Indwara zandurira mu mibu ziracyari ikibazo gikomeye cy’ubuzima rusange ku isi. Ubudahangarwa bw’udukoko dutera indwara, nka Culex pipiens pallens, ku miti isanzwe yo kwica udukoko burushaho kwiyongera iki kibazo. Muri ubu bushakashatsi, hakozwe urukurikirane rw’udukoko dushya twa thiophene-isoquinoline hybrids, twakozwe, dukorwa, kandi dupimwa nk’utundi dukoko dushobora kuba twa larvicides. Mu bintu byakozwe, ibikomoka kuri 5f, 6, na 7 byagaragaje imikorere ikomeye yo kwica larvicides ku tunyangingo twa Culex pipiens pallens dufite agaciro ka LC₅₀ ka 0.3, 0.1, na 1.85 μg/mL, uko bikurikirana. Ikigaragara ni uko ibikomoka kuri thiophene-isoquinoline byose uko ari cumi na bibiri byagaragaje uburozi buri hejuru cyane kurusha chlorpyrifos y’insecticide ya organophosphate (LC₅₀ = 293.8 μg/mL), byemeza uburozi buhanitse bw’ibi bintu. Igishimishije ni uko 1a y’ubukorano (thiophene semiester) yagaragaje imbaraga nyinshi (LC₅₀ = 0.004 μg/mL), kandi nubwo itaranonosorwa neza, imbaraga zayo zirenze iz’ibintu byose bya nyuma. Ubushakashatsi bwa tekiniki ku binyabuzima bwagaragaje ibimenyetso bikomeye by’uburozi bw’ubwonko, bigaragaza ko imikorere y’uturemangingo yangiritse. Gupima molekile no gukoresha molekile byashimangiye iki gitekerezo, bigaragaza imikoranire ikomeye na acetylcholinesterase (AChE) na nicotinic acetylcholine receptor (nAChR), bigaragaza uburyo bushobora gukoreshwa mu bikorwa bibiri. Imibare y’ubucucike bw’imitsi (DFT) yemeje kandi imiterere myiza ya elegitoroniki n’uburyo ibintu bikora. Ubudasa bw’imiterere n’imbaraga zihoraho z’uru ruhererekane rw’ibi bintu bishobora kugabanya ibyago byo kwangirika no koroshya ingamba zo gucunga ubudahangarwa binyuze mu guhindagurika cyangwa guhuzwa kw’ibice. Muri rusange, ibi bisubizo bigaragaza ko ibinyabutabire bya thiophene-isoquinoline ari amahitamo yizewe yo guteza imbere larvicides zo mu gisekuru gitaha zigamije inzira z’imitsi y’udukoko.
Imibu iri mu bintu bitera indwara zandura cyane, ikwirakwiza ubwoko bwinshi bw’udukoko twangiza kandi ikaba ibangamiye ubuzima rusange bw’isi. Ubwoko nka Culex pipiens, Aedes aegypti, na Anopheles gambiae buzwi cyane mu kwanduzanya virusi, bagiteri, n’udukoko, bigatera ubwandu bwinshi n’impfu nyinshi buri mwaka. Urugero, Culex pipiens ni yo itera virusi nyinshi nka virusi ya West Nile na virusi ya St. Louis encephalitis, ndetse n’indwara ziterwa n’udukoko nka malariya y’inyoni. Ubushakashatsi buherutse kandi bwagaragaje ko Culex pipiens igira uruhare runini mu kwanduzanya no kwanduzanya udukoko twangiza nka Bacillus cereus na Staphylococcus warwickii, byanduza ibiryo kandi bikongera ibibazo by’ubuzima rusange. Kuba imibu ibasha kwihanganira uburyo bwo kuyirwanya, kuyirwanya no kuyirwanya bituma bigorana kuyirwanya kandi ikaba itera ikibazo gikomeye.
Imiti yica udukoko ni igikoresho cy'ingenzi mu kurwanya imibu, cyane cyane mu gihe cy'icyorezo cy'indwara ziterwa n'imibu. Ubwoko butandukanye bw'imiti yica udukoko, harimo pyrethroids, organophosphates, na carbamates, ikoreshwa cyane mu kugabanya umubare w'imibu n'ikwirakwizwa ry'indwara. Ariko, ikoreshwa ry'iyi miti mu buryo bukwirakwira kandi burambye ryateje ibibazo bikomeye ku bidukikije no ku buzima rusange, harimo kwangirika kw'urusobe rw'ibinyabuzima, ingaruka mbi ku bwoko butari ubwabwo, ndetse n'iterambere ryihuse ry'ubudahangarwa bw'imiti mu mibu.11, 12, 13, 14Uku kudakora neza bigabanya cyane ubushobozi bw'imiti myinshi gakondo yica udukoko, bigaragaza ko hakenewe byihutirwa imiti mishya ifite uburyo bushya bwo kurwanya ibi bibazo bivuka.11, 12, 13, 14Kugira ngo bakemure izi mbogamizi zikomeye, abashakashatsi barimo gukoresha ubundi buryo nko kugenzura ibinyabuzima, ubuhanga mu by’imiterere y’uturemangingo, no gucunga neza ibinyabuzima bikomoka ku mikorobe (IVM). Ubu buryo bugaragaza icyizere cyo kurwanya imibu mu buryo burambye kandi burambye. Ariko, mu gihe cy’icyorezo n’ibibazo byihutirwa, uburyo bwo gukoresha imiti buracyari ingenzi kugira ngo habeho guhangana vuba.
Alkaloidi za Isoquinoline ni ibintu by'ingenzi birimo azote ikwirakwira cyane mu bwami bw'ibimera, harimo imiryango nka Amaryllidaceae, Rubiaceae, Magnoliaceae, Papaveraceae, Berberidaceae, na Menispermaceae.30 Ubushakashatsi bwakozwe mbere bwemeje ko alkaloidi za isoquinoline zifite ibikorwa bitandukanye bya biyoloji n'imiterere y'imiterere, harimo kwica udukoko, kurwanya diyabete, kurwanya ikibyimba, kurwanya indwara zifata imitsi, kurwanya ububyimbirwe, kurwanya bagiteri, kurwanya parasitiki, kurwanya antioxidant, kurwanya virusi, no kurinda ubwonko.
Muri ubu bushakashatsi, agaciro ka χ² ku bintu byose byari munsi y’umubare w’ingenzi, naho agaciro ka p kari hejuru ya 0.05. Ibi bisubizo byemeza ko ibipimo bya LC₅₀ byizerwa kandi bigaragaza ko isubiranyuma ry’ibipimo rishobora gusobanura neza isano yabonetse hagati y’ingano n’ibisubizo. Kubwibyo, agaciro ka LC₅₀ n’ibipimo by’uburozi (TIs) byabazwe hashingiwe ku kintu gikora cyane (1a) byizewe cyane kandi birakwiriye kugereranya ingaruka z’uburozi.
Kugira ngo dusuzume uburyo ibintu 12 bishya bya thiophene-isoquinoline bikorana n’ibikomoka kuri 1a hamwe n’ibice bibiri by’ingenzi by’imitsi—acetylcholinesterase (AChE) na nicotinic acetylcholine receptor (nAChR)—twakoze icyitegererezo cya molekile. Ibi bipimo byatoranijwe hashingiwe ku bimenyetso by’uburozi bw’imitsi byagaragaye mu isuzuma ry’urupfu rw’udukoko, bigaragaza ko ibimenyetso by’imitsi bidakora neza. Byongeye kandi, imiterere y’ibi binyabutabire bisa na organophosphates na neonicotinoids ishyigikira cyane guhitamo ibi bipimo, kuko organophosphates na neonicotinoids bigira ingaruka mbi zabyo mu gukumira AChE no gukora nAChR, uko bikurikirana.
Byongeye kandi, ibintu byinshi (harimo 1a, 2, 5a, 5b, 5e, 5f, na 7) bikorana na SER280. Ibisigazwa bya SER280 bigira uruhare mu kurema imiterere ya kristu kandi bibungabungwa mu miterere ya BT7 yasubiwemo. Ubu buryo butandukanye bwo gukorana bugaragaza ubushobozi bw'ibi bintu mu mwanya wabyo, aho SER280 na GLU359 bishobora kuba ahantu ho guhagarara hashobora gukoreshwa mu gihe cyo gufunga. Imikoranire ikunze kugaragara hagati y'ibintu bikomoka ku binyabuzima n'ibisigazwa by'ingenzi nka GLU359 na SER280, bigize SER-HIS-GLU catalytic triad izwi muri acetylcholinesterase y'abantu (AChE), bishyigikira igitekerezo cy'uko ibi bintu bishobora kugira ingaruka zikomeye ku AChE binyuze mu kwihuza n'ahantu hakomeye mu gukwirakwiza.29,61,64
Ikigaragara ni uko icyiciro cya 6 n'icyabanjirije 1a byagaragaje imikorere ikomeye cyane mu kurwanya imisemburo mu isuzuma ry'ibinyabuzima, bigaragaza agaciro ka LC₅₀ kari hasi cyane mu binyabutabire biri muri uru ruhererekane. Ku rwego rwa molekile, icyiciro cya 6 kigaragaza imikoranire ikomeye na chlorpyrifos ahantu ha GLU359, mu gihe icyiciro cya 1a gihurirana na BT7 yongeye guhindurwa binyuze mu mugozi wa hydrogen kuri SER280. GLU359 na SER280 byombi biri mu buryo bwa BT7 bwo guhuza bwa crystallographic kandi ni bimwe mu bigize triplet catalytic ya acetylcholinesterase (SER–HIS–GLU), bigaragaza akamaro k'iyi mikoranire mu kubungabunga imikorere y'ibinyabutabire (Ishusho ya 10).
Ukuntu byagaragaye ko ahantu hahurira ibintu biva kuri BT7 (harimo na BT7 y’umwimerere n’ibyavuguruwe) na chlorpyrifos, cyane cyane ku bisigazwa by’ingenzi mu gukora catalytic, bigaragaza cyane uburyo buhuriweho bwo gukumira ibi bintu. Muri rusange, ibi bisubizo byemeza ko ibintu biva kuri thiophene-isoquinoline ari ibintu bikomeye cyane bigabanya acetylcholinesterase bitewe n’imikoranire yabyo ihoraho kandi ifite akamaro mu mikorere yabyo.
Isano rikomeye riri hagati y’ibisubizo bya molekile mu gufunga no kugerageza kwa larval biyongerera icyizere ko acetylcholinesterase (AChE) na nicotinic acetylcholine receptor (nAChR) ari byo bintu by’ingenzi bitera uburozi mu mitsi bya thiophene-isoquinoline derivatives. Nubwo ibisubizo bya docking bitanga amakuru y’ingenzi ku bufatanye bwa receptor-ligand, bikwiye kumenyekana ko ingufu zo gufatanya zonyine zidahagije kugira ngo zisobanure neza akamaro ko kwica udukoko mu mubiri. Itandukaniro riri mu gaciro ka LC₅₀ hagati y’ibinyabutabire bifite imiterere isa ya docking rishobora guterwa n’ibintu nko guhagarara neza mu mikorere y’umubiri, kwinjiza, kuba biyoroherwa, no gukwirakwira mu dukoko.⁶⁰,⁶⁴Ariko, imiterere y’imiterere y’umubiri, ubwinshi bw’amajwi atuma umuntu yumva neza, hamwe n’imikorere ikomeye ya biyoloji bishyigikira cyane igitekerezo cy’uko AChE na nAChR ari byo bintu by’ingenzi bitera uburozi bw’ubwonko bwagaragaye.
Muri make, ubwoko bwa thiophene-isoquinoline hybrids bufite ibintu by'ingenzi by'imiterere n'imikorere bihuye cyane n'imiti yica udukoko izwiho gukora mu bwonko. Ubushobozi bwazo bwo gufata neza acetylcholinesterase (AChE) na nicotinic acetylcholine receptors (nAChRs) binyuze mu buryo bwuzuzanya bwerekana ubushobozi bwazo nk'imiti yica udukoko ifite intego ebyiri. Ubu buryo bubiri ntibutuma gusa habaho imikorere myiza yo kwica udukoko ahubwo bunatanga ingamba nziza zo gutsinda uburyo buriho bwo kurwanya imibu, bigatuma iyi miti itera icyizere mu iterambere ry'imiti irwanya imibu yo mu gihe kizaza.
Imiterere ya molekile (MD) ikoreshwa mu kwemeza no kongera ibisubizo byo gushyiramo molekile, bigatanga isuzuma ry’imikorere y’ibice by’umubiri n’ibice by’umubiri mu buryo bufatika kandi bushingiye ku gihe. Nubwo gushyiramo molekile bishobora gutanga amakuru y’ingenzi ku myanya ishobora gushyirwamo n’ibice by’umubiri, ni icyitegererezo kidahinduka kandi ntigishobora gusobanura ubwihindurize bwa receptor, imikorere ya solvent, cyangwa ihindagurika ry’igihe mu mikorere ya molekile. Kubwibyo, imiterere ya MD ni uburyo bw’ingenzi bwuzuzanya mu gusuzuma ubwiza bugoye, gukomera kw’imikoranire, n’impinduka mu miterere ya ligande na poroteyine uko igihe kigenda gihita.60,62,71
Dushingiye ku miterere yazo irusha izindi gufatana na acetylcholinesterase (AChE) ugereranije na nicotinic acetylcholine receptor (nAChR), twahisemo molekile y’ibanze 1a (ifite agaciro ka LC₅₀ kari hasi cyane) hamwe n’itsinda rya thiophene-isoquinoline 6 rikora cyane mu gupima imiterere ya molekile (MD). Intego yari ukureba niba imiterere yazo mu gace ka AChE ikomeje kuba ihamye hejuru ya 100 ns za simulation no kugereranya imikorere yazo yo gufatana n’iya chlorpyrifos na rebound cocrystallized AChE inhibitor BT7.
Isesengura rya molekile ryakozwe harimo guhindagurika kw'imizi (RMSD) kugira ngo harebwe uburyo ibintu bihagaze neza muri rusange; guhindagurika kw'imizi (RMSF) kugira ngo harebwe uburyo ibintu bihinduka; n'isesengura ry'imikoranire ya ligand-acceptor kugira ngo harebwe uburyo ibintu bihagaze neza, uburyo ibintu bihurirana n'amazi, n'uburyo ibintu bihurirana n'iy'ayoni (Amakuru y'inyongera). Nubwo agaciro ka RMSD na RMSF kuri ligand zose kagumye mu rugero ruhamye, bigaragaza ko nta mpinduka zikomeye mu buryo imiterere y'ibintu muri AChE-ligand complex (Ishusho ya 12), ibi bipimo byonyine ntibihagije kugira ngo bisobanure neza itandukaniro riri hagati y'ibice bihuza.
Igihe cyo kohereza: Ukuboza 15-2025