kev ua haujlwm ntawm cov tshuaj tua kab mob, tab sis kev hloov pauv hauv kev ua haujlwm ntawm cov tshuaj qhia tias lwm yam khoom siv physicochemical thiab pharmacokinetic yuav tsum tau ua kom zoo dua los txhim kho kev ua haujlwm kho mob. Kev tshawb fawb yav tom ntej yuav tsum tsom mus rau kev ua kom zoo dua cov qauv tshuaj ntawm cov tshuaj 7 thiab 10 kom txhim kho bioavailability thiab cellular uptake, xyuas kom meej tias kev sib cuam tshuam docking muaj zog tau txhais ua cov haujlwm tua kab mob tiag tiag. Kev tshawb fawb ntxiv, suav nrog cov bioassays ntxiv thiab kev txheeb xyuas kev sib raug zoo ntawm cov qauv (SAR), yuav tseem ceeb rau peb txoj kev nkag siab ntxiv txog seb cov tshuaj no ua haujlwm li PBP2a inhibitors thiab los tsim cov tshuaj tua kab mob zoo dua.
Cov tshuaj uas tsim los ntawm 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 tau pom tias muaj ntau yam kev ua haujlwm tua kab mob, nrog rau ntau yam tshuaj uas qhia tau tias muaj kev tiv thaiv tseem ceeb ntawm methicillin-resistant Staphylococcus aureus (MRSA). Kev tshuaj xyuas kev sib raug zoo ntawm cov qauv thiab kev ua haujlwm (SAR) tau qhia txog cov yam ntxwv tseem ceeb ntawm cov qauv uas ua rau muaj kev ua haujlwm tua kab mob ntawm cov tshuaj no.
Qhov muaj ob pawg acrylonitrile thiab anthracene tau ua pov thawj tias yog qhov tseem ceeb rau kev txhim kho cov haujlwm tiv thaiv kab mob. Pawg nitrile uas muaj zog heev hauv acrylonitrile yog qhov tsim nyog los pab txhawb kev sib cuam tshuam nrog cov protein ntawm cov kab mob, yog li ua rau muaj cov khoom tiv thaiv kab mob ntawm cov tshuaj. Cov tshuaj uas muaj ob qho tib si acrylonitrile thiab anthracene tau ua pov thawj tias muaj zog tiv thaiv kab mob. Qhov aromaticity ntawm pawg anthracene ua rau cov tshuaj no ruaj khov ntxiv, tej zaum yuav txhim kho lawv cov haujlwm ua haujlwm ntawm lub cev.
Qhov kev qhia txog cov nplhaib heterocyclic tau txhim kho qhov ua tau zoo ntawm cov tshuaj tua kab mob ntawm ntau yam derivatives. Tshwj xeeb, benzothiazole derivative 13b thiab acrylhydrazide derivative 6 tau qhia txog kev ua haujlwm tua kab mob siab tshaj plaws nrog thaj tsam inhibition ntawm kwv yees li 4 cm. Cov derivatives heterocyclic no tau qhia txog cov teebmeem tseem ceeb ntawm kev ua haujlwm ntawm lub cev, qhia tias cov qauv heterocyclic ua lub luag haujlwm tseem ceeb hauv cov teebmeem tua kab mob. Ib yam li ntawd, pyrimidinethione hauv compound 9, thiopyrazole hauv compound 10, thiab tetrazine nplhaib hauv compound 11 tau pab txhawb rau cov khoom tua kab mob ntawm cov tshuaj, ntxiv qhov tseem ceeb ntawm kev hloov kho heterocyclic.
Ntawm cov tshuaj sib xyaw ua ke, 6 thiab 13b sawv tawm rau lawv cov haujlwm tiv thaiv kab mob zoo heev. Qhov tsawg kawg nkaus inhibitory concentration (MIC) ntawm compound 6 yog 9.7 μg / 100 μL, thiab qhov tsawg kawg nkaus bactericidal concentration (MBC) yog 78.125 μg / 100 μL, qhia txog nws lub peev xwm zoo heev los tshem tawm methicillin-resistant Staphylococcus aureus (MRSA). Ib yam li ntawd, compound 13b muaj thaj tsam inhibition ntawm 4 cm thiab MIC thiab MBC tus nqi qis, lees paub nws cov haujlwm tiv thaiv kab mob muaj zog. Cov txiaj ntsig no qhia txog lub luag haujlwm tseem ceeb ntawm acrylohydrazide thiab benzothiazole functional pawg hauv kev txiav txim siab bioefficacy ntawm cov tshuaj no.
Qhov sib piv, cov tshuaj 7, 10, thiab 14 tau ua haujlwm tiv thaiv kab mob nruab nrab nrog thaj chaw tiv thaiv xws li 3.65 txog 3.9 cm. Cov tshuaj no xav tau cov tshuaj ntau dua kom tua tau cov kab mob tag nrho, raws li lawv cov nqi MIC thiab MBC siab. Txawm hais tias cov tshuaj no tsis tshua muaj zog dua li cov tshuaj 6 thiab 13b, lawv tseem qhia tau tias muaj peev xwm tiv thaiv kab mob ntau, qhia tias kev koom ua ke ntawm acrylonitrile thiab anthracene moieties rau hauv lub nplhaib heterocyclic pab txhawb rau lawv cov nyhuv tiv thaiv kab mob.
Cov tshuaj no muaj ntau hom kev ua haujlwm sib txawv, qee qhov muaj cov yam ntxwv tua kab mob thiab lwm qhov muaj cov nyhuv tua kab mob. Cov tshuaj 7, 11, 13a, thiab 15 muaj cov nyhuv tua kab mob thiab xav tau cov tshuaj tsawg dua kom tua tau cov kab mob tag nrho. Qhov sib txawv, cov tshuaj 6, 13b, thiab 14 muaj cov nyhuv tua kab mob thiab tuaj yeem tiv thaiv kev loj hlob ntawm cov kab mob ntawm cov tshuaj tsawg dua, tab sis xav tau cov tshuaj ntau dua kom tua tau cov kab mob tag nrho.
Zuag qhia tag nrho, qhov kev tshuaj xyuas kev sib raug zoo ntawm cov qauv thiab kev ua ub no qhia txog qhov tseem ceeb ntawm kev qhia txog acrylonitrile thiab anthracene moieties thiab heterocyclic structures kom ua tiav cov haujlwm tua kab mob tseem ceeb. Cov txiaj ntsig no qhia tau hais tias kev ua kom zoo dua ntawm cov khoom siv hauv cov qauv no thiab kev tshawb nrhiav ntxiv txog kev hloov kho kom zoo dua qub thiab kev nkag mus rau hauv daim nyias nyias yuav ua rau muaj kev tsim cov tshuaj tiv thaiv MRSA zoo dua.
Tag nrho cov tshuaj reagents thiab cov kuab tshuaj tau raug ntxuav thiab ziab siv cov txheej txheem txheem (El Gomhouria, Egypt). Cov ntsiab lus yaj tau txiav txim siab siv GallenKamp hluav taws xob melting point apparatus thiab tau tshaj tawm yam tsis muaj kev kho. Infrared (IR) spectra (cm⁻1) tau raug kaw tseg ntawm Department of Chemistry, Faculty of Science, Ain Shams University siv potassium bromide (KBr) pellets ntawm Thermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
Cov spectra 1H NMR tau txais ntawm 300 MHz siv lub GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) thiab BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.). Tetramethylsilane (TMS) tau siv ua tus qauv sab hauv nrog deuterated dimethyl sulfoxide (DMSO-d₆). Kev ntsuas NMR tau ua nyob rau ntawm Faculty of Science, Cairo University, Giza, Egypt. Kev tshuaj xyuas Elemental (CHN) tau ua tiav siv Perkin-Elmer 2400 Elemental Analyzer thiab cov txiaj ntsig tau txais yog qhov sib haum xeeb zoo nrog cov nqi xam.
Ib qho sib tov ntawm acid 3 (5 mmol) thiab thionyl chloride (5 ml) tau raug cua sov hauv lub dab dej ntawm 65 ° C rau 4 teev. Cov thionyl chloride ntau dhau tau raug tshem tawm los ntawm kev distillation hauv qab qhov siab txo qis. Cov khoom liab uas tau los tau raug sau thiab siv yam tsis tau ntxuav ntxiv. Melting point: 200-202 ° C, yield: 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. Tus kws tshuaj ntsuam xyuas. Xam rau C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Pom: C, 74.41; H, 3.34; N, 4.66%.
Ntawm 0°C, 4 (2 mmol, 0.7 g) tau yaj rau hauv anhydrous dioxane (20 ml) thiab hydrazine hydrate (2 mmol, 0.16 ml, 80%) tau ntxiv rau hauv dej thiab do rau 1 teev. Cov khoom khov uas tau precipitated tau sau los ntawm kev lim dej thiab recrystallized los ntawm ethanol los muab cov tshuaj 6.
Cov siv lead ua ntsuab, qhov chaw yaj 190-192 ℃, cov txiaj ntsig 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, pauv tau), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH =), 8.54 (s, 1H, CH =); Tus nqi xam rau C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Pom: C, 84.01; H, 4.38; N, 8.05%.
Yaj 4 (2 mmol, 0.7 g) rau hauv 20 ml ntawm cov kua anhydrous dioxane (muaj ob peb tee ntawm triethylamine), ntxiv phenylhydrazine/2-aminopyridine (2 mmol) thiab do ntawm chav sov rau 1 thiab 2 teev, raws li. Ncuav cov tshuaj sib tov rau hauv dej khov lossis dej thiab ua kom acidify nrog dilute hydrochloric acid. Lim cov khoom sib cais tawm thiab recrystallize los ntawm ethanol kom tau 7 thiab recrystallize los ntawm benzene kom tau 8.
Cov siv lead ua ntsuab, qhov chaw yaj 160-162 ℃, cov txiaj ntsig 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, pauv tau), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Tus nqi xam rau C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Pom: C, 81.96; H, 3.91; N, 8.91%.
4 (2 mmol, 0.7 g) tau yaj rau hauv 20 ml ntawm cov kua anhydrous dioxane (muaj ob peb tee ntawm triethylamine), 2-aminopyridine (2 mmol, 0.25 g) tau ntxiv thiab cov khoom sib tov tau do ntawm chav tsev kub rau 2 teev. Cov khoom sib tov tau nchuav rau hauv dej khov thiab acidified nrog dilute hydrochloric acid. Cov precipitate tsim tau lim tawm thiab recrystallized los ntawm benzene, muab cov siv lead ua ntsuab ntawm 8 nrog lub ntsiab lus yaj ntawm 146-148 ° C thiab cov txiaj ntsig ntawm 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, pauv tau), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); Xam rau C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Pom: C, 78.93; H, 3.97; N, 12.36%.
Cov tshuaj 4 (2 mmol, 0.7 g) tau yaj rau hauv 20 ml ntawm cov dioxane qhuav (muaj ob peb tee ntawm triethylamine thiab 2 mmol ntawm thiourea/semicarbazide) thiab cua sov hauv qab reflux rau 2 teev. Cov kuab tshuaj tau evaporated hauv vacuo. Cov seem tau recrystallized los ntawm dioxane kom muab cov khoom sib tov.