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Ua hoʻohuihui ʻia ka synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 a hoʻohana ʻia e hoʻohuihui i nā ʻano hui heterocyclic ikaika loa ma o kāna hana ʻana me nā nucleophiles nitrogen like ʻole. Ua wehewehe pono ʻia ke ʻano o kēlā me kēia hui heterocyclic i hoʻohuihui ʻia me ka hoʻohana ʻana i ka nānā spectroscopic a me elemental. ʻO ka ʻumi o nā hui heterocyclic hou he ʻumikumamākolu i hōʻike i ka hopena hoʻoikaika e kūʻē i nā bacteria multidrug-resistant (MRSA). I ​​waena o lākou, ua hōʻike nā hui 6, 7, 10, 13b, a me 14 i ka hana antibacterial kiʻekiʻe loa me nā wahi inhibition kokoke i 4 cm. Eia nō naʻe, ua hōʻike nā haʻawina docking molecular he ʻokoʻa nā pilina o nā hui i ka penicillin-binding protein 2a (PBP2a), kahi pahuhopu koʻikoʻi no ke kūʻē ʻana iā MRSA. Ua hōʻike kekahi mau hui e like me 7, 10 a me 14 i ka pilina kiʻekiʻe a me ka paʻa o ka launa pū ʻana ma kahi hana o PBP2a i hoʻohālikelike ʻia me ka ligand quinazolinone i hui pū ʻia. I ka hoʻohālikelike ʻana, ua haʻahaʻa nā helu docking o nā hui 6 a me 13b akā ua hōʻike mau i ka hana antibacterial koʻikoʻi, me ka hui 6 i loaʻa nā waiwai MIC haʻahaʻa loa (9.7 μg/100 μL) a me MBC (78.125 μg/100 μL). Ua hōʻike ka loiloi docking i nā pilina koʻikoʻi e pili ana i ka hoʻopaʻa ʻana o ka hydrogen a me ka π-stacking, ʻoi aku hoʻi me nā koena e like me Lys 273, Lys 316 a me Arg 298, i ʻike ʻia e launa pū ana me ka ligand co-crystallized i loko o ke ʻano kristal o PBP2a. He mea nui kēia mau koena no ka hana enzymatic o PBP2a. Hōʻike kēia mau hopena e hiki i nā hui i synthesized ke lawelawe ma ke ʻano he mau lāʻau anti-MRSA hoʻohiki, e hōʻike ana i ke koʻikoʻi o ka hoʻohui ʻana i ka molecular docking me nā bioassays e ʻike i nā moho therapeutic kūpono.
I nā makahiki mua o kēia kenekulia, ua kālele nui ʻia nā hana noiʻi ma ka hoʻomohala ʻana i nā kaʻina hana hou a maʻalahi no ka hana ʻana o kekahi mau ʻōnaehana heterocyclic hou me ka hana antimicrobial me ka hoʻohana ʻana i nā mea hoʻomaka i loaʻa koke.
Ua manaʻo ʻia nā ʻāpana Acrylonitrile he mau mea hoʻomaka koʻikoʻi no ka synthesis o nā ʻōnaehana heterocyclic kupaianaha he nui no ka mea he mau hui reactive kiʻekiʻe lākou. Eia kekahi, ua hoʻohana nui ʻia nā derivatives 2-cyanoacryloyl chloride i nā makahiki i hala iho nei no ka hoʻomohala ʻana a me ka synthesis o nā huahana koʻikoʻi ma ke kahua o nā noi pharmacological, e like me nā mea waena lāʻau lapaʻau1,2,3, nā precursors o anti-HIV, antiviral, anticancer, antibacterial, antidepressant a me nā antioxidant agents4,5,6,7,8,9,10. I kēia manawa, ua huki nui ʻia ka pono olaola o ka anthracene a me kāna mau derivatives, me kā lākou antibiotic, anticancer11,12, antibacterial13,14,15 a me nā waiwai insecticidal16,17,18,19,20,21. Hōʻike ʻia nā hui antimicrobial e loaʻa ana nā ʻāpana acrylonitrile a me anthracene ma nā Kiʻi 1 a me 2.
Wahi a ka World Health Organization (WHO) (2021), ʻo ke kū'ē ʻana i ka antimicrobial (AMR) he hoʻoweliweli honua i ke olakino a me ka hoʻomohala ʻana22,23,24,25. ʻAʻole hiki ke ho'ōla ʻia nā maʻi, e hopena ana i ka noho lōʻihi ʻana o ka haukapila a me ka pono no nā lāʻau lapaʻau pipiʻi, a me ka hoʻonui ʻia o ka make a me ke kīnā. ʻO ka nele o nā antimicrobial kūpono e alakaʻi pinepine ai i ka hāʻule ʻana o ka mālama ʻana no nā maʻi like ʻole, ʻoiai i ka wā o ka chemotherapy a me nā ʻoki kino nui.
Wahi a ka hōʻike a ka World Health Organization 2024, ua hoʻokomo ʻia ka methicillin-resistant Staphylococcus aureus (MRSA) a me E. coli i ka papa inoa o nā pathogens koʻikoʻi. Kūʻē nā bacteria ʻelua i nā antibiotics he nui, no laila ke hōʻike nei lākou i nā maʻi i paʻakikī ke mālama a me ka kaohi, a aia kahi pono wikiwiki e hoʻomohala i nā hui antimicrobial hou a maikaʻi hoʻi e hoʻoponopono i kēia pilikia. ʻO Anthracene a me kāna mau derivatives he mau antimicrobial kaulana i hiki ke hana ma nā bacteria Gram-positive a me Gram-negative. ʻO ka pahuhopu o kēia haʻawina, ʻo ia ke hana i kahi derivative hou e hiki ke hakakā i kēia mau pathogens i weliweli i ke olakino.
Ua hōʻike ka World Health Organization (WHO) he nui nā pathogens bacteria i kū'ē i nā antibiotics he nui, me ka methicillin-resistant Staphylococcus aureus (MRSA), kahi kumu maʻamau o ka maʻi ma ke kaiāulu a me nā wahi mālama ola. Ua hōʻike ʻia he 64% kiʻekiʻe ka nui o ka make ʻana o nā maʻi me nā maʻi MRSA ma mua o ka poʻe me nā maʻi i hiki ke hoʻopilikia i ka lāʻau. Eia kekahi, he pilikia honua ko E. coli no ka mea ʻo ka laina hope loa o ka pale ʻana i ka carbapenem-resistant Enterobacteriaceae (ʻo ia hoʻi, E. coli) ʻo colistin, akā ua hōʻike hou ʻia nā bacteria colistin-resistant ma kekahi mau ʻāina. 22,23,24,25
No laila, e like me ka World Health Organization Global Action Plan on Antimicrobial Resistance26, aia kahi pono wikiwiki no ka ʻike ʻana a me ka synthesis o nā antimicrobial hou. Ua hōʻike ʻia ka hiki nui o ka anthracene a me ka acrylonitrile ma ke ʻano he antibacterial27, antifungal28, anticancer29 a me nā mea antioxidant30 i nā pepa i paʻi ʻia he nui. Ma kēia ʻano, hiki ke ʻōlelo ʻia he mau moho maikaʻi kēia mau derivatives no ka hoʻohana ʻana e kūʻē i ka methicillin-resistant Staphylococcus aureus (MRSA).
Ua hoʻoikaika nā loiloi palapala mua iā mākou e hana i nā derivatives hou i loko o kēia mau papa. No laila, ua manaʻo ke aʻo ʻana i kēia manawa e hoʻomohala i nā ʻōnaehana heterocyclic hou e loaʻa ana nā ʻāpana anthracene a me acrylonitrile, e loiloi i ko lākou pono antimicrobial a me antibacterial, a noiʻi i kā lākou mau pilina paʻa me ka penicillin-binding protein 2a (PBP2a) ma o ka molecular docking. Ma ke kūkulu ʻana ma luna o nā haʻawina mua, ua hoʻomau ke aʻo ʻana i kēia manawa i ka synthesis, ka loiloi biological, a me ka nānā ʻana i ka computational o nā ʻōnaehana heterocyclic e ʻike i nā mea hoʻohiki antimethicillin-resistant Staphylococcus aureus (MRSA) me ka hana hoʻopaʻa PBP2a ikaika31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Ke kālele nei kā mākou noiʻi o kēia manawa i ka synthesis a me ka loiloi antimicrobial o nā hui heterocyclic hou e loaʻa ana nā ʻāpana anthracene a me acrylonitrile. Ua hoʻomākaukau ʻia a hoʻohana ʻia ʻo 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ma ke ʻano he poloka hale no ke kūkulu ʻana i nā ʻōnaehana heterocyclic hou.
Ua hoʻoholo ʻia ke ʻano o ka hui 4 me ka hoʻohana ʻana i ka ʻikepili spectral. Ua hōʻike ka spectrum 1H-NMR i ke alo o CH= ma 9.26 ppm, ua hōʻike ka spectrum IR i ke alo o kahi hui carbonyl ma 1737 cm−1 a me kahi hui cyano ma 2224 cm−1, a ua hōʻoia pū ka spectrum 13CNMR i ke ʻano i manaʻo ʻia (e ʻike i ka ʻāpana Hoʻokolohua).
Ua hoʻokō ʻia ka synthesis o 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ma o ka hydrolysis o nā hui aromatic 250, 41, 42, 53 me ka ethanolic sodium hydroxide solution (10%) e hāʻawi i nā waikawa 354, 45, 56, a laila i mālama ʻia me ka thionyl chloride ma kahi ʻauʻau wai e hāʻawi i ka acryloyl chloride derivative 4 i ka hua kiʻekiʻe (88.5%), e like me ka mea i hōʻike ʻia ma ke Kiʻi 3.
No ka hana ʻana i nā hui heterocyclic hou me ka hopena antibacterial i manaʻo ʻia, ua hoʻokō ʻia ka hopena o ka acyl chloride 4 me nā dinucleophiles like ʻole.
Ua mālama ʻia ka waikawa chloride 4 me ka hydrazine hydrate ma 0° no hoʻokahi hola. ʻO ka mea pōʻino, ʻaʻole i loaʻa ka pyrazolone 5. ʻO ka huahana he acrylamide derivative nona ka ʻano i hōʻoia ʻia e ka ʻikepili spectral. Ua hōʻike kāna spectrum IR i nā kaula absorption o C=O ma 1720 cm−1, C≡N ma 2228 cm−1 a me NH ma 3424 cm−1. Ua hōʻike ka spectrum 1H-NMR i kahi hōʻailona singlet hoʻololi o nā protons olefin a me nā protons NH ma 9.3 ppm (e ʻike i ka Māhele Hoʻokolohua).
Ua hoʻopili ʻia ʻelua mole o ka waikawa chloride 4 me hoʻokahi mole o ka phenylhydrazine e hāʻawi i ka N-phenylacryloylhydrazine derivative 7 i ka hua maikaʻi (77%) (Kiʻi 5). Ua hōʻoia ʻia ke ʻano o 7 e ka ʻikepili spectroscopy infrared, kahi i hōʻike i ka omo ʻana o ʻelua mau hui C=O ma 1691 a me 1671 cm−1, ka omo ʻana o ka hui CN ma 2222 cm−1 a me ka omo ʻana o ka hui NH ma 3245 cm−1, a ua hōʻike kāna spectrum 1H-NMR i ka hui CH ma 9.15 a me 8.81 ppm a me ka proton NH ma 10.88 ppm (e ʻike i ka ʻāpana Hoʻokolohua).
Ma kēia haʻawina, ua noiʻi ʻia ka hopena o ka acyl chloride 4 me 1,3-dinucleophiles. ʻO ka mālama ʻana o ka acyl chloride 4 me 2-aminopyridine i loko o 1,4-dioxane me TEA ma ke ʻano he kumu ma ka mahana o ka lumi i hāʻawi i ka acrylamide derivative 8 (Kiʻi 5), nona ke ʻano i ʻike ʻia me ka hoʻohana ʻana i ka ʻikepili spectral. Ua hōʻike nā spectra IR i nā hui absorption o ka cyano stretching ma 2222 cm−1, NH ma 3148 cm−1, a me carbonyl ma 1665 cm−1; Ua hōʻoia nā spectra 1H NMR i ke alo o nā protons olefin ma 9.14 ppm (e ʻike i ka Māhele Hoʻokolohua).
Hoʻopili ka hui 4 me ka thiourea e hāʻawi i ka pyrimidinethione 9; hoʻopili ka hui 4 me ka thiosemicarbazide e hāʻawi i ka thiopyrazole derivative 10 (Kiʻi 5). Ua hōʻoia ʻia nā ʻano o nā hui 9 a me 10 e ka loiloi spectral a me elemental (e ʻike i ka ʻāpana Hoʻokolohua).
Ua hoʻomākaukau ʻia ʻo Tetrazine-3-thiol 11 ma o ka hopena o ka hui 4 me ka thiocarbazide ma ke ʻano he 1,4-dinucleophile (Kiʻi 5), a ua hōʻoia ʻia kona ʻano e ka spectroscopy a me ka nānā ʻana o nā mea. I loko o ka spectrum infrared, ua ʻike ʻia ka pilina C=N ma 1619 cm−1. I ka manawa like, ua mālama kāna spectrum 1H-NMR i nā hōʻailona multiplate o nā protons aromatic ma 7.78–8.66 ppm a me nā protons SH ma 3.31 ppm (e ʻike i ka Māhele Hoʻokolohua).
Hoʻopili ʻo Acryloyl chloride 4 me 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, a me ethanolamine ma ke ʻano he 1,4-dinucleophiles e hana i nā ʻōnaehana heterocyclic hou (13–16).
Ua hōʻoia ʻia nā ʻano o kēia mau hui i hoʻohui hou ʻia e ka loiloi spectral a me elemental (e ʻike i ka ʻāpana Hoʻokolohua). Ua loaʻa ka 2-Hydroxyphenylacrylamide derivative 17 ma o ka hopena me 2-aminophenol ma ke ʻano he dinucleophile (Kiʻi 6), a ua hōʻoia ʻia kona ʻano e ka loiloi spectral a me elemental. Ua hōʻike ka spectrum infrared o ka hui 17 ua ʻike ʻia nā hōʻailona C=O a me C≡N ma 1681 a me 2226 cm−1, kēlā me kēia. I kēia manawa, ua mālama kāna spectrum 1H-NMR i ka hōʻailona singlet o ka proton olefin ma 9.19 ppm, a ua ʻike ʻia ka proton OH ma 9.82 ppm (e ʻike i ka ʻāpana Hoʻokolohua).
ʻO ka hopena o ka waikawa chloride 4 me hoʻokahi nucleophile (e laʻa, ethylamine, 4-toluidine, a me 4-methoxyaniline) i loko o dioxane ma ke ʻano he solvent a me TEA ma ke ʻano he catalyst ma ka mahana o ka lumi i hāʻawi i nā derivatives acrylamide crystalline ʻōmaʻomaʻo 18, 19a, a me 19b. Ua hōʻoia nā ʻikepili Elemental a me spectral o nā hui 18, 19a, a me 19b i nā ʻano o kēia mau derivatives (e ʻike i ka Māhele Hoʻokolohua) (Kiʻi 7).
Ma hope o ka nānā ʻana i ka hana antimicrobial o nā hui synthetic like ʻole, ua loaʻa nā hopena like ʻole e like me ka mea i hōʻike ʻia ma ka Papa 1 a me ke Kiʻi 8 (e nānā i ka faila kiʻi). Ua hōʻike nā hui āpau i hoʻāʻo ʻia i nā kekelē like ʻole o ka pale ʻana i ka bacteria Gram-positive MRSA, ʻoiai ua hōʻike ka bacteria Gram-negative Escherichia coli i ke kūʻē piha ʻana i nā hui āpau. Hiki ke hoʻokaʻawale ʻia nā hui i hoʻāʻo ʻia i ʻekolu mau māhele e pili ana i ke anawaena o ka ʻāpana pale ʻana e kūʻē iā MRSA. ʻO ka māhele mua ka mea hana nui loa a he ʻelima mau hui (6, 7, 10, 13b a me 14). ʻO ke anawaena o ka ʻāpana pale o kēia mau hui ua kokoke i 4 cm; ʻo nā hui hana nui loa ma kēia māhele ʻo ia nā hui 6 a me 13b. ʻO ka lua o ka māhele he hana waena a he ʻelima mau hui ʻē aʻe (11, 13a, 15, 18 a me 19a). ʻO ka ʻāpana pale o kēia mau hui mai 3.3 a 3.65 cm, me ka hui 11 e hōʻike ana i ka ʻāpana pale nui loa o 3.65 ± 0.1 cm. Ma ka ʻaoʻao ʻē aʻe, ʻo ka hui hope loa he ʻekolu mau hui (8, 17 a me 19b) me ka hana antimicrobial haʻahaʻa loa (ʻoi aku ka liʻiliʻi ma mua o 3 cm). Hōʻike ka Kiʻi 9 i ka hoʻolaha ʻana o nā wahi pale like ʻole.
ʻO ka noiʻi hou ʻana i ka hana antimicrobial o nā hui i hoʻāʻo ʻia e pili ana i ka hoʻoholo ʻana o ka MIC a me MBC no kēlā me kēia hui. Ua ʻokoʻa iki nā hopena (e like me ka mea i hōʻike ʻia ma nā Papa 2, 3 a me ke Kiʻi 10 (e nānā i ka faila kiʻi)), me nā hui 7, 11, 13a a me 15 i hoʻokaʻawale hou ʻia ʻo ia nā hui maikaʻi loa. Loaʻa iā lākou nā waiwai MIC a me MBC haʻahaʻa loa (39.06 μg/100 μL). ʻOiai ʻo nā hui 7 a me 8 he haʻahaʻa nā waiwai MIC (9.7 μg/100 μL), ʻoi aku ke kiʻekiʻe o kā lākou mau waiwai MBC (78.125 μg/100 μL). No laila, ua manaʻo ʻia ua nāwaliwali lākou ma mua o nā hui i ʻōlelo ʻia ma mua. Eia nō naʻe, ʻo kēia mau hui ʻeono ka mea i ʻoi aku ka maikaʻi o nā mea i hoʻāʻo ʻia, ʻoiai ʻo kā lākou mau waiwai MBC ma lalo o 100 μg/100 μL.
ʻOi aku ka liʻiliʻi o ka hana o nā hui (10, 14, 18 a me 19b) i hoʻohālikelike ʻia me nā hui ʻē aʻe i hoʻāʻo ʻia ʻoiai ʻo kā lākou waiwai MBC mai 156 a 312 μg/100 μL. Ma ka ʻaoʻao ʻē aʻe, ʻo nā hui (8, 17 a me 19a) ka mea i hoʻohiki iki ʻole ʻia no ka mea ʻo lākou nā waiwai MBC kiʻekiʻe loa (625, 625 a me 1250 μg/100 μL, kēlā me kēia).
ʻO ka mea hope loa, e like me nā pae hoʻomanawanui i hōʻike ʻia ma ka Papa 3, hiki ke hoʻokaʻawale ʻia nā hui i hoʻāʻo ʻia i ʻelua mau māhele e pili ana i kā lākou ʻano hana: nā hui me ka hopena bactericidal (7, 8, 10, 11, 13a, 15, 18, 19b) a me nā hui me ka hopena antibacterial (6, 13b, 14, 17, 19a). I waena o lākou, makemake ʻia nā hui 7, 11, 13a a me 15, e hōʻike ana i ka hana pepehi kanaka ma kahi haʻahaʻa loa (39.06 μg/100 μL).
ʻO ka ʻumi o nā hui he ʻumikumamākolu i hoʻāʻo ʻia ua hōʻike i ka hiki ke kūʻē i ka methicillin-resistant Staphylococcus aureus (MRSA) kūʻē i ka antibiotic. No laila, ua ʻōlelo ʻia ka nānā hou ʻana me nā pathogens kūʻē i ka antibiotic (ʻoi aku ka isolates kūloko e uhi ana i nā bacteria pathogenic Gram-positive a me Gram-negative) a me nā hū pathogenic, a me ka hoʻāʻo cytotoxic o kēlā me kēia hui e loiloi i kona palekana.
Ua hana ʻia nā haʻawina docking molecular e loiloi i ka hiki o nā hui i synthesized ʻia e like me nā mea hoʻopaʻa o ka penicillin-binding protein 2a (PBP2a) i loko o ka methicillin-resistant Staphylococcus aureus (MRSA). ʻO PBP2a kahi enzyme koʻikoʻi i komo i ka biosynthesis o ka paia cell bacteria, a ʻo ka pale ʻana o kēia enzyme ke hoʻopilikia nei i ka hoʻokumu ʻana o ka paia cell, a ʻo ka hopena e alakaʻi ana i ka lysis bacteria a me ka make cell1. Ua helu ʻia nā hopena docking ma ka Papa 4 a ua wehewehe ʻia me nā kikoʻī hou aku i loko o ka faila ʻikepili hoʻohui, a hōʻike nā hopena ua hōʻike kekahi mau hui i ka pilina paʻa ikaika no PBP2a, ʻoiai nā koena kahua hana koʻikoʻi e like me Lys 273, Lys 316, a me Arg 298. ʻO nā pilina, me ka hydrogen bonding a me ka π-stacking, ua like loa me nā mea o ka co-crystallized quinazolinone ligand (CCL), e hōʻike ana i ka hiki o kēia mau hui e like me nā mea hoʻopaʻa ikaika.
Ua hōʻike ikaika ka ʻikepili docking molekala, me nā ʻano helu ʻē aʻe, ʻo ka pale ʻana o PBP2a ke kumu nui i kuleana no ka hana antibacterial i ʻike ʻia o kēia mau hui. Ua hōʻike hou aku nā helu docking a me nā waiwai root mean square deviation (RMSD) i ka pilina pili a me ke kūpaʻa, e kākoʻo ana i kēia kuhiakau. E like me ka mea i hōʻike ʻia ma ka Papa 4, ʻoiai ua hōʻike kekahi mau hui i ka pilina pili maikaʻi, ʻoi aku ka kiʻekiʻe o nā helu docking o kekahi mau hui (e laʻa, 7, 9, 10, a me 14) ma mua o ka ligand co-crystallized, e hōʻike ana he ikaika paha ko lākou pilina me nā koena kahua hana o PBP2a. Eia nō naʻe, ua hōʻike nā hui bioactive loa 6 a me 13b i nā helu docking haʻahaʻa iki (-5.98 a me -5.63, kēlā me kēia) i hoʻohālikelike ʻia me nā ligands ʻē aʻe. Hōʻike kēia ʻoiai hiki ke hoʻohana ʻia nā helu docking e wānana i ka pilina pili, ʻo nā mea ʻē aʻe (e laʻa, ke kūpaʻa o ka ligand a me nā pilina molekala i loko o ke kaiapuni olaola) he kuleana koʻikoʻi hoʻi i ka hoʻoholo ʻana i ka hana antibacterial. ʻO ka mea nui, ʻo nā waiwai RMSD o nā hui i synthesized ʻia ma lalo o 2 Å, e hōʻoia ana i ko lākou mau kūlana docking e kūlike me ke ʻano hoʻopaʻa o ka ligand co-crystallized, e kākoʻo hou ana i ko lākou hiki ke lilo i mau mea hoʻopaʻa PBP2a ikaika.
ʻOiai ʻo nā helu docking a me nā waiwai RMS e hāʻawi i nā wānana waiwai nui, ʻaʻole maopopo mau ka pilina ma waena o kēia mau hopena docking a me ka hana antimicrobial i ka nānā mua ʻana. ʻOiai ua kākoʻo ikaika ʻia ka pale ʻana o PBP2a ma ke ʻano he kumu nui e hoʻopilikia ai i ka hana antimicrobial, hōʻike kekahi mau ʻokoʻa he kuleana koʻikoʻi ko nā waiwai olaola ʻē aʻe. Ua hōʻike nā hui 6 a me 13b i ka hana antimicrobial kiʻekiʻe loa, me ke anawaena o ka wahi inhibition o 4 cm a me nā waiwai MIC haʻahaʻa loa (9.7 μg/100 μL) a me MBC (78.125 μg/100 μL), ʻoiai ko lākou mau helu docking haʻahaʻa i hoʻohālikelike ʻia me nā hui 7, 9, 10 a me 14. Hōʻike kēia ʻoiai ʻo ka pale ʻana o PBP2a e hāʻawi i ka hana antimicrobial, ʻo nā mea e like me ka solubility, bioavailability a me nā dynamics interaction i loko o ke kaiapuni bacteria e hoʻopilikia pū i ka hana holoʻokoʻa. Hōʻike ka Kiʻi 11 i ko lākou mau kūlana docking, e hōʻike ana ua hiki nō i nā hui ʻelua, ʻoiai me nā helu nakinaki haʻahaʻa, ke launa pū me nā koena koʻikoʻi o PBP2a, e hoʻopaʻa ana i ka complex inhibition. Hōʻike kēia ʻoiai ʻo ka docking molecular e hāʻawi i nā ʻike koʻikoʻi i ka pale ʻana o PBP2a, pono e noʻonoʻo ʻia nā mea olaola ʻē aʻe e hoʻomaopopo piha i nā hopena antimicrobial maoli o kēia mau hui.
Ma ka hoʻohana ʻana i ke ʻano kristal o PBP2a (PDB ID: 4CJN), ua kūkulu ʻia nā palapala pilina 2D a me 3D o nā hui hana nui loa 6 a me 13b i hoʻopaʻa ʻia me ka penicillin-binding protein 2a (PBP2a) o methicillin-resistant Staphylococcus aureus (MRSA). Hoʻohālikelike kēia mau palapala i nā ʻano pilina o kēia mau hui me ka ligand quinazolinone co-crystallized (CCL) i hoʻopaʻa hou ʻia, e hōʻike ana i nā pilina koʻikoʻi e like me ka hydrogen bonding, π-stacking, a me nā pilina ionic.
Ua ʻike ʻia kekahi ʻano like no ka hui 7, kahi i hōʻike i kahi helu docking kiʻekiʻe (-6.32) a me kahi anawaena like o ka inhibition zone (3.9 cm) i ka hui 10. Eia nō naʻe, ʻoi aku ka kiʻekiʻe o kona MIC (39.08 μg/100 μL) a me MBC (39.06 μg/100 μL), e hōʻike ana he pono ia i nā ʻano kiʻekiʻe e hōʻike i ka hopena antibacterial. Hōʻike kēia ʻoiai ua hōʻike ka hui 7 i ka ikaika o ka nakinaki ʻana i nā haʻawina docking, ʻo nā mea e like me ka bioavailability, cellular uptake, a i ʻole nā ​​​​​​waiwai physicochemical ʻē aʻe e kaupalena i kona pono olaola. ʻOiai ua hōʻike ka hui 7 i nā waiwai bactericidal, ʻaʻole ia i kūpono i ka pale ʻana i ka ulu ʻana o ka bacteria i hoʻohālikelike ʻia me nā hui 6 a me 13b.
Ua hōʻike ka Hui 10 i kahi ʻokoʻa koʻikoʻi me ka helu docking kiʻekiʻe loa (-6.40), e hōʻike ana i ka pilina paʻa ikaika iā PBP2a. Eia nō naʻe, ua like kona anawaena o ka ʻāpana inhibition (3.9 cm) me ka hui 7, a ʻo kona MBC (312 μg/100 μL) ua ʻoi aku ke kiʻekiʻe ma mua o nā hui 6, 7, a me 13b, e hōʻike ana i ka hana bactericidal nāwaliwali. Hōʻike kēia ʻoiai ʻoiai nā wānana docking maikaʻi, ʻaʻole i emi ka hopena o ka hui 10 i ka pepehi ʻana iā MRSA ma muli o nā mea palena ʻē aʻe e like me ka solubility, ke kūpaʻa, a i ʻole ka permeability maikaʻi ʻole o ka membrane bacteria. Kākoʻo kēia mau hopena i ka hoʻomaopopo ʻana ʻoiai ke pāʻani nei ka inhibition PBP2a i kahi kuleana koʻikoʻi i ka hana antibacterial, ʻaʻole ia e wehewehe piha i nā ʻokoʻa o ka hana olaola i ʻike ʻia ma waena o nā hui i hoʻāʻo ʻia. Hōʻike kēia mau ʻokoʻa e pono nā loiloi hoʻokolohua hou aʻe a me nā loiloi olaola hohonu e wehewehe piha i nā ʻano antibacterial i pili.
Hōʻike nā hopena docking molecular ma ka Papa 4 a me ka Waihona ʻIkepili Hoʻohui i ka pilina paʻakikī ma waena o nā helu docking a me ka hana antimicrobial. ʻOiai ʻoi aku ka haʻahaʻa o nā helu docking o nā hui 6 a me 13b ma mua o nā hui 7, 9, 10, a me 14, hōʻike lākou i ka hana antimicrobial kiʻekiʻe loa. Hōʻike kā lākou mau palapala launa (i hōʻike ʻia ma ke Kiʻi 11) ʻoiai ʻo kā lākou mau helu nakinaki haʻahaʻa, hana mau lākou i nā pilina hydrogen koʻikoʻi a me nā pilina π-stacking me nā koena koʻikoʻi o PBP2a hiki ke hoʻopaʻa i ka complex enzyme-inhibitor ma ke ʻano biologically pono. ʻOiai ʻo nā helu docking haʻahaʻa o 6 a me 13b, hōʻike kā lākou hana antimicrobial i hoʻonui ʻia e pono e noʻonoʻo ʻia nā waiwai ʻē aʻe e like me ka solubility, stability, a me ka cellular uptake me ka ʻikepili docking i ka wā e loiloi ai i ka hiki ke inhibitor. Hōʻike kēia i ke koʻikoʻi o ka hoʻohui ʻana i nā haʻawina docking me ka loiloi antimicrobial hoʻokolohua e loiloi pololei i ka hiki ke therapeutic o nā hui hou.
Hōʻike kēia mau hopena ʻoiai he mea hana ikaika ka docking molecular no ka wānana ʻana i ka pilina pili a me ka ʻike ʻana i nā ʻano hana hiki ke kāohi, ʻaʻole pono e hilinaʻi wale ʻia e hoʻoholo i ka pono antimicrobial. Hōʻike ka ʻikepili molecular he mea nui ka pale ʻana o PBP2a e hoʻopilikia ana i ka hana antimicrobial, akā hōʻike nā loli i ka hana olaola e pono e hoʻomaikaʻi ʻia nā waiwai physicochemical a me pharmacokinetic ʻē aʻe e hoʻonui i ka pono therapeutic. Pono nā haʻawina e hiki mai ana e kālele i ka hoʻonui ʻana i ke ʻano kemika o nā hui 7 a me 10 e hoʻomaikaʻi i ka bioavailability a me ka lawe ʻana o ke kelepona, e hōʻoia ana e unuhi ʻia nā pilina docking ikaika i ka hana antimicrobial maoli. ʻO nā haʻawina hou aʻe, me nā bioassays hou aʻe a me ka loiloi pilina-hana (SAR), e koʻikoʻi ia e hoʻonui i ko mākou ʻike pehea e hana ai kēia mau hui ma ke ʻano he mau mea hoʻopaʻa PBP2a a e hoʻomohala i nā mea antimicrobial ʻoi aku ka maikaʻi.
Ua hōʻike nā hui i hana ʻia mai 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 i nā ʻano like ʻole o ka hana antimicrobial, me kekahi mau hui e hōʻike ana i ka pale nui ʻana o ka methicillin-resistant Staphylococcus aureus (MRSA). Ua hōʻike ka loiloi pilina hana-ʻano (SAR) i nā hiʻohiʻona koʻikoʻi o ke ʻano hana ma lalo o ka pono antimicrobial o kēia mau hui.
ʻO ke alo o nā hui acrylonitrile a me anthracene i hōʻoia ʻia he mea koʻikoʻi no ka hoʻonui ʻana i ka hana antimicrobial. Pono ka hui nitrile reactive kiʻekiʻe i loko o ka acrylonitrile e hoʻomaʻamaʻa i ka launa pū ʻana me nā protein bacteria, a laila e hāʻawi ana i nā waiwai antimicrobial o ka hui. Ua hōʻike mau nā hui i loaʻa ka acrylonitrile a me ka anthracene i nā hopena antimicrobial ikaika. ʻO ka aromaticity o ka hui anthracene i hoʻopaʻa hou i kēia mau hui, e hoʻonui ana i kā lākou hana olaola.
ʻO ka hoʻolauna ʻana o nā apo heterocyclic i hoʻomaikaʻi nui i ka pono antibacterial o kekahi mau derivatives. Ma ke ʻano kūikawā, ua hōʻike ka benzothiazole derivative 13b a me ka acrylhydrazide derivative 6 i ka hana antibacterial kiʻekiʻe loa me kahi ʻāpana inhibition o kahi o 4 cm. Ua hōʻike kēia mau derivatives heterocyclic i nā hopena olaola koʻikoʻi, e hōʻike ana he kuleana koʻikoʻi ko ke ʻano heterocyclic i nā hopena antibacterial. Pēlā nō, ua kōkua ka pyrimidinethione i loko o ka hui 9, thiopyrazole i loko o ka hui 10, a me ke apo tetrazine i loko o ka hui 11 i nā waiwai antibacterial o nā hui, e hōʻike hou ana i ke koʻikoʻi o ka hoʻololi heterocyclic.
Ma waena o nā hui i hana ʻia, ua kū ʻo 6 a me 13b no kā lākou mau hana antibacterial maikaʻi loa. ʻO ka palena iki o ka inhibitory concentration (MIC) o ka hui 6 he 9.7 μg/100 μL, a ʻo ka palena iki o ka bactericidal concentration (MBC) he 78.125 μg/100 μL, e hōʻike ana i kona hiki ke hoʻomaʻemaʻe i ka methicillin-resistant Staphylococcus aureus (MRSA). Pēlā nō, he 4 cm ka palena o ka hui 13b a me nā waiwai MIC a me MBC haʻahaʻa, e hōʻoia ana i kāna hana antibacterial ikaika. Hōʻike kēia mau hopena i nā kuleana koʻikoʻi o nā hui hana acrylohydrazide a me benzothiazole i ka hoʻoholo ʻana i ka bioefficacy o kēia mau hui.
I ka hoʻohālikelike ʻana, ua hōʻike nā hui 7, 10, a me 14 i ka hana antibacterial waena me nā wahi inhibition mai 3.65 a 3.9 cm2. Pono kēia mau hui i nā ʻāpana kiʻekiʻe e pepehi loa i nā bacteria, e like me ka mea i hōʻike ʻia e ko lākou mau waiwai MIC a me MBC kiʻekiʻe. ʻOiai ʻaʻole i hana nui kēia mau hui ma mua o nā hui 6 a me 13b, ua hōʻike mau lākou i ka hiki ke antibacterial koʻikoʻi, e hōʻike ana i ka hoʻohui ʻia ʻana o nā ʻāpana acrylonitrile a me anthracene i loko o ke apo heterocyclic e hāʻawi i kā lākou hopena antibacterial.
He ʻokoʻa nā ʻano hana o nā hui, hōʻike kekahi i nā waiwai bactericidal a ʻo kekahi e hōʻike ana i nā hopena bacteriostatic. ʻO nā hui 7, 11, 13a, a me 15 he bactericidal a koi i nā ʻano haʻahaʻa e pepehi loa i ka bacteria. I ka hoʻohālikelike ʻana, ʻo nā hui 6, 13b, a me 14 he bacteriostatic a hiki ke kāohi i ka ulu ʻana o ka bacteria ma nā ʻano haʻahaʻa, akā koi i nā ʻano kiʻekiʻe e pepehi loa i ka bacteria.
Ma keʻano holoʻokoʻa, hōʻike ka loiloi pilina hana-ʻano i ke koʻikoʻi o ka hoʻolauna ʻana i nā ʻāpana acrylonitrile a me anthracene a me nā ʻano heterocyclic e hoʻokō i ka hana antibacterial koʻikoʻi. Hōʻike kēia mau hopena i ka hoʻonui ʻana i kēia mau ʻāpana kūkulu a me ka ʻimi ʻana i nā hoʻololi hou aʻe e hoʻomaikaʻi i ka solubility a me ka membrane permeability e alakaʻi i ka hoʻomohala ʻana i nā lāʻau anti-MRSA ʻoi aku ka maikaʻi.
Ua hoʻomaʻemaʻe ʻia a hoʻomaloʻo ʻia nā reagents a me nā solvents āpau me ka hoʻohana ʻana i nā kaʻina hana maʻamau (El Gomhouria, ʻAigupita). Ua hoʻoholo ʻia nā kiko heheʻe me ka hoʻohana ʻana i kahi mea hana kiko heheʻe uila GallenKamp a ua hōʻike ʻia me ka ʻole o ka hoʻoponopono. Ua hoʻopaʻa ʻia nā spectra Infrared (IR) (cm⁻1) ma ka 'Oihana Kemika, Faculty of Science, Ain Shams University me ka hoʻohana ʻana i nā pellets potassium bromide (KBr) ma kahi spectrometer Thermo Electron Nicolet iS10 FTIR (Thermo Fisher Scientific, Waltham, MA, USA).
Ua loaʻa nā spectra 1H NMR ma 300 MHz me ka hoʻohana ʻana i kahi spectrometer GEMINI NMR (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) a me kahi spectrometer BRUKER 300 MHz NMR (BRUKER Manufacturing & Engineering, Inc.). Ua hoʻohana ʻia ʻo Tetramethylsilane (TMS) ma ke ʻano he kūlana kūloko me ka deuterated dimethyl sulfoxide (DMSO-d₆). Ua hana ʻia nā ana NMR ma ke Kula ʻEpekema, ke Kulanui ʻo Cairo, Giza, ʻAigupita. Ua hana ʻia ka loiloi Elemental (CHN) me ka hoʻohana ʻana i kahi Perkin-Elmer 2400 Elemental Analyzer a ua kūlike nā hopena i loaʻa me nā waiwai i helu ʻia.
Ua hoʻomehana ʻia kahi hui ʻana o ka waikawa 3 (5 mmol) a me ka thionyl chloride (5 ml) i loko o ka ʻauʻau wai ma 65 °C no 4 h. Ua wehe ʻia ka thionyl chloride keu ma o ka distillation ma lalo o ke kaomi i hoʻemi ʻia. Ua hōʻiliʻili ʻia ka mea paʻa ʻulaʻula i loaʻa a hoʻohana ʻia me ka ʻole o ka hoʻomaʻemaʻe hou ʻana. Kikowaena heheʻe: 200-202 °C, 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. Luna kālailai. I helu ʻia no C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Loaʻa: C, 74.41; H, 3.34; N, 4.66%.
Ma 0°C, ua hoʻoheheʻe ʻia ʻo 4 (2 mmol, 0.7 g) i loko o ka dioxane anhydrous (20 ml) a ua hoʻohui ʻia ka hydrazine hydrate (2 mmol, 0.16 ml, 80%) i kulu a hoʻoulu ʻia no 1 h. Ua hōʻiliʻili ʻia ka mea paʻa i hoʻoheheʻe ʻia ma o ka kānana ʻana a ua hoʻoheheʻe hou ʻia mai ka ethanol e hāʻawi i ka hui 6.
Nā kristal ʻōmaʻomaʻo, kiko heheʻe 190-192 ℃, 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, hiki ke hoʻololi ʻia), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Ka waiwai i helu ʻia no C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Loaʻa: C, 84.01; H, 4.38; N, 8.05%.
E hoʻoheheʻe i ka 4 (2 mmol, 0.7 g) i loko o 20 ml o ka hopena dioxane anhydrous (loaʻa kekahi mau kulu o ka triethylamine), e hoʻohui i ka phenylhydrazine/2-aminopyridine (2 mmol) a hoʻoulu i ka mahana o ka lumi no 1 a me 2 h, kēlā me kēia. E ninini i ka hui hopena i loko o ka hau a i ʻole ka wai a hoʻomāʻaʻa me ka waikawa hydrochloric dilute. E kānana i ka mea paʻa i hoʻokaʻawale ʻia a hoʻohou hou mai ka ethanol e loaʻa ai ka 7 a hoʻohou hou mai ka benzene e loaʻa ai ka 8.
Nā kristal ʻōmaʻomaʻo, kiko heheʻe 160-162 ℃, 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, hiki ke hoʻololi ʻia), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Ka waiwai i helu ʻia no C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Loaʻa: C, 81.96; H, 3.91; N, 8.91%.
Ua hoʻoheheʻe ʻia ʻo 4 (2 mmol, 0.7 g) i loko o 20 ml o ka hopena dioxane anhydrous (loaʻa kekahi mau kulu o ka triethylamine), ua hoʻohui ʻia ʻo 2-aminopyridine (2 mmol, 0.25 g) a ua hoʻoulu ʻia ka hui ʻana ma ka mahana o ka lumi no 2 h. Ua ninini ʻia ka hui hopena i loko o ka wai hau a ua hoʻohuihui ʻia me ka waikawa hydrochloric dilute. Ua kānana ʻia ka precipitate i hana ʻia a ua hoʻāla hou ʻia mai ka benzene, e hāʻawi ana i nā kristal ʻōmaʻomaʻo o 8 me kahi kiko heheʻe o 146-148 °C a me kahi hua o 82.5%; spectrum 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, hiki ke hoʻololi ʻia), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); I helu ʻia no C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Loaʻa: C, 78.93; H, 3.97; N, 12.36%.
Ua hoʻoheheʻe ʻia ka hui 4 (2 mmol, 0.7 g) i loko o 20 ml o ka dioxane maloʻo (loaʻa kekahi mau kulu o ka triethylamine a me 2 mmol o ka thiourea/semicarbazide) a ua hoʻomehana ʻia ma lalo o ka reflux no 2 h. Ua hoʻoheheʻe ʻia ka mea hoʻoheheʻe i loko o ka vacuo. Ua hoʻopili hou ʻia ke koena mai ka dioxane e hāʻawi i kahi hui.