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I hangaia te synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4, ā, i whakamahia hei hanga i ngā momo matū heterocyclic tino kaha mā te tauhohenga ki ngā momo nucleophile hauota. I tino tautuhia te hanganga o ia matū heterocyclic i hangaia mā te whakamahi i te tātaritanga spectroscopic me te huānga. Tekau o ngā matū heterocyclic hou tekau mā toru i whakaatu i te whai huatanga whakatenatena ki ngā huakita ātete-maha-rongoā (MRSA). I ​​roto i ēnei, ko ngā matū 6, 7, 10, 13b, me te 14 i whakaatu i te mahi antibacterial teitei rawa atu me ngā rohe aukati tata ki te 4 cm. Heoi, i whakaatuhia e ngā rangahau hononga ngota he rerekē ngā hononga here o ngā matū ki te pūmua here-penicillin 2a (PBP2a), he whāinga matua mō te ātete MRSA. Ko ētahi matū pēnei i te 7, 10 me te 14 i whakaatu i te kaha here me te pumau taunekeneke teitei ake i te pae kaha o PBP2a ki te whakataurite ki te ligand quinazolinone kua whakakotahihia. He rerekē, he iti ake ngā kaute tākai o ngā matū 6 me 13b engari he nui tonu te kaha patu huakita, ko te matū 6 te iti rawa o ngā uara MIC (9.7 μg/100 μL) me te MBC (78.125 μg/100 μL). I whakaatuhia e te tātari tākai ngā taunekeneke matua tae atu ki te here hauwai me te tākai-π, inā koa ki ngā toenga pērā i a Lys 273, Lys 316 me Arg 298, i tautuhia he taunekeneke ki te ligand kua whakakōkīhia i roto i te hanganga tioata o PBP2a. He mea nui ēnei toenga mō te mahi whākōkī o PBP2a. E kī ana ēnei hua ka taea e ngā matū kua hangaia te mahi hei rongoā anti-MRSA whai hua, e whakaatu ana i te hiranga o te whakakotahi i te tākai ngota me ngā whakamātautau koiora hei tautuhi i ngā kaitono rongoā whai hua.
I ngā tau tōmua o tēnei rautau, ko te arotahi matua o ngā mahi rangahau ko te whakawhanake i ngā tikanga me ngā tikanga hou, māmā hoki mō te hanga i ētahi pūnaha heterocyclic auaha me te mahi patu huakita mā te whakamahi i ngā rauemi tīmatanga e wātea ana.
E kiia ana ngā wāhanga Acrylonitrile he rauemi tīmatanga nui mō te hanga i ngā pūnaha heterocyclic whakamiharo maha nā te mea he pūhui tino tauhohe. Heoi anō, kua whakamahia whānuitia ngā matū 2-cyanoacryloyl chloride i ngā tau tata nei mō te whakawhanake me te hanga i ngā hua tino nui i roto i te mara o ngā tono rongoā, pērā i ngā takawaenga rongoā1,2,3, ngā matū mua o te anti-HIV, te antiviral, te anticancer, te antibacterial, te antidepressant me ngā antioxidant agents4,5,6,7,8,9,10. Nō nā tata nei, kua aro nui te whai huatanga koiora o te anthracene me ōna matū, tae atu ki ō rātou āhuatanga paturopi, anticancer11,12, antibacterial13,14,15 me ngā āhuatanga patu pepeke16,1718,19,20,21. Kei roto i ngā Pikitia 1 me te 2 ngā matū antimicrobial kei roto ngā wāhanga acrylonitrile me te anthracene.
E ai ki te World Health Organization (WHO) (2021), ko te ātete ki ngā huakita he tūmomo mōrearea ā-ao mō te hauora me te whanaketanga22,23,24,25. Kāore e taea te whakaora i ngā tūroro, ā, ka roa ake te noho ki te hōhipera me te hiahia ki ngā rongoā utu nui ake, tae atu ki te pikinga o te mate me te hauātanga. Ko te kore o ngā huakita whai hua ka arahi i te korenga o te maimoatanga mō ngā momo mate, inā koa i te wā o te chemotherapy me ngā pokanga nui.
E ai ki te pūrongo a te World Health Organization 2024, kei roto i te rārangi o ngā mate pāwera matua te Staphylococcus aureus ātete-methicillin (MRSA) me te E. coli. He ātete ngā huakita e rua ki te maha o ngā paturopi, nō reira he mate uaua ki te rongoā me te whakahaere, ā, he hiahia nui ki te whakawhanake i ngā matū patu huakita hou me te whai hua hei whakatika i tēnei raruraru. He rongonui ngā patu huakita a Anthracene me ōna huakita ka taea te mahi ki ngā huakita Gram-pai me ngā huakita Gram-kino. Ko te whāinga o tēnei rangahau he hanga i tētahi huakita hou ka taea te whawhai ki ēnei mate pāwera e kino ana ki te hauora.
E ai ki te pūrongo a te World Health Organization (WHO) he maha ngā mate huakita e ātete ana ki ngā momo paturopi maha, tae atu ki te Staphylococcus aureus ātete-methicillin (MRSA), he take noa o te mate i roto i te hapori me ngā wāhi tiaki hauora. E ai ki ngā pūrongo he 64% teitei ake te mate o ngā tūroro e pangia ana e te mate MRSA i ērā e pāngia ana e te mate e ngawari ana ki te rongoā. Hei tāpiri, he mōrearea ā-ao te E. coli nā te mea ko te ārai whakamutunga ki ngā Enterobacteriaceae ātete-carbapenem (arā, E. coli) ko te colistin, engari kua pūrongohia tata nei ngā huakita ātete-colistin i roto i ētahi whenua. 22,23,24,25
Nō reira, e ai ki te Mahere Mahi Ao mō te Ātete ki ngā Pūmua26 a te Whakahaere Hauora o te Ao, he mea nui te kimi me te hanga i ngā pūmua hou hei patu huakita. Kua whakamāramahia te kaha nui o te anthracene me te acrylonitrile hei patu huakita27, hei patu huakita28, hei patu mate pukupuku29 me te patu antioxidant30 i roto i ngā tuhinga maha kua whakaputaina. I runga i tēnei, ka taea te kī he pai ēnei matū hei whakamahi hei patu i te Staphylococcus aureus ātete-methicillin (MRSA).
Nā ngā arotake tuhinga o mua i akiaki mātou ki te hanga i ngā momo hou i roto i ēnei akomanga. Nō reira, ko te whāinga o tēnei rangahau he whakawhanake i ngā pūnaha heterocyclic hou kei roto ngā wāhanga anthracene me te acrylonitrile, te aromatawai i ō rātou whai huatanga antimicrobial me te antibacterial, me te tirotiro i ō rātou taunekeneke here pea ki te penicillin-binding protein 2a (PBP2a) mā te hononga ngota. I runga i ngā rangahau o mua, i haere tonu te rangahau o tēnei rangahau ki te hanga, te aromatawai koiora, me te tātari rorohiko o ngā pūnaha heterocyclic hei tautuhi i ngā kaihoko Staphylococcus aureus ātete-antimethicillin (MRSA) me te kaha aukati PBP2a31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Ko tā mātou rangahau o nāianei e arotahi ana ki te hanga me te aromatawai paturopi o ngā pūhui heterocyclic hou kei roto ngā wāhanga anthracene me te acrylonitrile. I whakaritea te 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4, ā, i whakamahia hei poraka hanga mō te hanganga o ngā pūnaha heterocyclic hou.
I whakatauhia te hanganga o te pūhui 4 mā te whakamahi i ngā raraunga āwhata. I whakaatuhia e te āwhata 1H-NMR te aroaro o te CH= i te 9.26 ppm, i whakaatuhia e te āwhata IR te aroaro o te rōpū carbonyl i te 1737 cm−1 me te rōpū cyano i te 2224 cm−1, ā, i whakaūhia hoki e te āwhata 13CNMR te hanganga kua whakaarohia (tirohia te wāhanga Whakamātautau).
I oti te hanga o te 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 mā te waikura i ngā rōpū kakara 250, 41, 42, 53 me te otinga hauwai konutai etanolic (10%) hei whakaputa waikawa 354, 45, 56, i muri mai ka rongoatia ki te thionyl chloride i runga i te kaukau wai hei whakaputa i te acryloyl chloride derivative 4 i roto i te hua nui (88.5%), e whakaaturia ana i te Pikitia 3.
Hei waihanga i ngā pūhui heterocyclic hou me te whai huatanga paturopi e tumanakohia ana, i whakahaerehia te tauhohenga o te acyl chloride 4 me ngā momo dinucleophile.
I rongoatia te waikawa pūhaumāota 4 ki te hydrazine hydrate i te 0° mō te haora kotahi. Engari, kāore i whiwhihia te pyrazolone 5. He hua acrylamide te hua, ā, i whakaūtia tōna hanganga e ngā raraunga hihi. I whakaatuhia e tōna hihi IR ngā roopu mimiti o C=O i te 1720 cm−1, C≡N i te 2228 cm−1 me te NH i te 3424 cm−1. I whakaatuhia e te hihi 1H-NMR he tohu whakawhiti takitahi o ngā proton olefin me ngā proton NH i te 9.3 ppm (tirohia te Wāhanga Whakamātautau).
E rua ngā mole o te waikawa pūhaumāota 4 i tauhohehia ki te mole kotahi o te phenylhydrazine hei hanga i te N-phenylacryloylhydrazine derivative 7 i roto i te hua pai (77%) (Pikitia 5). I whakaūhia te hanganga o te 7 e ngā raraunga tirotiro infrared, i whakaatu i te mimiti o ngā rōpū C=O e rua i te 1691 me te 1671 cm−1, te mimiti o te rōpū CN i te 2222 cm−1 me te mimiti o te rōpū NH i te 3245 cm−1, ā, i whakaatuhia e tana whānuitanga 1H-NMR te rōpū CH i te 9.15 me te 8.81 ppm me te pūmua NH i te 10.88 ppm (tirohia te wāhanga Whakamātautau).
I roto i tēnei rangahau, i tirotirohia te tauhohenga o te acyl chloride 4 me te 1,3-dinucleophiles. Ko te maimoatanga o te acyl chloride 4 me te 2-aminopyridine i roto i te 1,4-dioxane me te TEA hei turanga i te pāmahana rūma i puta ai te acrylamide derivative 8 (Pikitia 5), ​​ko tōna hanganga i tautuhia mā te whakamahi i ngā raraunga spectral. I whakaatuhia e ngā spectral IR ngā roopu mimiti o te cyano stretching i te 2222 cm−1, NH i te 3148 cm−1, me te carbonyl i te 1665 cm−1; i whakaūhia e ngā spectral 1H NMR te aroaro o ngā proton olefin i te 9.14 ppm (tirohia te Wāhanga Whakamātautau).
Ka tauhohe te matū 4 ki te thiourea ka puta ko te pyrimidinethione 9; ka tauhohe te matū 4 ki te thiosemicarbazide ka puta ko te thiopyrazole derivative 10 (Pikitia 5). I whakaūhia ngā hanganga o ngā matū 9 me te 10 mā te tātaritanga ā-pūnaha me te tātaritanga ā-ira (tirohia te wāhanga Whakamātautau).
I whakaritea a Tetrazine-3-thiol 11 mā te tauhohenga o te pūhui 4 me te thiocarbazide hei 1,4-dinucleophile (Pikitia 5), ​​ā, i whakaūtia tōna hanganga mā te tirotiro ira me te tātari huānga. I roto i te ira whero-whero, i puta te here C=N i te 1619 cm−1. I taua wā anō, i pupuri tonu tana ira 1H-NMR i ngā tohu pereti maha o ngā pūmua kakara i te 7.78–8.66 ppm me ngā pūmua SH i te 3.31 ppm (tirohia te Wāhanga Whakamātautau).
Ka tauhohe te Acryloyl chloride 4 ki te 1,2-diaminobenzene, 2-aminothiophenol, waikawa anthranilic, 1,2-diaminoethane, me te ethanolamine hei 1,4-dinucleophiles hei hanga i ngā pūnaha heterocyclic hou (13–16).
I whakaūngia ngā hanganga o ēnei pūhui hou i hangaia mā te tātaritanga ā-ira me te tātaritanga huānga (tirohia te wāhanga Whakamātautau). I whiwhihia te 2-Hydroxyphenylacrylamide derivative 17 mā te tauhohenga ki te 2-aminophenol hei dinucleophile (Pikitia 6), ā, i whakaūngia tōna hanganga mā te tātaritanga ā-ira me te tātaritanga huānga. I whakaatuhia e te ā-ira whero o te pūhui 17 ko ngā tohu C=O me C≡N i puta i te 1681 me te 2226 cm−1, ia. I taua wā, i mau tonu te tohu kotahi o te proton olefin i roto i tana ā-ira 1H-NMR i te 9.19 ppm, ā, i puta te proton OH i te 9.82 ppm (tirohia te wāhanga Whakamātautau).
Nā te tauhohenga o te waikawa pūhaumāota 4 me te kotahi nucleophile (hei tauira, te ethylamine, 4-toluidine, me te 4-methoxyaniline) i roto i te dioxane hei whakarewa me te TEA hei whakakorikori i te pāmahana rūma i puta ai he kiriuhi acrylamide tioata matomato 18, 19a, me te 19b. Nā ngā raraunga huānga me ngā raraunga ā-ira o ngā pūhui 18, 19a, me te 19b i whakaū ngā hanganga o ēnei matū (tirohia te Wāhanga Whakamātautau) (Pikitia 7).
I muri i te tirotiro i te kaha patu huakita o ngā momo matū hanga, i puta mai ngā hua rerekē e ai ki te Ripanga 1 me te Pikitia 8 (tirohia te kōnae pikitia). I whakaatuhia e ngā matū katoa i whakamatautauria he rerekē ngā taumata aukati ki te huakita Gram-pai MRSA, ko te huakita Gram-kino Escherichia coli i whakaatu i te ātete katoa ki ngā matū katoa. Ka taea te wehewehe i ngā matū i whakamatautauria ki ngā wāhanga e toru i runga i te diameter o te rohe aukati ki te MRSA. Ko te wāhanga tuatahi te mea tino kaha, ā, e rima ngā matū (6, 7, 10, 13b me te 14). Ko te diameter o te rohe aukati o ēnei matū e tata ana ki te 4 cm; ko ngā matū tino kaha i roto i tēnei wāhanga ko ngā matū 6 me te 13b. Ko te wāhanga tuarua he āhua kaha, ā, e rima atu ngā matū (11, 13a, 15, 18 me te 19a). Ko te rohe aukati o ēnei matū i waenga i te 3.3 ki te 3.65 cm, me te matū 11 e whakaatu ana i te rohe aukati nui rawa atu o te 3.65 ± 0.1 cm. I tētahi atu ringa, e toru ngā matū i roto i te rōpū whakamutunga (8, 17 me te 19b) me te iti rawa o te kaha patu huakita (iti iho i te 3 cm). E whakaatu ana te Pikitia 9 i te tohatoha o ngā rohe aukati rerekē.
Ko te rangahau anō mō ​​te mahi patu huakita o ngā matū i whakamatautauria i uru ki te whakatau i te MIC me te MBC mō ia matū. He paku rerekē ngā hua (e whakaaturia ana i roto i ngā Ripanga 2, 3 me te Pikitia 10 (tirohia te kōnae pikitia)), me ngā matū 7, 11, 13a me te 15 i te āhua nei kua whakarōpūtia anō hei matū pai rawa atu. He rite tonu te iti o ngā uara MIC me te MBC (39.06 μg/100 μL). Ahakoa he iti ake ngā uara MIC o ngā matū 7 me te 8 (9.7 μg/100 μL), he teitei ake ō rātou uara MBC (78.125 μg/100 μL). Nō reira, i kiia he ngoikore ake i ngā matū kua whakahuatia i mua. Heoi, ko ēnei matū e ono te mea tino whai hua o ērā i whakamatautauria, nā te mea he iti iho ō rātou uara MBC i te 100 μg/100 μL.
Kāore i te tino kaha ngā matū (10, 14, 18 me te 19b) i whakaritea ki ētahi atu matū i whakamatautauria nā te mea ko ō rātou uara MBC i waenga i te 156 ki te 312 μg/100 μL. I tētahi atu taha, ko ngā matū (8, 17 me te 19a) ngā mea kāore i tino whai hua nā te mea ko rātou ngā uara MBC teitei rawa (625, 625 me te 1250 μg/100 μL, ia).
Hei whakamutunga, e ai ki ngā taumata manawanui e whakaaturia ana i te Ripanga 3, ka taea te wehewehe i ngā matū kua whakamatautauria kia rua ngā wāhanga i runga i tā rātou momo mahi: ngā matū he pānga patu huakita (7, 8, 10, 11, 13a, 15, 18, 19b) me ngā matū he pānga patu huakita (6, 13b, 14, 17, 19a). I roto i ēnei, ko ngā matū 7, 11, 13a me te 15 te mea e pai ake ana, e whakaatu ana i te mahi whakamate i te kukū tino iti (39.06 μg/100 μL).
Tekau o ngā matū tekau mā toru i whakamatautauria i whakaatu i te kaha ki te patu i te Staphylococcus aureus ātete-paturopi (MRSA). Nō reira, e taunakihia ana kia tirotirohia anōtia me ētahi atu mate pāwera ātete-paturopi (ina koa ko ngā momo motuhake o te rohe e kapi ana i ngā huakita Gram-pai me ngā huakita Gram-kino) me ngā rewena mate, me te whakamātautau cytotoxic o ia matū hei aromatawai i tōna haumaru.
I whakahaerehia ngā rangahau hononga ngota hei aromatawai i te kaha o ngā matū kua hangaia hei aukati i te pūmua here-penicillin 2a (PBP2a) i roto i te Staphylococcus aureus ātete-methicillin (MRSA). Ko te PBP2a he whākōkī matua e uru ana ki te hanga pakitara pūtau huakita, ā, ko te aukati i tēnei whākōkī ka whakararu i te hanganga pakitara pūtau, ka mutu ka arahi ki te pakaru o te huakita me te mate pūtau1. Kua whakarārangihia ngā hua hononga ki te Ripanga 4, ā, kua whakaahuahia kia taipitopito atu i roto i te kōnae raraunga tāpiri, ā, e whakaatu ana ngā hua he maha ngā matū i whakaatu i te kaha here ki te PBP2a, inā koa ko ngā toenga pae hohe matua pērā i a Lys 273, Lys 316, me Arg 298. Ko ngā taunekeneke, tae atu ki te here hauwai me te π-stacking, he tino rite ki ērā o te ligand quinazolinone kua whakakotahihia (CCL), e tohu ana i te kaha o ēnei matū hei aukati kaha.
Ko ngā raraunga hononga ngota, me ētahi atu tawhā rorohiko, i tino whakaatu ko te aukati PBP2a te tikanga matua e whai kawenga ana mō te mahi patu huakita i kitea o ēnei pūhui. Ko ngā kaute hononga me ngā uara pakiaka toharite tapawhā (RMSD) i whakaatu ake i te hononga me te pumau here, e tautoko ana i tēnei ariā. E ai ki te Ripanga 4, ahakoa he pai te hononga o ētahi pūhui, ko ētahi pūhui (hei tauira, 7, 9, 10, me te 14) he nui ake ngā kaute hononga i te ligand kua whakakotahihia, e tohu ana he kaha ake pea ā rātou taunekeneke ki ngā toenga pae hohe o PBP2a. Heoi, ko ngā pūhui tino bioactive 6 me te 13b i whakaatu i ngā kaute hononga iti ake (-5.98 me te -5.63, ia) ki te whakataurite ki ētahi atu ligand. E whakaatu ana tēnei ahakoa ka taea te whakamahi i ngā kaute hononga ki te matapae i te hononga here, ko ētahi atu āhuatanga (hei tauira, te pumau ligand me ngā taunekeneke ngota i roto i te taiao koiora) he mahi nui ki te whakatau i te mahi patu huakita. He mea nui kia mōhiotia, ko ngā uara RMSD o ngā pūhui katoa i hangaia i raro iho i te 2 Å, e whakaū ana ko ō rātou tūnga piri he rite te hanganga ki te āhua here o te ligand kua whakakotahihia, e tautoko ana i tō rātou kaha hei aukati PBP2a kaha.
Ahakoa he nui ngā matapae a ngā kaute hononga me ngā uara RMS, kāore i te mārama tonu te hononga i waenga i ēnei hua hononga me te mahi patu huakita i te tirohanga tuatahi. Ahakoa e tautokona ana te aukati PBP2a hei mea matua e awe ana i te mahi patu huakita, he maha ngā rerekētanga e kī ana he mea nui anō hoki ētahi atu āhuatanga koiora. Ko ngā matū 6 me te 13b i whakaatu i te mahi patu huakita teitei rawa atu, me te diameter rohe aukati o te 4 cm me ngā uara MIC iti rawa (9.7 μg/100 μL) me te MBC (78.125 μg/100 μL), ahakoa he iti ake ō rātou kaute hononga ki ngā matū 7, 9, 10 me te 14. E kī ana tēnei ahakoa he whai wāhi te aukati PBP2a ki te mahi patu huakita, ko ngā mea pēnei i te wairewa, te waatea koiora me ngā āhuatanga taunekeneke i roto i te taiao huakita ka awe anō hoki i te mahi whānui. E whakaatu ana te Pikitia 11 i ō rātou tūnga hononga, e tohu ana ko ngā matū e rua, ahakoa he iti noa ngā kaute here, ka taea tonu te taunekeneke me ngā toenga matua o te PBP2a, ka taea ai te whakau i te matatini aukati. E whakaatu ana tēnei ahakoa he nui ngā māramatanga nui e whakaratohia ana e te hononga ngota ngota ki te aukati i te PBP2a, me whai whakaaro ki ētahi atu āhuatanga koiora kia tino mārama ai ki ngā pānga patu huakita o ēnei matū ki te ao tūturu.
Mā te whakamahi i te hanganga tioata o PBP2a (PDB ID: 4CJN), i hangaia he mahere taunekeneke 2D me te 3D o ngā matū tino kaha 6 me te 13b i honoa ki te pūmua here-penicillin 2a (PBP2a) o te Staphylococcus aureus ātete-methicillin (MRSA). Ka whakatauritehia e ēnei mahere ngā tauira taunekeneke o ēnei matū ki te ligand quinazolinone kua honoa anōtia (CCL), e whakaatu ana i ngā taunekeneke matua pēnei i te here hauwai, te whakarārangi-π, me ngā taunekeneke ionic.
I kitea tētahi tauira ōrite mō te pūhui 7, i whakaatu i tētahi kaute taunga teitei (-6.32) me tētahi diameter rohe aukati rite (3.9 cm) ki te pūhui 10. Heoi, ko tōna MIC (39.08 μg/100 μL) me te MBC (39.06 μg/100 μL) he nui ake, e tohu ana me nui ake ngā kukū hei whakaatu i te pānga patu huakita. E whakaatu ana tēnei ahakoa i whakaatu te pūhui 7 i te kaha here i roto i ngā rangahau taunga, ko ngā āhuatanga pēnei i te waatea koiora, te tango pūtau, me ētahi atu āhuatanga ā-tinana me te matū ka whakawhāiti i tōna whai huatanga koiora. Ahakoa i whakaatu te pūhui 7 i ngā āhuatanga patu huakita, he iti ake tōna whai huatanga ki te aukati i te tipu huakita ki te whakataurite ki ngā pūhui 6 me te 13b.
I whakaatuhia e te Pūhui 10 tētahi rerekētanga nui ake me te kaute hononga teitei rawa (-6.40), e tohu ana i te kaha o te hononga ki te PBP2a. Heoi, ko tōna whānui rohe aukati (3.9 cm) he rite ki te pūhui 7, ā, ko tōna MBC (312 μg/100 μL) he nui ake i ngā pūhui 6, 7, me 13b, e tohu ana i te ngoikore o te mahi patu huakita. E whakaatu ana tēnei ahakoa ngā matapae hononga pai, kāore i te tino whai hua te pūhui 10 ki te patu i te MRSA nā ētahi atu āhuatanga whakawhāiti pēnei i te wairewa, te pumau, te ngoikore rānei o te uruhanga o te kiriuhi huakita. E tautoko ana ēnei hua i te māramatanga ahakoa he mahi nui te aukati PBP2a i roto i te mahi patu huakita, kāore e tino whakamārama i ngā rerekētanga o te mahi koiora i kitea i waenga i ngā pūhui i whakamatautauria. E kī ana ēnei rerekētanga me whai atu ngā tātaritanga whakamātautau me ngā aromatawai koiora hohonu hei whakamārama katoa i ngā tikanga patu huakita e whai wāhi ana.
Ko ngā hua o te hononga ngota i roto i te Ripanga 4 me te Kōnae Raraunga Tāpiri e whakaatu ana i te whanaungatanga uaua i waenga i ngā kaute hononga me te mahi patu huakita. Ahakoa he iti ake ngā kaute hononga o ngā pūhui 6 me te 13b i ngā pūhui 7, 9, 10, me te 14, ko rātou te hunga tino kaha patu huakita. Ko ā rātou mahere taunekeneke (e whakaaturia ana i te Pikitia 11) e tohu ana ahakoa he iti ake ā rātou kaute here, kei te hanga tonu rātou i ngā here hauwai nui me ngā taunekeneke π-stacking me ngā toenga matua o PBP2a ka taea te whakau i te matatini whākōkī-aukati i roto i te huarahi whai hua koiora. Ahakoa he iti noa ngā kaute hononga o te 6 me te 13b, ko tā rātou mahi patu huakita kua whakarei ake e kī ana me whai whakaaro ki ētahi atu āhuatanga pēnei i te wairewa, te pumau, me te tango pūtau me ngā raraunga hononga i te aromatawai i te pūmanawa aukati. E whakaatu ana tēnei i te hiranga o te whakakotahi i ngā rangahau hononga me te tātaritanga whakamātautau patu huakita hei aromatawai tika i te pūmanawa rongoā o ngā pūhui hou.
E whakaatu ana ēnei hua ahakoa he taputapu kaha te hononga ngota ngota mō te matapae i te hononga here me te tautuhi i ngā tikanga aukati pea, kaua e whakawhirinaki ki a ia anake hei whakatau i te whai huatanga o te patu huakita. E kī ana ngā raraunga ngota ngota ko te aukati PBP2a he mea matua e awe ana i te mahi patu huakita, engari e kī ana ngā huringa o te mahi koiora me arotau i ētahi atu āhuatanga ā-tinana me te pharmacokinetic hei whakarei ake i te whai huatanga rongoā. Me arotahi ngā rangahau ā muri ake nei ki te arotau i te hanganga matū o ngā pūhui 7 me te 10 hei whakapai ake i te waatea koiora me te tango pūtau, me te whakarite kia whakamaoritia ngā taunekeneke hononga kaha ki te mahi patu huakita tuturu. Ko ngā rangahau anō, tae atu ki ngā whakamātautau koiora tāpiri me te tātari hononga hanganga-mahi (SAR), he mea nui hei whakawhānui ake i tō tātou māramatanga ki te mahi a ēnei pūhui hei aukati PBP2a me te whakawhanake i ngā kaihoko patu huakita whai hua ake.
I whakaatuhia e ngā matū i hangaia mai i te 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ngā taumata rerekē o te mahi patu huakita, me ētahi matū e whakaatu ana i te aukati nui o te Staphylococcus aureus ātete-methicillin (MRSA). I ​​whakaatuhia e te tātaritanga whanaungatanga hanganga-mahi (SAR) ngā āhuatanga hanganga matua e tautoko ana i te whai huatanga patu huakita o ēnei matū.
I kitea te hiranga o te noho mai o ngā rōpū acrylonitrile me te anthracene hei whakarei ake i te mahi patu huakita. He mea nui te rōpū nitrile tino tauhohe i roto i te acrylonitrile hei whakahaere i ngā taunekeneke me ngā pūmua huakita, ā, ka whai wāhi atu ki ngā āhuatanga patu huakita o te matū. Ko ngā matū kei roto ko te acrylonitrile me te anthracene i whakaatu tonu i ngā pānga patu huakita kaha ake. Nā te kakara o te rōpū anthracene i whakau ake i ēnei matū, ā, tera pea ka whakarei ake i tā rātou mahi koiora.
Nā te whakaurunga o ngā mowhiti heterocyclic i tino whakapai ake te whai huatanga patu huakita o ētahi momo matū. Ina koa, ko te benzothiazole derivative 13b me te acrylhydrazide derivative 6 i whakaatu i te kaha patu huakita teitei rawa atu me te rohe aukati tata ki te 4 cm. I whakaatuhia e ēnei matū heterocyclic he pānga koiora nui ake, e tohu ana he mahi nui tā te hanganga heterocyclic i roto i ngā pānga patu huakita. Waihoki, ko te pyrimidinethione i roto i te matū 9, te thiopyrazole i roto i te matū 10, me te mowhiti tetrazine i roto i te matū 11 i whai wāhi ki ngā āhuatanga patu huakita o ngā matū, e whakaatu ana i te hiranga o te whakarerekētanga heterocyclic.
I roto i ngā matū i hangaia, i tū te 6 me te 13b mō ā rāua mahi patu huakita pai rawa atu. Ko te kukū aukati iti rawa (MIC) o te matū 6 he 9.7 μg/100 μL, ā, ko te kukū patu huakita iti rawa (MBC) he 78.125 μg/100 μL, e whakaatu ana i tōna kaha pai ki te whakakore i te Staphylococcus aureus ātete-methicillin (MRSA). Waihoki, he rohe aukati te matū 13b o te 4 cm me ngā uara MIC me te MBC iti, e whakaū ana i tōna kaha patu huakita kaha. E whakaatu ana ēnei hua i ngā mahi matua o ngā rōpū mahi a te acrylohydrazide me te benzothiazole ki te whakatau i te whai huatanga koiora o ēnei matū.
He rerekē, ko ngā matū 7, 10, me te 14 i whakaatu i te kaha huakita ngawari me ngā rohe aukati mai i te 3.65 ki te 3.9 cm. I hiahiatia e ēnei matū he kukū teitei ake hei patu katoa i ngā huakita, e whakaatuhia ana e ō rātou uara MIC me te MBC teitei. Ahakoa he iti ake te kaha o ēnei matū i ngā matū 6 me te 13b, i whakaatu tonu i te kaha huakita nui, e kī ana ko te whakaurunga o ngā wāhanga acrylonitrile me te anthracene ki roto i te mowhiti heterocyclic ka whai wāhi ki tō rātou pānga huakita.
He rerekē ngā momo mahi a ngā matū, ko ētahi he āhuatanga patu huakita, ko ētahi he pānga patu huakita. He patu huakita ngā matū 7, 11, 13a, me te 15, ā, me iti ake ngā kukū hei patu katoa i ngā huakita. He rerekē, he patu huakita ngā matū 6, 13b, me te 14, ā, ka taea te aukati i te tipu o ngā huakita i ngā kukū iti ake, engari me nui ake ngā kukū hei patu katoa i ngā huakita.
I te nuinga o te wā, e whakaatu ana te tātaritanga whanaungatanga hanganga-ngāwari i te hiranga o te whakauru i ngā wāhanga acrylonitrile me te anthracene me ngā hanganga heterocyclic hei whakatutuki i te mahi antibacterial nui. E whakaatu ana ēnei hua ko te arotautanga o ēnei wāhanga hanganga me te tūhuratanga o ngā whakarerekētanga atu hei whakapai ake i te wairewatanga me te urunga o te kiriuhi ka arahi pea ki te whanaketanga o ngā rongoā anti-MRSA whai hua ake.
I purea, ā, i whakamaroketia ngā matū me ngā whakarewa katoa mā te whakamahi i ngā tikanga paerewa (El Gomhouria, Ihipa). I whakatauhia ngā pūwāhi rewa mā te whakamahi i tētahi taputapu pūwāhi rewa hiko GallenKamp, ā, ka ripoatatia me te kore he whakatikatika. I tuhia ngā hihi infrared (IR) (cm⁻1) i te Tari Matū, te Wāhanga Pūtaiao, Te Whare Wānanga o Ain Shams mā te whakamahi i ngā pire pāhare pākawa (KBr) i runga i tētahi mita Thermo Electron Nicolet iS10 FTIR (Thermo Fisher Scientific, Waltham, MA, USA).
I whiwhihia ngā irahiko 1H NMR i te 300 MHz mā te whakamahi i tētahi irahiko GEMINI NMR (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) me tētahi irahiko BRUKER 300 MHz NMR (BRUKER Manufacturing & Engineering, Inc.). I whakamahia te Tetramethylsilane (TMS) hei paerewa ā-roto me te deuterated dimethyl sulfoxide (DMSO-d₆). I whakahaerehia ngā inenga NMR i te Wāhanga Pūtaiao, Te Whare Wānanga o Cairo, Giza, Ihipa. I whakahaerehia te tātari huānga (CHN) mā te whakamahi i tētahi Perkin-Elmer 2400 Elemental Analyzer, ā, he pai te ōrite o ngā hua i whiwhi ki ngā uara i tatauhia.
I whakamahanahia he ranunga o te waikawa 3 (5 mmol) me te thionyl chloride (5 ml) i roto i te kaukau wai i te 65 °C mō te 4 hāora. I tangohia te thionyl chloride taikaha mā te whakatōtō i raro i te pēhanga iti. I kohia te totoka whero i puta mai, ā, i whakamahia me te kore he purenga anō. Te ira rewa: 200-202 °C, te hua: 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. Kaitātari. I tatauhia mō C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. I kitea: C, 74.41; H, 3.34; N, 4.66%.
I te 0°C, i whakarewaina te 4 (2 mmol, 0.7 g) ki roto i te dioxane anhydrous (20 ml) ā, i tāpirihia te hydrazine hydrate (2 mmol, 0.16 ml, 80%) mā te maturuturu, ā, i whakaohokia mō te 1 hāora. I kohia te totoka i whakapūmautia mā te tātari, ā, i whakakōkītia anō mai i te etanoru hei hanga i te matū 6.
Ngā tioata kakariki, te ira rewa 190-192℃, te hua 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, ka taea te whakawhiti), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Uara tatau mō C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. I kitea: C, 84.01; H, 4.38; N, 8.05%.
Whakarewahia te 4 (2 mmol, 0.7 g) ki roto i te 20 ml o te otinga dioxane anhydrous (kei roto ētahi pata o te triethylamine), tāpirihia te phenylhydrazine/2-aminopyridine (2 mmol) ka whakaohokia i te pāmahana rūma mō te 1 me te 2 h, ia. Ringihia te ranunga tauhohenga ki roto i te hukapapa, i te wai rānei, ka whakakawahia ki te waikawa hauwaiwai waimeha. Tātarihia te totoka kua wehea ka whakakōkī anō mai i te etanoru kia whiwhi ai i te 7, ka whakakōkī anō mai i te benzene kia whiwhi ai i te 8.
Ngā tioata kakariki, te ira rewa 160-162℃, te hua 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, ka taea te whakawhiti), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Uara tatau mō C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. I kitea: C, 81.96; H, 3.91; N, 8.91%.
I whakarewaina te 4 (2 mmol, 0.7 g) ki roto i te 20 ml o te wairewa dioxane anhydrous (kei roto ētahi pata o te triethylamine), i tāpirihia te 2-aminopyridine (2 mmol, 0.25 g) ā, i whakaohokia te ranunga i te pāmahana rūma mō te 2 h. I ringihia te ranunga tauhohenga ki roto i te wai hukapapa, ā, i whakakawaihia ki te waikawa hauwaiwai waimeha. I tātarihia te matū i hangaia, ā, i whakakākanohia anō mai i te benzene, ka puta he tioata kakariki o te 8 me te ira rewa o te 146-148 °C me te hua o te 82.5%; te whānuitanga whero-whero (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, ka taea te whakawhiti), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); I tatauhia mō C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. I kitea: C, 78.93; H, 3.97; N, 12.36%.
I whakarewaina te matū 4 (2 mmol, 0.7 g) ki roto i te 20 ml o te dioxane maroke (kei roto ētahi pata o te triethylamine me te 2 mmol o te thiourea/semicarbazide) ā, i whakamahanatia i raro i te reflux mō te 2 hāora. I mimitia te whakarewa i roto i te vacuum. I whakakōata anōtia te toenga mai i te dioxane kia puta he ranunga.