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E mepụtara ma jiri synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 iji mepụta ọtụtụ ihe ndị na-arụ ọrụ nke ọma site na mmeghachi omume ya na nucleophiles nitrogen dị iche iche. E ji nyocha spectroscopic na elemental kọwaa nhazi nke ihe ọ bụla a na-emepụta heterocyclic. Iri n'ime ihe iri na atọ a na-emepụta heterocyclic gosipụtara irè na-agba ume megide nje bacteria na-eguzogide ọgwụ (MRSA). N'ime ha, ihe ndị a na-emepụta 6, 7, 10, 13b, na 14 gosiri ọrụ kachasị elu nke nje bacteria na mpaghara mgbochi dị nso na 4 cm. Agbanyeghị, ọmụmụ ihe gbasara molekul gosiri na ihe ndị a nwere njikọ dị iche iche na protein penicillin-binding 2a (PBP2a), nke bụ isi ihe mgbaru ọsọ maka iguzogide MRSA. Ụfọdụ ihe ndị dị ka 7, 10 na 14 gosipụtara njikọ dị elu na nkwụsi ike mmekọrịta na ebe PBP2a na-arụ ọrụ ma e jiri ya tụnyere quinazolinone ligand co-crystallized. N'ụzọ dị iche, ngwakọta 6 na 13b nwere obere akara docking mana ha ka gosipụtara ọrụ nje bacteria dị ukwuu, ebe ngwakọta 6 nwere uru MIC kacha ala (9.7 μg/100 μL) na MBC (78.125 μg/100 μL). Nyocha docking kpughere mmekọrịta dị mkpa gụnyere njikọ hydrogen na π-stacking, ọkachasị na residues dị ka Lys 273, Lys 316 na Arg 298, nke achọpụtara dị ka mmekọrịta na ligand co-crystallized na nhazi kristal nke PBP2a. Residues ndị a dị mkpa maka ọrụ enzymatic nke PBP2a. Nsonaazụ ndị a na-egosi na ngwakọta ndị a haziri ahazi nwere ike ije ozi dị ka ọgwụ mgbochi MRSA na-ekwe nkwa, na-egosipụta mkpa ọ dị ijikọta docking molecular na bioasys iji chọpụta ndị nwere ike ịgwọ ọrịa dị irè.
N'ime afọ ole na ole mbụ nke narị afọ a, mgbalị nyocha lekwasịrị anya n'ịmepụta usoro na ụzọ ọhụrụ dị mfe maka imepụta ọtụtụ sistemụ heterocyclic ọhụrụ yana ọrụ nje site na iji ihe mmalite dị mfe.
A na-ewere akụkụ Acrylonitrile dị ka ihe mmalite dị mkpa maka imepụta ọtụtụ sistemụ heterocyclic dị egwu n'ihi na ha bụ ihe ndị na-emeghachi omume nke ukwuu. Ọzọkwa, ejirila ihe ndị sitere na 2-cyanoacryloyl chloride mee ihe n'ọtụtụ afọ ndị na-adịbeghị anya maka mmepe na njikọta nke ngwaahịa dị oke mkpa n'ọhịa nke ojiji ọgwụ, dị ka ọgwụ etiti1,2,3, ihe ndị na-ebute ụzọ maka mgbochi HIV, nje virus, ọrịa kansa, nje bacteria, ọgwụ mgbochi mkpali na ihe ndị na-egbochi ọrịa antioxidant4,5,6,7,8,9,10. N'oge na-adịbeghị anya, arụmọrụ bayọlọji nke anthracene na ihe ndị sitere na ya, gụnyere ọgwụ nje ha, ọgwụ mgbochi kansa11,12, nje bacteria13,14,15 na ihe ndị na-egbu nje16,17, adọtala ọtụtụ mmasị18,19,20,21. E gosipụtara ihe ndị sitere na antimicrobial nwere acrylonitrile na anthracene na Foto 1 na 2.
Dịka Òtù Ahụ Ike Ụwa (WHO) (2021) si kwuo, iguzogide ọgwụ nje (AMR) bụ ihe iyi egwu zuru ụwa ọnụ maka ahụike na mmepe22,23,24,25. A pụghị ịgwọ ndị ọrịa, nke na-eme ka ha nọrọ ogologo oge n'ụlọ ọgwụ na mkpa maka ọgwụ ndị dị oke ọnụ, yana mmụba nke ọnwụ na nkwarụ. Enweghị ọgwụ nje dị irè na-edugakarị na ọdịda ọgwụgwọ maka ọrịa dị iche iche, karịsịa n'oge chemotherapy na nnukwu ịwa ahụ.
Dịka akụkọ nke Òtù Ahụ Ike Ụwa nke 2024 si kwuo, a gụnyere Staphylococcus aureus (MRSA) na E. coli nke na-eguzogide methicillin na ndepụta nke nje ndị kacha mkpa. Nje bacteria abụọ a na-eguzogide ọtụtụ ọgwụ nje, ya mere ha na-anọchite anya ọrịa ndị siri ike ịgwọ na ịchịkwa, ọ dịkwa mkpa ngwa ngwa ịmepụta ihe mgbochi nje ọhụrụ na nke dị irè iji dozie nsogbu a. Anthracene na ihe ndị sitere na ya bụ ọgwụ nje a ma ama nke nwere ike ime ihe na nje bacteria Gram-positive na Gram-negative. Ebumnuche nke ọmụmụ ihe a bụ ịmepụta ihe ọhụrụ nke nwere ike ịlụso nje ndị a ọgụ nke dị ize ndụ nye ahụike.
Òtù Ahụike Ụwa (WHO) na-akọ na ọtụtụ nje bacteria na-eguzogide ọtụtụ ọgwụ nje, gụnyere Staphylococcus aureus na-eguzogide methicillin (MRSA), ihe na-akpatakarị ọrịa n'obodo na ebe nlekọta ahụike. A kọrọ na ndị ọrịa nwere ọrịa MRSA nwere ọnụọgụ ọnwụ dị elu nke 64% karịa ndị nwere ọrịa ndị na-ebute ọgwụ. Na mgbakwunye, E. coli na-etinye ihe egwu zuru ụwa ọnụ n'ihi na usoro nchebe ikpeazụ megide Enterobacteriaceae na-eguzogide carbapenem (ya bụ, E. coli) bụ colistin, mana a kọọla nje bacteria na-eguzogide colistin n'oge na-adịbeghị anya n'ọtụtụ mba. 22,23,24,25
Ya mere, dịka Atụmatụ Ọrụ Mba Nile nke Òtù Ahụ Ike Ụwa si kwuo na Mgbochi Nguzogide Mgbochi Ọgwụ Mgbukpọ26, ọ dị mkpa ngwa ngwa ịchọpụta na imepụta ọgwụ nje ọhụrụ. Enwere ike ịkọwa nnukwu ikike nke anthracene na acrylonitrile dị ka ihe nje bacteria27, antifungal28, anticancer29 na antioxidant30 n'ọtụtụ akwụkwọ ebipụtara. N'akụkụ a, enwere ike ikwu na ihe ndị a bụ ezigbo ihe ndị a ga-eji megide Staphylococcus aureus na-eguzogide methicillin (MRSA).
Nyocha akwụkwọ ndị gara aga kpaliri anyị ịmepụta ihe ọhụrụ dị iche iche na klaasị ndị a. Ya mere, ọmụmụ ihe a bu n'obi ịmepụta sistemụ heterocyclic ọhụrụ nwere anthracene na acrylonitrile moieties, nyochaa irè ha na-eji egbochi nje na nje bacteria, ma nyochaa mmekọrịta njikọ ha na protein penicillin-binding 2a (PBP2a) site na docking molecular. Dabere na ọmụmụ ndị gara aga, ọmụmụ ihe a gara n'ihu na njikọta, nyocha bayọlọji, na nyocha mgbakọ na mwepụ nke sistemụ heterocyclic iji chọpụta ihe ndị na-egbochi Staphylococcus aureus (MRSA) na-ekwe nkwa na ha nwere ọrụ mgbochi PBP2a dị ike31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Nnyocha anyị ugbu a lekwasịrị anya na njikọta na nyocha nje nke ihe ndị dị ndụ heterocyclic ọhụrụ nwere anthracene na acrylonitrile. 3-(anthracene-9-yl)-2-cyanoacryloyl chloride 4 ka e ji mee ihe ma jiri ya mee ihe dị ka blọk ụlọ maka iwulite sistemụ heterocyclic ọhụrụ.
E ji data spectral chọpụta nhazi nke compound 4. 1H-NMR spectrum gosiri ọnụnọ nke CH= na 9.26 ppm, IR spectrum gosiri ọnụnọ nke otu carbonyl na 1737 cm−1 na otu cyano na 2224 cm−1, 13CNMR spectrum kwadokwara nhazi a tụrụ aro (lee ngalaba nnwale).
E mepụtara ngwakọta nke 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 site na hydrolysis nke otu aromatic 250, 41, 42, 53 na ngwọta ethanolic sodium hydroxide (10%) iji nye asịd 354, 45, 56, nke e mechara jiri thionyl chloride gwọọ na mmiri ịsa ahụ iji nye acryloyl chloride derivative 4 na nnukwu mkpụrụ (88.5%), dịka egosiri na Foto 3.
Iji mepụta ihe ndị ọhụrụ dị iche iche nwere ike ime ka nje bacteria ghara ịdị irè, e mere mmeghachi omume nke acyl chloride 4 na dinucleophiles dị iche iche.
E jiri hydrazine hydrate gwọọ acid chloride 4 na 0° ruo otu awa. N'ụzọ dị mwute, enwetaghị pyrazolone 5. Ngwaahịa a bụ ihe sitere na acrylamide nke data spectral kwadoro nhazi ya. Ọkwa IR ya gosiri eriri absorption nke C=O na 1720 cm−1, C≡N na 2228 cm−1 na NH na 3424 cm−1. Ọkwa 1H-NMR gosiri akara mgbanwe nke proton olefin na proton NH na 9.3 ppm (lee Ngalaba Nnwale).
E jiri otu mole phenylhydrazine megharịa moles abụọ nke acid chloride 4 iji nye N-phenylacryloylhydrazine derivative 7 ezigbo mkpụrụ (77%) (Foto nke 5). E gosipụtara nhazi nke 7 site na data infrared spectroscopy, nke gosiri nnabata nke otu C=O abụọ na 1691 na 1671 cm−1, nnabata nke otu CN na 2222 cm−1 na nnabata nke otu NH na 3245 cm−1, spectrum 1H-NMR ya gosiri otu CH na 9.15 na 8.81 ppm na NH proton na 10.88 ppm (lee ngalaba nnwale).
N'ọmụmụ ihe a, a nyochachara mmeghachi omume nke acyl chloride 4 na 1,3-dinucleophiles. Ọgwụgwọ nke acyl chloride 4 na 2-aminopyridine na 1,4-dioxane na TEA dị ka ntọala na okpomọkụ ụlọ nyere acrylamide derivative 8 (Foto 5), nke a chọpụtara nhazi ya site na iji data spectral. IR spectra gosiri eriri absorption nke cyano agbatị na 2222 cm−1, NH na 3148 cm−1, na carbonyl na 1665 cm−1; 1H NMR spectra kwadoro ọnụnọ nke olefin protons na 9.14 ppm (lee Ngalaba Nnwale).
Ngwakọta nke 4 na-emeghachi omume na thiourea iji nye pyrimidinethione 9; ngwakọta nke 4 na-emeghachi omume na thiosemiccarbazide iji nye thiopyrazole derivative 10 (Foto nke 5). E gosipụtara nhazi nke ngwakọta nke 9 na 10 site na nyocha spectral na elemental (lee ngalaba nnwale).
E ji mmeghachi omume nke compound 4 na thiocarbazide dị ka 1,4-dinucleophile kwadebe Tetrazine-3-thiol 11 (Foto nke 5), e gosikwara nhazi ya site na spectroscopy na elemental analysis. Na infrared spectrum, njikọ C=N pụtara na 1619 cm−1. N'otu oge ahụ, 1H-NMR spectrum ya jigidere akara multiplate nke aromatic protons na 7.78–8.66 ppm na SH protons na 3.31 ppm (lee Ngalaba Nnwale).
Acryloyl chloride 4 na-emeghachi omume na 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, na ethanolamine dị ka 1,4-dinucleophiles iji mepụta sistemụ heterocyclic ọhụrụ (13–16).
E jiri nyocha spectral na elemental kwado nhazi nke ihe ndị a emepụtara ọhụrụ (lee ngalaba nnwale). E nwetara 2-Hydroxyphenylacrylamide derivative 17 site na mmeghachi omume na 2-aminophenol dị ka dinucleophile (Foto nke 6), a kwadokwara nhazi ya site na nyocha spectral na elemental. Ọdịdị infrared nke ihe mejupụtara 17 gosiri na akara C=O na C≡N pụtara na 1681 na 2226 cm−1, n'otu n'otu. Ka ọ dị ugbu a, spectrum 1H-NMR ya jigidere akara singlet nke proton olefin na 9.19 ppm, proton OH pụtara na 9.82 ppm (lee ngalaba nnwale).
Mmeghachi omume nke acid chloride 4 na otu nucleophile (dịka ọmụmaatụ, ethylamine, 4-toluidine, na 4-methoxyaniline) na dioxane dị ka ihe mgbaze na TEA dị ka ihe na-akpali akpali na okpomọkụ ụlọ nyere kristal acrylamide akwụkwọ ndụ akwụkwọ ndụ 18, 19a, na 19b. Data ihe na spectral nke ihe mejupụtara 18, 19a, na 19b kwadoro nhazi nke ihe ndị a (lee Ngalaba Nnwale) (Foto 7).
Mgbe enyochachara ọrụ nje nke ọtụtụ ihe mejupụtara sịntetik, enwetara nsonaazụ dị iche iche dịka egosiri na Tebụl 1 na Foto 8 (lee faịlụ eserese). Ihe mejupụtara niile a nwalere gosiri ọkwa dị iche iche nke mgbochi megide nje bacteria Gram-positive MRSA, ebe nje bacteria Gram-negative Escherichia coli gosipụtara iguzogide zuru oke na ihe mejupụtara niile. Enwere ike kewaa ihe mejupụtara ndị a nwalere n'ime ụdị atọ dabere na dayameta nke mpaghara mgbochi megide MRSA. Nkebi nke mbụ bụ nke kachasị arụ ọrụ ma nwee ihe mejupụtara ise (6, 7, 10, 13b na 14). Dayameta nke mpaghara mgbochi nke ihe mejupụtara ndị a dị nso na 4 cm; ihe mejupụtara ndị kacha arụ ọrụ na nkebi a bụ ihe mejupụtara 6 na 13b. Nkebi nke abụọ na-arụ ọrụ nke ọma ma nwee ihe mejupụtara ise ọzọ (11, 13a, 15, 18 na 19a). Mpaghara mgbochi nke ihe mejupụtara ndị a sitere na 3.3 ruo 3.65 cm, ebe ihe mejupụtara 11 na-egosi mpaghara mgbochi kachasị nke 3.65 ± 0.1 cm. N'aka nke ọzọ, otu ikpeazụ nwere ihe atọ (8, 17 na 19b) nwere obere ọrụ nje (ihe na-erughị 3 cm). Foto nke 9 na-egosi nkesa nke mpaghara mgbochi dị iche iche.
Nnyocha ọzọ nke ọrụ ọgwụ nje nke ihe ndị a nwalere gụnyere ịchọpụta MIC na MBC maka ihe ọ bụla mejupụtara ya. Nsonaazụ ya dịtụ iche (dịka egosiri na Tebụl 2, 3 na Foto 10 (lee faịlụ eserese)), ebe o doro anya na a na-ahazi ihe ndị dị na 7, 11, 13a na 15 dị ka ihe kacha mma. Ha nwere otu ụkpụrụ MIC na MBC kacha ala (39.06 μg/100 μL). Ọ bụ ezie na ihe ndị dị na 7 na 8 nwere ụkpụrụ MIC dị ala (9.7 μg/100 μL), ụkpụrụ MBC ha dị elu (78.125 μg/100 μL). Ya mere, a na-ewere ha dị ka ndị na-adịghị ike karịa ihe ndị a kpọtụrụ aha na mbụ. Agbanyeghị, ihe ndị dị na isii a bụ ndị kacha arụ ọrụ nke ọma n'ime ndị a nwalere, ebe ọ bụ na ụkpụrụ MBC ha dị n'okpuru 100 μg/100 μL.
Ngwakọta (10, 14, 18 na 19b) adịchaghị arụ ọrụ ma e jiri ya tụnyere ngwakọta ndị ọzọ a nwalere n'ihi na uru MBC ha sitere na 156 ruo 312 μg/100 μL. N'aka nke ọzọ, ngwakọta (8, 17 na 19a) bụ ndị kacha nwee nkwa ebe ha nwere uru MBC kachasị elu (625, 625 na 1250 μg/100 μL, n'otu n'otu).
N'ikpeazụ, dịka ọkwa ndidi egosiri na Tebụl 3 si dị, enwere ike kewaa ngwakọta ndị a nwalere n'ime ụdị abụọ dabere na ụzọ ha si arụ ọrụ: ngwakọta ndị nwere mmetụta nje bacteria (7, 8, 10, 11, 13a, 15, 18, 19b) na ngwakọta ndị nwere mmetụta nje bacteria (6, 13b, 14, 17, 19a). N'ime ha, a na-ahọrọ ngwakọta 7, 11, 13a na 15, nke na-egosi ọrụ igbu egbu na obere mkpokọta (39.06 μg/100 μL).
Iri n'ime ihe iri na atọ e nwalere gosiri na ha nwere ike iguzogide Staphylococcus aureus (MRSA) nke na-eguzogide ọgwụ nje (methicillin-resistance antibiotics). Ya mere, a na-atụ aro ka e jiri ọgwụ nje ndị na-eguzogide ọgwụ nje (karịsịa nje bacteria Gram-positive na Gram-negative) na yist ndị na-ebute ọrịa mee nyocha ọzọ, tinyere nnwale cytotoxic nke ihe ọ bụla iji chọpụta nchekwa ya.
E mere ọmụmụ ihe gbasara molekul iji chọpụta ike nke ihe ndị a na-emepụta dị ka ihe mgbochi nke penicillin-binding protein 2a (PBP2a) na Staphylococcus aureus (MRSA) nke na-eguzogide methicillin. PBP2a bụ enzyme dị mkpa nke na-etinye aka na biosynthesis nke mgbidi mkpụrụ ndụ nje bacteria, mgbochi nke enzyme a na-egbochikwa mmepụta mgbidi mkpụrụ ndụ, nke na-eduga na lysis nke nje bacteria na ọnwụ mkpụrụ ndụ1. E depụtara nsonaazụ docking na Tebụl 4 ma kọwaa nke ọma na faịlụ data mgbakwunye, nsonaazụ ya na-egosikwa na ọtụtụ ihe ndị mejupụtara gosipụtara njikọ siri ike maka PBP2a, ọkachasị ihe fọdụrụ na saịtị dị mkpa dịka Lys 273, Lys 316, na Arg 298. Mmekọrịta ahụ, gụnyere njikọ hydrogen na π-stacking, yiri nke co-crystallized quinazolinone ligand (CCL), na-egosi ike nke ihe ndị a dị ka ihe mgbochi siri ike.
Data docking molecular, yana paramita ndị ọzọ na kọmputa, gosiri nke ọma na mgbochi PBP2a bụ isi ihe na-akpata ọrụ nje bacteria a hụrụ nke ihe ndị a. Akara docking na uru nke mkpuru osisi (RMSD) gosipụtara njikọ na nkwụsi ike njikọ, na-akwado echiche a. Dịka egosiri na Tebụl 4, ebe ọtụtụ ihe mejupụtara gosiri njikọ dị mma, ụfọdụ ihe mejupụtara (dịka ọmụmaatụ, 7, 9, 10, na 14) nwere akara docking dị elu karịa ligand co-crystallized, na-egosi na ha nwere ike inwe mmekọrịta siri ike na ihe fọdụrụ na saịtị na-arụ ọrụ nke PBP2a. Agbanyeghị, ihe mejupụtara bioactive 6 na 13b gosipụtara akara docking dị ntakịrị ala (-5.98 na -5.63, n'otu n'otu) ma e jiri ya tụnyere ligands ndị ọzọ. Nke a na-egosi na ọ bụ ezie na enwere ike iji akara docking buru amụma njikọ, ihe ndị ọzọ (dịka ọmụmaatụ, nkwụsi ike ligand na mmekọrịta molecular na gburugburu ebe obibi) na-arụkwa ọrụ dị mkpa n'ịchọpụta ọrụ nje bacteria. Ihe dị mkpa bụ na uru RMSD nke ihe niile e ji mee ihe dị n'okpuru 2 Å, na-egosi na ọnọdụ ha na-ejikọta ọnụ kwekọrọ na nhazi njikọ nke ligand co-crystallized, na-akwadokwa ikike ha dị ka ndị na-egbochi PBP2a dị ike.
Ọ bụ ezie na akara docking na ụkpụrụ RMS na-enye amụma bara uru, njikọ dị n'etiti nsonaazụ docking ndị a na ọrụ nje anaghị apụta ìhè mgbe niile na nlele mbụ. Ọ bụ ezie na a na-akwado mgbochi PBP2a nke ọma dị ka isi ihe na-emetụta ọrụ nje, ọtụtụ ọdịiche na-egosi na ihe ndị ọzọ dị ndụ na-arụkwa ọrụ dị mkpa. Ngwakọta 6 na 13b gosipụtara ọrụ nje kachasị elu, yana ma dayameta mpaghara mgbochi nke 4 cm na uru MIC kacha ala (9.7 μg/100 μL) na MBC (78.125 μg/100 μL), n'agbanyeghị obere akara docking ha ma e jiri ya tụnyere ogige 7, 9, 10 na 14. Nke a na-egosi na ọ bụ ezie na mgbochi PBP2a na-enye aka na ọrụ nje, ihe ndị dị ka mgbaze, nnweta bioavailability na mmekọrịta na gburugburu ebe obibi nje na-emetụtakwa ọrụ zuru oke. Foto 11 na-egosi ọnọdụ docking ha, na-egosi na ogige abụọ ahụ, ọbụlagodi na obere akara njikọ, ka nwere ike ịmekọrịta na ihe fọdụrụ nke PBP2a, nke nwere ike ime ka mgbagwoju mgbochi ahụ sie ike. Nke a na-eme ka ọ pụta ìhè na ọ bụ ezie na itinye ihe ndị dị ndụ na-enye nghọta dị mkpa na mgbochi PBP2a, a ghaghị ịtụle ihe ndị ọzọ dị ndụ iji ghọta nke ọma mmetụta nje bacteria nke ihe ndị a.
Site na iji usoro kristal nke PBP2a (PDB ID: 4CJN), e wuru maapụ mmekọrịta 2D na 3D nke ogige kachasị arụ ọrụ 6 na 13b nke ejiri protein penicillin-binding 2a (PBP2a) nke Staphylococcus aureus na-eguzogide methicillin (MRSA) kpuchie. Maapụ ndị a na-atụnyere usoro mmekọrịta nke ogige ndị a na quinazolinone ligand (CCL) nke a kpọgharịrị akpọchi, na-egosipụta mmekọrịta dị mkpa dịka njikọ hydrogen, π-stacking, na mmekọrịta ionic.
A hụrụ ụdị ihe yiri nke ahụ maka ngwakọta 7, nke gosiri akara docking dị elu (-6.32) na dayameta mpaghara mgbochi yiri nke ahụ (3.9 cm) na ngwakọta 10. Agbanyeghị, MIC ya (39.08 μg/100 μL) na MBC (39.06 μg/100 μL) dị elu nke ukwuu, na-egosi na ọ chọrọ nnukwu njupụta iji gosipụta mmetụta nje bacteria. Nke a na-egosi na ọ bụ ezie na ngwakọta 7 gosipụtara njikọ siri ike na ọmụmụ docking, ihe ndị dị ka bioavailability, cell ablation, ma ọ bụ ihe ndị ọzọ nwere ike igbochi arụmọrụ bayọlọji ya. Ọ bụ ezie na ngwakọta 7 gosiri ihe ndị na-egbu nje bacteria, ọ dịchaghị irè n'igbochi uto nje bacteria ma e jiri ya tụnyere ngwakọta 6 na 13b.
Njikọta 10 gosiri nnukwu ọdịiche dị na akara docking kachasị elu (-6.40), nke na-egosi njikọ siri ike na PBP2a. Agbanyeghị, mpaghara dayameta mgbochi ya (3.9 cm) yiri compound 7, MBC ya (312 μg/100 μL) dị elu karịa compound 6, 7, na 13b, nke na-egosi ọrụ nje bacteria na-adịghị ike. Nke a na-egosi na n'agbanyeghị amụma docking dị mma, compound 10 adịghị arụ ọrụ nke ọma n'igbu MRSA n'ihi ihe ndị ọzọ na-egbochi ya dịka ịgbaze, nkwụsi ike, ma ọ bụ enweghị ike ịbanye na akpụkpọ ahụ nje bacteria. Nsonaazụ ndị a na-akwado nghọta na ọ bụ ezie na mgbochi PBP2a na-arụ ọrụ dị mkpa na ọrụ nje bacteria, ọ naghị akọwa nke ọma ọdịiche dị na ọrụ nje bacteria a hụrụ n'etiti compound ndị a nwalere. Ọdịiche ndị a na-egosi na ọ dị mkpa ka nyocha nnwale ndị ọzọ na nyocha bayọlọji miri emi iji kọwaa nke ọma usoro nje bacteria metụtara.
Ndochi molekul na-egosi na Tebụl 4 na Faịlụ Data Mgbakwunye na-egosi mmekọrịta dị mgbagwoju anya dị n'etiti akara docking na ọrụ nje. Ọ bụ ezie na ngwakọta 6 na 13b nwere akara docking dị ala karịa ngwakọta 7, 9, 10, na 14, ha na-egosipụta ọrụ nje kachasị elu. Maapụ mmekọrịta ha (egosiri na Foto 11) na-egosi na n'agbanyeghị obere akara njikọ ha, ha ka na-emepụta njikọ hydrogen dị mkpa na mmekọrịta π-stacking na ihe fọdụrụ dị mkpa nke PBP2a nke nwere ike ime ka mgbagwoju anya enzyme-inhibitor kwụsie ike n'ụzọ bara uru na bayoloji. N'agbanyeghị obere akara docking nke 6 na 13b, ọrụ nje ha ka mma na-egosi na a ga-atụle ihe ndị ọzọ dị ka mgbaze, nkwụsi ike, na nnabata sel na njikọ data docking mgbe a na-enyocha ikike inhibitor. Nke a na-egosi mkpa ọ dị ijikọta ọmụmụ docking na nyocha nje nnwale iji nyochaa ikike ọgwụgwọ nke ogige ọhụrụ nke ọma.
Nsonaazụ ndị a na-egosi na ọ bụ ezie na itinye ihe na molekul bụ ngwá ọrụ dị ike maka ịkọ amụma njikọ na ịchọpụta usoro mgbochi nwere ike ime, ekwesighi ịdabere naanị ya iji chọpụta irè ọgwụ nje. Data molekul na-egosi na mgbochi PBP2a bụ isi ihe na-emetụta ọrụ nje, mana mgbanwe na ọrụ bayoloji na-egosi na a ga-emeziwanye ihe ndị ọzọ dị na physicochemical na pharmacokinetic iji melite arụmọrụ ọgwụgwọ. Ọmụmụ ihe ndị ga-eme n'ọdịnihu kwesịrị ilekwasị anya na imeziwanye nhazi kemịkalụ nke compounds 7 na 10 iji melite nnweta bioavailability na nnabata cellular, na-ahụ na mmekọrịta docking siri ike na-atụgharị ka ọ bụrụ ọrụ nje nje n'ezie. Ọmụmụ ihe ndị ọzọ, gụnyere nyocha biosuys na nyocha mmekọrịta nhazi-ọrụ (SAR), ga-adị oke mkpa iji mee ka nghọta anyị dịkwuo mma banyere otu ihe ndị a si arụ ọrụ dị ka ihe mgbochi PBP2a na ịmepụta ihe ndị na-egbochi nje bacteria dị irè karị.
Ngwakọta e ji 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 mepụta gosiri oke ọrụ nje dị iche iche, ọtụtụ ihe mejupụtara ya na-egosi nnukwu mgbochi nke Staphylococcus aureus (MRSA) na-eguzogide methicillin. Nyocha mmekọrịta nhazi na ọrụ (SAR) gosiri isi ihe ndị dị mkpa na-akpata irè nje bacteria nke ihe ndị a.
Ọnụnọ nke otu acrylonitrile na anthracene gosiri na ọ dị oke mkpa maka ịkwalite ọrụ nje. Otu nitrile nke na-arụ ọrụ nke ọma dị na acrylonitrile iji mee ka mmekọrịta ya na protein nje dị mfe, si otú a na-enye aka na njirimara nje nke ihe mejupụtara ya. Ihe mejupụtara ya nwere acrylonitrile na anthracene gosipụtara mmetụta nje bacteria siri ike mgbe niile. Ụtọ nke otu anthracene mere ka ihe ndị a kwụsie ike, nke nwere ike ime ka ọrụ ha dịkwuo mma.
Mwebata nke mgbanaka heterocyclic mere ka irè nje bacteria dị na ọtụtụ ihe ndị e ji agwọ ọrịa dịkwuo mma. Karịsịa, benzothiazole derivative 13b na acrylhydrazide derivative 6 gosiri ọrụ nje bacteria kachasị elu nke nwere mpaghara mgbochi nke ihe dị ka 4 cm. Ihe ndị a heterocyclic derivatives gosiri mmetụta dị mkpa karịa na ihe ndị dị ndụ, na-egosi na nhazi heterocyclic na-arụ ọrụ dị mkpa na mmetụta nje bacteria. N'otu aka ahụ, pyrimidinethione na compound 9, thiopyrazole na compound 10, na tetrazine ring na compound 11 nyere aka na njirimara nje bacteria nke ihe ndị ahụ, na-eme ka ọ pụta ìhè mkpa mgbanwe heterocyclic dị.
N'ime ihe ndị e ji mee ihe, 6 na 13b pụtara ìhè maka ọrụ ha dị oke mma nke nje bacteria. Mbelata mgbochi kacha nta (MIC) nke ihe mejupụtara 6 bụ 9.7 μg/100 μL, ebe mbelata nje bacteria kacha nta (MBC) bụ 78.125 μg/100 μL, nke na-egosi ikike ya dị mma iwepụ Staphylococcus aureus na-eguzogide methicillin (MRSA). N'otu aka ahụ, ihe mejupụtara 13b nwere mpaghara mgbochi nke 4 cm na obere uru MIC na MBC, na-akwado ọrụ nje bacteria dị ike ya. Nsonaazụ ndị a na-egosi ọrụ dị mkpa nke otu ọrụ acrylohydrazide na benzothiazole na-arụ n'ịchọpụta bioeficacy nke ihe mejupụtara ndị a.
N'ụzọ dị iche, ngwakọta 7, 10, na 14 gosipụtara ọrụ nje bacteria dị obere nke nwere mpaghara mgbochi sitere na 3.65 ruo 3.9 cm. Ngwakọta ndị a chọrọ oke njupụta iji gbuo nje bacteria kpamkpam, dịka uru MIC na MBC ha dị elu si gosipụta. Ọ bụ ezie na ngwakọta ndị a adịchaghị arụ ọrụ dịka ngwakọta 6 na 13b, ha ka gosipụtara nnukwu ike nje bacteria, na-egosi na itinye acrylonitrile na anthracene n'ime mgbanaka heterocyclic na-enye aka na mmetụta nje bacteria ha.
Ngwakọta ndị a nwere ụzọ dị iche iche ha si arụ ọrụ, ụfọdụ na-egosi ihe ndị na-egbu nje bacteria, ndị ọzọ na-egosipụtakwa mmetụta nje bacteria. Ngwakọta 7, 11, 13a, na 15 na-egbu nje bacteria ma chọọ obere mkpokọta iji gbuo nje bacteria kpamkpam. N'ụzọ dị iche, ngwakọta 6, 13b, na 14 na-egbochi nje bacteria ma nwee ike igbochi uto nje bacteria na obere mkpokọta, mana ha chọrọ nnukwu mkpokọta iji gbuo nje bacteria kpamkpam.
N'ozuzu, nyocha mmekọrịta nhazi na ọrụ na-egosi mkpa ọ dị iwebata acrylonitrile na anthracene moieties na heterocyclic structures iji nweta ọrụ nje bacteria dị mkpa. Nsonaazụ ndị a na-egosi na imeziwanye ihe ndị a na inyocha mgbanwe ndị ọzọ iji melite mgbaze na ikike membrane permeability nwere ike ibute mmepe nke ọgwụ mgbochi MRSA dị irè karị.
E jiri usoro ọkọlọtọ (El Gomhouria, Egypt) hichaa ma kpọọ nkụ ihe niile e ji eme ihe na ihe mgbaze. E jiri ngwa GallenKamp eletrọniki na-agbaze ihe chọpụta ebe ịgbaze ihe, a na-akọkwa ha na-enweghị mgbazi. E dekọrọ spectra infrared (IR) (cm⁻1) na Ngalaba Kemistri, Faculty of Science, Ain Shams University site na iji potassium bromide (KBr) pellets na Thermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
E ji igwe GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) na igwe BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.) nweta spectrometer 1H NMR na 300 MHz. E jiri Tetramethylsilane (TMS) mee ihe dị ka ọkọlọtọ dị n'ime ya na deuterated dimethyl sulfoxide (DMSO-d₆). E mere nha NMR na Faculty of Science, Mahadum Cairo, Giza, Egypt. E jiri Perkin-Elmer 2400 Elemental Analyzer mee nyocha elemental (CHN) ma nsonaazụ ndị e nwetara kwekọrọ na ụkpụrụ agbakọrọ.
E tinyere ngwakọta nke acid 3 (5 mmol) na thionyl chloride (5 ml) n'ime mmiri ịsa ahụ na okpomọkụ 65 °C ruo awa anọ. E wepụrụ thionyl chloride gabigara ókè site na mwepu n'okpuru nrụgide dị ala. A chịkọtara ihe siri ike uhie nke si na ya pụta ma jiri ya na-enweghị nhicha ọzọ. Ebe ịgbaze: 200-202 °C, mkpụrụ: 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. Onye nyocha. A gbakọọla maka C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Achọpụtara: C, 74.41; H, 3.34; N, 4.66%.
Na okpomọkụ 0°C, a gbazere 4 (2 mmol, 0.7 g) na anhydrous dioxane (20 ml) ma tinye hydrazine hydrate (2 mmol, 0.16 ml, 80%) na-agbada ma gwakọta ya ruo otu awa. A na-anakọta ihe siri ike ahụ a kpọchiri akpọchi site na nzacha ma weghachite ya na ethanol iji nye ihe mejupụtara 6.
Kristal akwụkwọ ndụ akwụkwọ ndụ, ebe agbaze 190-192℃, na-emepụta 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, enwere ike ịgbanwe agbanwe), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); Uru agbakọrọ maka C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Achọpụtara: C, 84.01; H, 4.38; N, 8.05%.
Gwakọta 4 (2 mmol, 0.7 g) na 20 ml nke mmiri ọgwụ dioxane anhydrous (nwere obere ntapụ triethylamine), tinye phenylhydrazine/2-aminopyridine (2 mmol) ma gwakọta ya na okpomọkụ ụlọ maka awa 1 na 2, n'otu n'otu. Wụsa ngwakọta mmeghachi omume ahụ n'ime ice ma ọ bụ mmiri wee mee ka ọ dị ka acidify na acid hydrochloric diluted. Wepụ ihe siri ike nkewa ahụ ma weghachite ya na ethanol iji nweta 7 ma weghachite ya na benzene iji nweta 8.
Kristal akwụkwọ ndụ akwụkwọ ndụ, ebe agbaze 160-162℃, na-emepụta 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, enwere ike ịgbanwe), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteroaromatic); Uru agbakọrọ maka C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Achọpụtara: C, 81.96; H, 3.91; N, 8.91%.
A gbazere 4 (2 mmol, 0.7 g) na 20 ml nke mmiri ọgwụ dioxane anhydrous (nwere ntakịrị ntapụ triethylamine), tinye 2-aminopyridine (2 mmol, 0.25 g) ma kpalie ngwakọta ahụ na okpomọkụ ụlọ ruo awa 2. A wụsara ngwakọta mmeghachi omume ahụ n'ime mmiri ice ma tinye acid hydrochloric acid a gwakọtara agwakọta. A na-ehichapụ ihe e kere eke ahụ ma jiri benzene mee ka ọ dịghachi ọhụrụ, na-enye kristal akwụkwọ ndụ akwụkwọ ndụ nke 8 nwere ebe agbaze nke 146-148 °C na mmepụta nke 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, enwere ike ịgbanwe agbanwe), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); A gbakọrọ maka C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Achọpụtara: C, 78.93; H, 3.97; N, 12.36%.
A gbazere ngwakọta nke 4 (2 mmol, 0.7 g) na 20 ml nke dioxane akọrọ (nwere ntakịrị ntapụ triethylamine na 2 mmol nke thiourea/semicarbazide) ma kpoo ya ọkụ n'okpuru reflux ruo awa 2. A gbazere ihe mgbaze ahụ na vacuo. E si na dioxane ahụ mepụtaghachi ihe fọdụrụnụ iji nye ngwakọta.