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Gin ma ki lwongo ni synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ki yubu ki ki tiyo kwede me yubu jami mapol ma tiyo matek ma rwate ki jami ma pat pat ma ki lwongo ni nitrogen nucleophiles. Kit ma jami ma ki yubu ni tye kwede ki nyutu maber kun kitiyo ki jami ma ki lwongo ni spectroscopic ki elemental analysis. Apar ki ikom apar wiye adek ma ki yubu ma ki lwongo ni heterocyclic compounds onyutu tic maber i kom kwidi two ma pe cang i kom yadi mapol (MRSA). I kin gii, jami ma ki rubu 6, 7, 10, 13b, ki 14 onyutu tic ma malo me lweny i kom kwidi two ki kabedo ma gengo ne cok ki 4 cm. Ento, kwan ma kitimo ikom jami ma ki lwongo ni molecular docking onyutu ni jami ni tye ki kit ma pat pat me mako penicillin-binding protein 2a (PBP2a), ma obedo gin ma pire tek pi gengo MRSA. Jami mogo ma calo 7, 10 ki 14 gunyutu rwate ma malo ki rwate i kabedo ma PBP2a tiyo iye ka kiporo ki co-crystallized quinazolinone ligand. Ka i poro, jami ma ki lwongo ni compound 6 ki 13b onongo tye ki rwom me docking ma piny ento pud onyutu tic ma pire tek me lweny i kom kwidi two, ki compound 6 onongo tye ki MIC (9.7 μg/100 μL) ki MBC (78.125 μg/100 μL) ma piny loyo. Kwedo lok i kom jami ma ki lwongo ni Docking onyutu ni jami ma pire tek ma tye iye hydrogen bonding ki π-stacking, tutwale ki residues calo Lys 273, Lys 316 ki Arg 298, ma kinongo ni gitye ka tic ki co-crystallized ligand i crystal structure pa PBP2a. Jami ma odong ni pire tek pi tic pa enzyme pa PBP2a. Adwogi eni nyutu ni jami ma ki yubu ni twero tic calo yadi maber me lweny i kom MRSA, ma nyutu teko me keto jami ma ki lwongo ni molecular docking ki bioassays me nongo yadi ma tiyo maber.
I mwaka manok mukwongo me cencwari ni, tic me kwedo ngec onwongo tye i kom yubu yoo manyen, ma yot ki diro me yubu jami ma pat pat ma tye ki tic me lweny i kom kwidi two kun kitiyo ki jami ma nonge oyot.
Gin ma ki lwongo ni Acrylonitrile moieties ki ngeyo calo gin ma pire tek me cako yubu jami mapol ma pat pat pien gi tye jami ma tiyo matek. Medo ikom meno, 2-cyanoacryloyl chloride derivatives ni ki tiyo kwede i mwaka manok ma okato ni me dongo ki yubu jami ma pire tek i lok ma mako tic ki yadi, ma calo yat ma ki lwongo ni intermediates1,2,3, precursors me anti-HIV, antiviral, anticancer, antibacterial, antidepressant ki antioxidant lutic4,5,6,7,8,9,10. I kare ni, tic pa anthracene ki jami ma aa ki iye, medo ki yat ma neko kwidi, ma gengo two kanca11,12, ma neko kwidi13,14,15 ki jami ma neko kwidi16,17, okelo tam madwong18,19,20,21. Gin ma ki lwongo ni antimicrobial ma tye ki acrylonitrile ki anthracene moieties ki nyutu gi i cal 1 ki 2.
Malube ki lok pa dul ma kwako yot kom i wilobo (WHO) (2021), teko me lweny i kom kwidi two (AMR) tye gin ma twero balo yotkom ki dongo lobo i wilobo22,23,24,25. Lutwo pe gitwero cang, ma weko gi bedo i ot yat pi kare malac ki mito yat ma wel ne tek, kacel ki medo to ki goro. Pek pa yat ma tiyo maber me lweny i kom kwidi pol kare kelo peko me cango two mapol, tutwal i kare me cango two ki i kare me cango two madongo.
Malube ki ripot pa World Health Organization 2024, methicillin-resistant Staphylococcus aureus (MRSA) ki E. coli ki keto gi i kin two ma pire tek. Kwidi aryo ni gi tek i kom yadi mapol, ki dong gi nyutu two ma tek me cango ki gengo, ki tye gin ma mite oyotoyot me yubu jami manyen ma tiyo maber me lweny i kom peko eni. Anthracene ki jami ma aa ki iye obedo jami ma ki ngeyo maber ma twero tic i kom kwidi ma ki lwongo ni Gram-positive ki Gram-negative. Yub me kwan man tye me yubu gin manyen ma twero lweny i kom two ma kelo peko i kom yotkom.
Dul ma kwako yot kom i wilobo (WHO) owaco ni kwidi mapol ma gi kelo two gi twero lweny ki yat mapol, medo ki methicillin-resistant Staphylococcus aureus (MRSA), ma obedo two ma pol kare kelo two i kin gang ki kabedo me yot kom. Lutwo ma tye ki two MRSA ki waco ni gitye ki wel dano ma too ma malo ki 64% loyo jo ma tye ki two ma twero bino pi yat. Medo ikom meno, E. coli kelo peko i wilobo pien gin ma gengo two ma ki lwongo ni carbapenem-resistant Enterobacteriaceae (ie, E. coli) tye colistin, ento colistin-resistant bacteria dong ki coyo i lobe mapol. 22,23,24,25
Pi meno, malube ki yub pa World Health Organization Global Action Plan on Antimicrobial Resistance26, tye gin ma mite oyotoyot pi nongo ki yubu jami manyen ma gengo two. Teko madit pa anthracene ki acrylonitrile ma calo jami ma neko kwidi27, antifungal28, anticancer29 ki antioxidant30 ki nyutu i papara mapol ma ki coyo. I kom lok man, ki twero waco ni jami ma ki kwanyo ki ikom gi ni ber me tic kwede i kom yat ma ki lwongo ni methicillin-resistant Staphylococcus aureus (MRSA).
Neno lok ma ki coyo con ocuko cwinywa me yubu jami manyen ma aa ki i dul magi. Pi meno, kwan ma tye i kare ni tye me yubu jami manyen ma tye ki anthracene ki acrylonitrile moieties, me temo tic gi me lweny i kom kwidi two ki kwidi two, ki kwedo kit ma gi rwate kwede ki penicillin-binding protein 2a (PBP2a) kun kitiyo ki molecular docking. Medo i kom kwan mukato, kwan ma tye i kare ni omede ki yubu, nyamo jami makwo, ki nyamo jami ma ki lwongo ni heterocyclic systems me nongo jami ma twero gengo antimethicillin-resistant Staphylococcus aureus (MRSA) ma tye ki teko me gengo PBP2a tic31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.
Kwedo ngec wa ma tye ka time i kare ni tye ka neno kit ma ki yubu kwede ki jami ma gengo kwidi two ma pat pat ma tye ki anthracene ki acrylonitrile. 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ki yubu ki ki tiyo kwede macalo gin ma ki tiyo kwede me gedo jami manyen ma ki lwongo ni heterocyclic systems.
Kit ma ki yubu kwede gin ma ki lwongo ni compound 4 ni ki nongo kun kitiyo ki ngec ma ki nongo ki i kom jami ma ki lwongo ni spectral data. Labol me 1H-NMR onyutu ni tye CH= i 9.26 ppm, labol me IR onyutu ni tye gurup me carbonyl i 1737 cm−1 ki gurup me cyano i 2224 cm−1, ki labol me 13CNMR bene omoko kit ma ki yubu kwede (nen dul me temo).
Kit ma ki yubu kwede 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 ki cobo ki hydrolysis pa aromatic groups 250, 41, 42, 53 ki ethanolic sodium hydroxide solution (10%) me miyo acid 354, 45, 65, ma ki tiyo kwede ki thionide i kom pii lwok me miyo acryloyl chloride derivative 4 ma tye ki rwom ma malo (88.5%), ma ki nyutu i cal 3.
Me yubu jami manyen ma ki lwongo ni heterocyclic ma tye ki teko me neko kwidi two, tic pa acyl chloride 4 ki dinucleophiles ma pat pat ki otimo.
Acid chloride 4 ni ki tiyo kwede ki hydrazine hydrate i 0° pi cawa acel. Ki cwer cwiny, pyrazolone 5 pi ki nongo ne. Gin ma ki yubu ni obedo gin ma ki lwongo ni acrylamide ma kit ma ki yubu kwede ki moko ki jami ma ki nongo ki i kom jami ma ki neno. Gin ma ki lwongo ni IR spectrum onyutu dul ma mako C=O i 1720 cm−1, C≡N i 2228 cm−1 ki NH i 3424 cm−1. Gin ma ki lwongo ni 1H-NMR onyutu gin ma ki lwongo ni exchange singlet signal pa olefin protons ki NH protons i 9.3 ppm (nen Experimental Section).
Mole aryo me acid chloride 4 ki rubu ki mole acel me phenylhydrazine me nongo N-phenylacryloylhydrazine derivative 7 ma tye ki adwogi maber (77%) (lanyut 5). Kit ma 7 tye kwede ki moko ki jami ma ki nongo ki i infrared spectroscopy, ma onyutu nongo dul C=O aryo i 1691 ki 1671 cm−1, mako dul CN i 2222 cm−1 ki mako dul NH i 3245 cm−1, ki 1H-NMR spectrum ne onyutu dul 15 ki p88pm. NH proton i 10.88 ppm (nen dul ma ki temo).
I kwan man, kit ma acyl chloride 4 ki 1,3-dinucleophiles gi rwate kwede ki kwedo. Kit ma ki tiyo kwede ki acyl chloride 4 ki 2-aminopyridine i 1,4-dioxane ki TEA ma calo gin ma ki keto i rwom me lyeto me ot okelo acrylamide derivative 8 (lanyut 5), ma ki ngeyo kit ma ki yubu kwede kun kitiyo ki ngec ma ki nongo. IR spectra onyutu dul ma ki lwongo ni absorption bands pa cyano ma odongo i 2222 cm−1, NH i 3148 cm−1, ki carbonyl i 1665 cm−1; 1H NMR spectra moko ni tye pa olefin protons i 9.14 ppm (nen dul ma ki temo).
Gin ma ki lwongo ni Compound 4 rwate ki thiourea me miyo pyrimidinethione 9; gin ma ki lwongo ni compound 4 rwate ki thiosemicarbazide me miyo thiopyrazole derivative 10 (lanyut 5). Kit ma ki yubu kwede jami 9 ki 10 ki moko ki jami ma ki lwongo ni spectral ki elemental analysis (nen dul ma ki temo).
Tetrazine-3-thiol 11 ki yubu ki rwate pa gin ma ki lwongo ni compound 4 ki thiocarbazide ma calo 1,4-dinucleophile (lanyut 5), ki kit ma ki yubu kwede ki moko ki spectroscopy ki elemental analysis. I kin piny ma ki lwongo ni infrared spectrum, C=N bond onen i 1619 cm−1. I kare acel, 1H-NMR spectrum ne ogwoko lanyut mapol pa aromatic protons i 7.78–8.66 ppm ki SH protons i 3.31 ppm (nen Experimental Section).
Acryloyl chloride 4 rwate ki 1,2-diaminobenzene, 2-aminothiophenol, anthranilic acid, 1,2-diaminoethane, ki ethanolamine calo 1,4-dinucleophiles me yubu heterocyclic system manyen (13-16).
Kit ma jami ma ki yubu manyen ni tye kwede ki moko ki jami ma ki lwongo ni spectral ki elemental analysis (nen dul ma ki temo). 2-Hydroxyphenylacrylamide derivative 17 ki nongo ki i rwate ki 2-aminophenol ma calo dinucleophile (lanyut 6), ki kit ma ki yubu kwede ki moko ki i kom jami ma ki neno ki jami ma ki neno. Gin ma ki lwongo ni infrared spectrum pa gin ma ki lwongo ni compound 17 onyutu ni C=O ki C≡N onyutu i 1681 ki 2226 cm−1, kit meno. I kare meno, 1H-NMR spectrum ne ogwoko lanyut acel pa olefin proton i 9.19 ppm, ki OH proton onen i 9.82 ppm (nen dul me temo).
Kit ma acid chloride 4 rwate kwede ki nucleophile acel (me labolle, ethylamine, 4-toluidine, ki 4-methoxyaniline) i dioxane ma calo gin ma ki tiyo kwede me juku ki TEA ma calo gin ma ki tiyo kwede i rwom me lyeto me ot okelo gin ma ki lwongo ni green crystalline acrylamide derivatives 18, 19a, ki 19b. Lok ma mako jami ma ki lwongo ni elemental ki spectral pa jami 18, 19a, ki 19b moko kit ma jami eni tye kwede (nen dul ma ki temo) (lanyut 7).
Iyonge temo tic pa jami ma pat pat ma ki yubu me lweny i kom kwidi two, adwogi ma pat pat kinongo kit ma ki nyutu kwede i Table 1 ki cal 8 (nen cal). Jami ma ki temo ni weng onyutu rwom me gengo ma pat pat i kom kwidi ma ki lwongo ni Gram-positive bacterium MRSA, kun kwidi ma ki lwongo ni Gram-negative bacterium Escherichia coli onyutu ni gi gengo jami ni weny. Jami ma ki temo ni ki twero poko gii i dul adek malube ki dit pa kabedo ma gengo two MRSA. Dul mukwongo onwongo tye ma tiyo matek ki onwongo tye ki jami abic (6, 7, 10, 13b ki 14). Lamal pa kabedo ma ki gengo iye jami eni onwongo tye cok ki 4 cm; jami ma tiyo matek loyo i dul ni obedo jami 6 ki 13b. Dul me aryo ni onwongo tye ka tic maber ki tye ki jami mukene abic (11, 13a, 15, 18 ki 19a). Kabedo ma ki gengo iye jami eni tye i kin 3.3 onyo 3.65 cm, ki gin ma ki lwongo ni compound 11 nyutu kabedo ma ki gengo iye ma dit loyo ma tye 3.65 ± 0.1 cm. Ki tung cing kany, dul me agiki ni tye ki jami adek (8, 17 ki 19b) ma tye ki tic ma lapiny loyo (ma pe okato 3 cm). cal me 9 nyutu poko pa dul ma pat pat ma gengo tic.
Kwedo mukene i kom tic pa jami ma ki temo ni kwako moko MIC ki MBC pi jami acel acel. Adwogi ni obale manok (kit ma ki nyutu kwede i Table 2, 3 ki cal 10 (nen cal)), ki jami ma ki rubu 7, 11, 13a ki 15 ma nen calo ki dwoko gi calo jami maber loyo. Gubedo ki wel MIC ki MBC ma lapiny loyo (39.06 μg/100 μL). Kadi bed ni jami 7 ki 8 onongo tye ki wel MIC ma lapiny (9.7 μg/100 μL), wel MBC gi onongo tye malo (78.125 μg/100 μL). Pi meno, onongo kiterogi calo gin ma goro loyo jami ma kiloko i komgi malo-ni. Ento, jami abicel eni gubedo maber loyo i kin ma ki temo, ma calo wel MBC gi onwongo tye piny 100 μg/100 μL.
Jami ma ki rubu (10, 14, 18 ki 19b) onongo pe tiyo maber ka kiporo ki jami mukene ma ki temo pien wel MBC gi onongo tye i kin 156 nio wa i 312 μg/100 μL. Ki tung cing kany, jami ma ki rubu (8, 17 ki 19a) onwongo pe ki gen pien onwongo tye ki wel MBC ma malo (625, 625 ki 1250 μg/100 μL, kit meno).
Me agiki ne, malube ki rwom me diyo cwiny ma ki nyutu i Table 3, jami ma ki temo ni ki twero poko ne i dul aryo malube ki kit ma gi tiimo kwede: jami ma tye ki teko me neko kwidi (7, 8, 10, 11, 13a, 15, 18, 19b) ki jami ma tye ki teko me neko kwidi (6, 13b, 17b, 1914). I kin gi, jami ma ki rubu 7, 11, 13a ki 15 aye ki maro, ma nyutu tic me neko i rwom ma lapiny (39.06 μg/100 μL).
Jami apar ki ikom apar wiye adek ma ki temo ni onyutu teko me lweny i kom yat ma gengo two ma ki lwongo ni methicillin-resistant Staphylococcus aureus (MRSA). Pi meno, medo temo ki jami ma kelo two ma pe cang ki yat (tutwale jami ma ki kwanyo ma tye ki kwidi ma kelo two ma ki lwongo ni Gram-positive ki Gram-negative) ki pathogenic yeasts ki miiyo tam iye, kacel ki temo cytotoxic compound acel acel me neno ka ber ne.
Kwedo lok ma mako jami ma ki lwongo ni Molecular docking ki otimo me temo teko pa jami ma ki yubu ni calo gin ma gengo penicillin-binding protein 2a (PBP2a) i methicillin-resistant Staphylococcus aureus (MRSA). PBP2a obedo enzyme ma pire tek ma tye i yub pa cell wall pa kwidi two, ki gengo enzyme man balo yub pa cell wall, ma lacen kelo rweny pa bacteria ki to pa cell1. Adwogi me docking ni ki keto i Table 4 ki ki tito ne matut i karatac me ngec ma ki medo, ki adwogi ni nyutu ni jami mapol onyutu teko me mako PBP2a, tutwale kabedo ma tye ka tic calo Lys 273, Lys 316, ki Arg 298. Kit ma gi rwate kwede, medo ki hydrogen bonding ki π-stacking, onongo rom aroma ki ma co-crystallized quinazolinone ligand (CCL), ma nyutu teko pa jami eni ma calo gin ma gengo jami.
Lok ma ki nongo ki ikom jami ma ki lwongo ni molecular docking, kacel ki jami mukene ma ki kwano, nyutu ni PBP2a inhibition obedo gin ma pire tek ma oweko ki neno tic pa jami magi ma neko kwidi two. Wel ma ki nongo ki i rwom me rwate (RMSD) omedo ki nyutu rwate ki rwom me rwate, ma miiyo kony i kom lok man. Kit ma ki nyutu kwede i Table 4, kadi bed ni jami mapol onyutu rwate maber, jami mogo (me labolle, 7, 9, 10, ki 14) onongo tye ki rwom me rwate ma malo loyo co-crystallized ligand, ma nyutu ni gitwero bedo ki rwate matek ki kabedo ma tye ka tic pa PBP2a. Ento, jami ma tiyo maber loyo 6 ki 13b onyutu rwom me rwate ma piny (-5.98 ki -5.63, kit meno) ka kiporo ki jami mukene ma ki lwongo ni ligands. Man nyutu ni kadi bed ni rwom me docking twero tic me byeko rwom me rwate, jami mukene (me labolle, rwom me ligand ki rwate pa molecular i kabedo ma kwo) bene tye ki tic ma pire tek me moko tic pa kwidi two. Ki lok adaa, wel RMSD pa jami ma ki yubu ni tye piny ki 2 Å, ma moko ni kit ma gi rwate kwede tye ma rwate ki kit ma gi rwate kwede ki jami ma ki lwongo ni co-crystallized ligand, ma medo teko gi me bedo calo jami ma gengo PBP2a.
Kadi bed ni rwom me docking ki wel me RMS miyo tam ma pire tek, rwate ma tye i kin adwogi me docking magi ki tic pa jami ma gengo two pe nen ka maleng i neno mukwongo. Kadi bed ni gengo PBP2a ki miiyo kony matek calo gin ma pire tek ma weko tic pa jami ma gengo two, apoka poka mapol nyutu ni jami mukene ma tye i kom dano bene tye ki tic ma pire tek. Gin ma ki lwongo ni Compounds 6 ki 13b onyutu tic ma malo me lweny i kom kwidi two, ki rwom me gengo two ma romo 4 cm ki rwom me MIC (9.7 μg/100 μL) ki MBC (78.125 μg/100 μL) ma piny loyo, kede bed ni rwom me docking gi tye piny ka kiporo ki compounds 7, 9, 10 ki 14 kadi bed ni man nyutu ni. Gengo PBP2a konyo tic pa jami ma neko kwidi, jami ma calo rwom me gonyo, bedo ki jami makwo ki kit ma gi rwate kwede i kin kwidi bene gi gudo tic pa kwidi. cal 11 nyutu kit ma gi cung kwede, ma nyutu ni jami aryo ni weng, kede ma rwom me mako gi tye piny, pud gitwero tic ki jami ma pire tek ma odong i PBP2a, ma twero dwoko rwom me gengo ne piny. Man nyutu ni kadi bed ni dul kom ma ki lwongo ni molecular docking miyo ngec ma pire tek i kom gengo PBP2a, jami mukene ma mako kwo omyera ki nen me niang maber kit ma jami eni twero lweny kwede i kom kwidi two.
Nono kit ma ki yubu kwede PBP2a (PDB ID: 4CJN), 2D ki 3D ma nyutu kit ma jami ma tiyo matek loyo 6 ki 13b ma ki keto i penicillin-binding protein 2a (PBP2a) pa methicillin-resistant Staphylococcus aureus (MRSA) ki yubu. Map magi poro kit ma jami magi gi rwate kwede ki re-docked co-crystallized quinazolinone ligand (CCL), ma nyutu rwate ma pire tek calo hydrogen bonding, π-stacking, ki ionic interactions.
Kit ma rom ki meno ki neno pi gin ma ki lwongo ni compound 7, ma onyutu rwom ma malo (-6.32) ki rwom me gengo ma rom (3.9 cm) ki compound 10. Ento, MIC ne (39.08 μg/100 μL) ki MBC (39.06 μg/100 μL) onongo tye ma malo, ma nyutu ni mito rwom ma malo me nyutu tic me neko kwidi two. Man nyutu ni kadi bed ni gin ma ki lwongo ni compound 7 onyutu teko me mako jami i kwan me docking, jami ma calo bioavailability, cellular uptake, onyo jami mukene ma twero gengo tic pa jami makwo. Kadi bed ni gin ma ki lwongo ni compound 7 onyutu teko me neko kwidi, ento onongo pe tiyo maber me gengo dongo pa kwidi ka kiporo ki gin ma ki lwongo ni compound 6 ki 13b.
Gin ma ki lwongo ni Compound 10 onyutu apoka poka madit ki wel ma malo loyo (-6.40), ma nyutu ni tye ki rwate matek ki PBP2a. Ento, rwom me gengo ne (3.9 cm) onwongo rom ki gin ma ki lwongo ni compound 7, ki MBC (312 μg/100 μL) onwongo tye malo loyo compound 6, 7, ki 13b, ma nyutu ni tic me neko kwidi ne nok. Man nyutu ni kadi bed ni jami ma ki byeko ni tye maber, gin ma ki lwongo ni compound 10 onongo pe tiyo maber me neko MRSA pi jami mukene ma gengo calo goro, bedo ma ocung, onyo pe twero donyo i kom bacteria. Adwogi eni miiyo kony me niang ni kadi bed ni gengo PBP2a tiyo tic ma pire tek i tic pa kwidi two, ento pe tito maber apokapoka ma tye i tic pa jami makwo ma ki neno i kin jami ma ki temo. Apokapoka eni nyutu ni medo kwedo jami ma ki temo ki jami makwo ma rwate ki jami makwo mitte me niang maber kit ma jami ma neko kwidi two ni tiyo kwede.
Adwogi me keto jami ma tye i Table 4 ki Supplementary Data File nyutu wat ma tye i kin rwom me keto jami ki tic pa jami ma gengo two. Kadi bed ni jami 6 ki 13b tye ki rwom me rwate ma piny loyo jami 7, 9, 10, ki 14, gin nyutu tic ma malo me lweny i kom kwidi two. Map me rwate gi (ma ki nyutu i cal 11) nyutu ni kadi bed ni rwom me rwate gi tye piny, gin pud gi yubu hydrogen bonds ma pire tek ki π-stacking interactions ki key residues me PBP2a ma twero gwoko enzyme-inhibitor complex i yoo ma konyo kwo. Kadi bed ni rwom me 6 ki 13b ni tye piny, tic gi me lweny i kom kwidi ma ki medo ni nyutu ni jami mukene calo rwom me pii, bedo ma ocung matek, ki rwom me tic pa cell omyera ki nen kacel ki rwom me rwom ma ki nongo ka kitye ka pimo teko me gengo two. Man nyutu kit ma pire tek kwede me keto kwan me docking kacel ki kwan ma kitimo i kom jami ma kelo two me temo maber kit ma jami manyen twero konyo kwede dano.
Adwogi eni nyutu ni kadi bed ni dul kom ma ki lwongo ni molecular docking obedo gin ma tiyo matek me byeko kit ma jami ma mako jami makwo ni twero mako kwede ki me ngeyo kit ma twero gengo kwede, pe omyera ki jenge i kome keken me moko kit ma jami ma gengo two ni tiyo kwede. Lok ma ki nongo ki i kom jami makwo nyutu ni gengo PBP2a obedo gin ma pire tek ma weko tic pa jami ma neko kwidi two, ento alokaloka i tic pa jami makwo nyutu ni jami mukene ma kwako kom ki jami ma kwako yat omyera ki yub maber me medo tic pa yat. Kwan me anyim omyera oket cwinye i kom yubu kit ma jami ma ki lwongo ni compounds 7 ki 10 ni tye kwede me medo rom pa jami ma kwo ki jami ma ki nongo ki i cell, me neno ni jami ma ki keto i kom gi ki loko i tic me lweny i kom kwidi two. Kwano mukene, medo ki jami ma ki lwongo ni bioassays ki structure-activity relationship (SAR) analysis, obi bedo gin ma pire tek me medo niang wa kit ma jami eni tiyo kwede calo PBP2a inhibitors ki me yubu jami ma tiyo maber me lweny i kom kwidi two.
Jami ma ki yubu ki 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 onyutu rwom me tic ma pat pat me lweny i kom kwidi two, ki jami mapol ma nyutu gengo methicillin-resistant Staphylococcus aureus (MRSA). Kwedo lok ma mako kit ma jami ni tye kwede (SAR) onyutu jami ma pire tek ma tye i te tic pa jami magi ma gengo two.
Bedo tye pa dul acrylonitrile ki anthracene onyutu ni pire tek me medo tic pa jami ma neko kwidi. Gin ma ki lwongo ni highly reactive nitrile group i acrylonitrile mitte me konyo rwate ki jami ma ki lwongo ni bacterial proteins, ma weko gi konyo i kom jami ma gengo two. Jami ma tye ki acrylonitrile ki anthracene nyutu teko me lweny i kom kwidi two. Kit ma ngwec pa dul anthracene ni omedo kwede jami eni, ma twero medo tic gi.
Kelo dul ma ki lwongo ni heterocyclic rings oweko tic pa jami mapol ma ki kwanyo ki ikom kwidi two ni odongo. I kom lok, benzothiazole derivative 13b ki acrylhydrazide derivative 6 onyutu tic ma malo me lweny i kom kwidi two ki kabedo ma gengo ne ma romo 4 cm. Jami ma ki nongo ki ikom jami makwo ma pat pat ni onyutu adwogi ma pire tek ikom jami makwo, ma nyutu ni kit ma jami ma pat pat ni tye kwede ni tye ki tic ma pire tek ikom adwogi me lweny i kom kwidi two. I yo acel-lu, pyrimidinethione i dul me 9, thiopyrazole i dul me 10, ki tetrazine ring i dul me 11 gu konyo i kom teko me lweny i kom kwidi two, ma medo nyutu teko me loko jami ma pat pat.
I kin jami ma ki yubu, 6 ki 13b gu nen maber pi tic gi maber me lweny i kom kwidi two. Gin ma gengo (MIC) pa gin ma ki lwongo ni compound 6 onwongo tye 9.7 μg/100 μL, ki gin ma ki lwongo ni bactericidal concentration (MBC) onwongo tye 78.125 μg/100 μL, ma nyutu teko ne maber me kwanyo yat ma ki lwongo ni methicillin-resistant Staphylococcus aureus (MRSA). I yo acel-lu, gin ma ki lwongo ni compound 13b onongo tye ki kabedo ma gengo ne ma romo 4 cm ki MIC ki MBC ma lapiny, ma moko ni en tye ki teko me lweny i kom kwidi two. Adwogi eni nyutu tic ma pire tek pa acrylohydrazide ki benzothiazole i moko kit ma jami eni tiyo kwede.
Ka i poro, jami ma ki rubu ni 7, 10, ki 14 onyutu tic ma rwate ki kwidi two ki kabedo ma gengo ne ma romo 3.65 nio wa i 3.9 cm. Jami eni mito rwom ma malo me neko kwidi ni, ma ki nyutu ki rwom me MIC ki MBC ma malo. Kadi bed ni jami magi onongo pe tiyo maber calo jami 6 ki 13b, gin onongo pud gitye ka nyutu teko me lweny i kom kwidi two, ma nyutu ni keto acrylonitrile ki anthracene i dul ma ki lwongo ni heterocyclic ring konyo me lweny i kom kwidi two.
Jami ma ki rubu ni tye ki kit tic ma pat pat, mogo nyutu teko me neko kwidi two ki mukene nyutu teko me gengo kwidi two. Gin ma ki rubu 7, 11, 13a, ki 15 gi neko kwidi ki mito rwom ma lapiny me neko kwidi. Ka i poro, jami ma ki rubu 6, 13b, ki 14 gi gengo kwidi two ki twero gengo dongo pa kwidi two i rwom ma lapiny, ento mito rwom ma malo me neko kwidi two.
I kom lok, yub me rwate ki tic pa jami ni nyutu teko me kelo acrylonitrile ki anthracene moieties ki heterocyclic structures me nongo tic ma pire tek me lweny i kom kwidi two. Adwogi eni nyutu ni yubu jami ma ki yubu ni maber ki yenyo yoo mukene me medo rom pa jami ma ki lwongo ni membrane permeability twero kelo dongo pa yadi ma tiyo maber me lweny i kom MRSA.
Jami weny ma ki tiyo kwede ki jami ma ki lwongo ni solvents ki yubu gi ki ki juku kun ki tiyo ki yoo ma ki ngeyo (El Gomhouria, Egypt). Ka ma pii mol iye ki moko kun kitiyo ki jami ma ki lwongo ni GallenKamp ma ki lwongo ni electronic melting point apparatus ki ki coyo labongo loko ne. Infrared (IR) spectra (cm⁻1) ki coyo i Department of Chemistry, Faculty of Science, Ain Shams University kun kitiyo ki potassium bromide (KBr) pellets i kom Thermo Electron Nicolet iS10 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
1H NMR spectra ki nongo i 300 MHz kun kitiyo ki GEMINI NMR spectrometer (GEMINI Manufacturing & Engineering, Anaheim, CA, USA) ki BRUKER 300 MHz NMR spectrometer (BRUKER Manufacturing & Engineering, Inc.). Tetramethylsilane (TMS) onwongo ki tiyo kwede ma calo gin ma ki tiyo kwede ki deuterated dimethyl sulfoxide (DMSO-d₆). Pim pa NMR ki otimo i Faculty of Science, Cairo University, Giza, Egypt. Kwedo jami ma ki lwongo ni Elemental Analyzer (CHN) ki otimo kun kitiyo ki Perkin-Elmer 2400 Elemental Analyzer ki adwogi ma kinongo ni rwate ki wel ma ki kwano.
Rubu pa acid 3 (5 mmol) ki thionyl chloride (5 ml) ki lyeto i pii ma ki lwoko i 65 °C pi cawa 4. Thionyl chloride ma okato ni ki kwanyo ki distillation i te rwom ma piny. Gin ma ki nongo ki red ni ki kwanyo ki tic kwede labongo medo lwoko ne. Kabedo me lyeto: 200-202 °C, gin ma ki nongo: 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. Lakwan. Ki kwano pi C18H10ClNO (291.73): C, 74.11; H, 3.46; N, 4.80. Ki nongo: C, 74.41; H, 3.34; N, 4.66%.
I 0°C, 4 (2 mmol, 0.7 g) ki onyo i anhydrous dioxane (20 ml) ki hydrazine hydrate (2 mmol, 0.16 ml, 80%) ki medo iye ki ki buru ne pi cawa acel. Gin ma ki lwongo ni precipitated solid ni ki kwanyo ki i filtration ki ki dwoko ne ki i ethanol me nongo gin ma ki lwongo ni compound 6.
Gin ma ki lwongo ni green crystals, melting point 190-192°C, miyo 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, exchangeable), 7.69-8.51 (m, 18H, heteroaromatic), 9.16 (s, 1H, CH=), 8.54 (s, 1H, CH=); wel ma ki kwano pi C33H21N3O (475.53): C, 83.35; H, 4.45; N, 8.84. Ki nongo: C, 84.01; H, 4.38; N, 8.05%.
Lar 4 (2 mmol, 0.7 g) i 20 ml me anhydrous dioxane solution (ma tye ki pii manok me triethylamine), med phenylhydrazine/2-aminopyridine (2 mmol) ki rub i rwom me lyeto me ot pi cawa 1 ki 2, kit meno. Ony gin ma ki rubu ni i ice onyo pii ki i ket acid ki hydrochloric acid ma ki lwongo ni dilute hydrochloric acid. Kwany gin ma ki poko ni ki i lok ki i ethanol me nongo 7 ki i lok ki i benzene me nongo 8.
Gin ma ki lwongo ni green crystals, ma romo 160-162°C, kelo 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, exchangeable), 9.15 (s, 1H, CH=), 8.81 (s, 1H, CH=), 6.78-8.58 (m, 23H, heteromatic); wel ma ki kwano pi C42H26N4O2 (618.68): C, 81.54; H, 4.24; N, 9.06. Ki nongo: C, 81.96; H, 3.91; N, 8.91%.
4 (2 mmol, 0.7 g) ki onyo i 20 ml me anhydrous dioxane solution (ma tye ki pii manok me triethylamine), 2-aminopyridine (2 mmol, 0.25 g) ki medo ki gin ma ki rubu ni ki buru ne i rwom me lyeto me ot pi cawa 2. Gin ma ki rubu ni ki keto i pii ma ngiic ki ki medo acid ki hydrochloric acid ma ki lwongo ni dilute hydrochloric acid. Gin ma ki yubu ni ki kwanyo ki i benzene, ma miyo jami ma ryangi 8 ki rwom me lyel pa 146-148 °C ki rwom me 82.5%; ler ma ki lwongo ni 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, exchangeable), 9.14 (s, 1H, CH=), 7.36-8.55 (m, 13H, heteroaromatization); Ki kwano pi C23H15N3O (348.38): C, 79.07; H, 4.33; N, 12.03. Ki nongo: C, 78.93; H, 3.97; N, 12.36%.
Gin ma ki lwongo ni Compound 4 (2 mmol, 0.7 g) ki onyo i 20 ml me dioxane ma otwo (ma tye ki pii manok me triethylamine ki 2 mmol me thiourea/semicarbazide) ki ki lyeto i te reflux pi cawa 2. Gin ma ki lwongo ni solvent ni ki kwanyo woko i vacuo. Gin ma odong ni ki loko ki dioxane me miiyo gin ma ki rubu.