Izifo ezithwalwa omiyane ziseyinkinga enkulu yezempilo yomphakathi emhlabeni jikelele. Ukumelana okukhulayo kwezifo ezithwala izifo, njenge-Culex pipiens pallens, ezibulala izinambuzane zendabuko kwenza le nkinga ibe yimbi nakakhulu. Kulolu cwaningo, uchungechunge lwezinhlobo ezintsha ze-thiophene-isoquinoline hybrids zaklanywa, zahlanganiswa, futhi zahlolwa njengezinambuzane ezingaba khona. Phakathi kwamakhemikhali ahlanganisiwe, ama-derivatives angu-5f, 6, kanye no-7 abonise umsebenzi obalulekile wokubulala izinambuzane ngokumelene nezibungu ze-Culex pipiens pallens ezinamanani e-LC₅₀ angu-0.3, 0.1, kanye no-1.85 μg/mL, ngokulandelana. Okuphawulekayo ukuthi zonke izinhlobo ze-thiophene-isoquinoline eziyishumi nambili zibonise ubuthi obuphezulu kakhulu kune-chlorpyrifos yezinambuzane ze-organophosphate (LC₅₀ = 293.8 μg/mL), okuqinisekisa ubuthi obuphezulu bala makhemikhali. Ngokuthakazelisayo, i-synthetic intermediate 1a (i-thiophene semiester) ibonise amandla aphezulu kakhulu (LC₅₀ = 0.004 μg/mL), futhi nakuba ingakalungiswa ngokugcwele, amandla ayo asadlula lawo wonke ama-derivatives okugcina. Izifundo ze-Mechanistic biological zembule izimpawu eziqinile ze-neurotoxicity, eziphakamisa ukusebenza kwe-cholinergic okungasebenzi kahle. Ukufakwa kwama-molecular docking kanye nokulingisa kwe-molecular dynamics kuqinisekisile lokhu okubonwayo, kwembula ukusebenzisana okuqinile okuqondile ne-acetylcholinesterase (AChE) kanye ne-nicotinic acetylcholine receptor (nAChR), okuphakamisa indlela engaba khona yesenzo esiphindwe kabili. Izibalo ze-Density functional theory (DFT) ziqinisekisile ngokwengeziwe izakhiwo ze-elekthronikhi ezinhle kanye nokusebenza kabusha kwama-compounds asebenzayo. Ukuhlukahluka kwesakhiwo kanye namandla aphezulu njalo alolu chungechunge lwama-compounds kunganciphisa ingozi yokumelana okuwela futhi kube lula amasu okuphatha ukumelana ngokujikeleza noma ukuhlanganiswa kwama-compound. Sekukonke, le miphumela ikhombisa ukuthi ama-hybrid e-thiophene-isoquinoline ayindlela ethembisayo yokuthuthukiswa kwama-larvicides esizukulwane esilandelayo ahlose izindlela ze-neurophysiological zama-vector ezinambuzane.
Omiyane baphakathi kwezifo ezithwala izifo ezithelelanayo eziphumelela kakhulu, basakaza izinhlobo eziningi zamagciwane ayingozi futhi babeka usongo olukhulu empilweni yomphakathi womhlaba. Izinhlobo ezifana ne-Culex pipiens, i-Aedes aegypti, kanye ne-Anopheles gambiae zaziwa kakhulu ngokudlulisa amagciwane, amabhaktheriya, kanye nezilokazane, okubangela izigidi zezifo kanye nokufa okuningi minyaka yonke. Isibonelo, i-Culex pipiens iyilokazane elikhulu lama-arbovirus njengegciwane laseWest Nile kanye negciwane laseSt. Louis encephalitis, kanye nezifo ezithwala izifo ezifana nomalaleveva wezinyoni. Ucwaningo lwamuva luye lwabonisa nokuthi i-Culex pipiens idlala indima ebalulekile ekusabalaliseni nasekudluliseleni kwamabhaktheriya ayingozi njenge-Bacillus cereus kanye ne-Staphylococcus warwickii, angcolisa ukudla futhi abhebhethekise izinkinga zempilo yomphakathi. Ukuzivumelanisa nezimo okuphezulu, ukusinda, kanye nokumelana komiyane nezindlela zokulawula kwenza kube nzima ukuwalawula futhi kube usongo oluqhubekayo.
Izibulala-zinambuzane zamakhemikhali ziyithuluzi elibalulekile ekulawuleni omiyane, ikakhulukazi ngesikhathi sokuqubuka kwezifo ezithwalwa omiyane. Izinhlobo ezahlukene zezibulala-zinambuzane, okuhlanganisa ama-pyrethroids, ama-organophosphates, nama-carbamates, zisetshenziswa kabanzi ukunciphisa inani lomiyane kanye nokudluliswa kwezifo. Kodwa-ke, ukusetshenziswa kabanzi kwala makhemikhali isikhathi eside kuholele ekukhathazekeni okukhulu kwemvelo kanye nempilo yomphakathi, okuhlanganisa ukuphazamiseka kwemvelo, imiphumela eyingozi ezinhlotsheni ezingahlosiwe, kanye nokuthuthukiswa okusheshayo kokumelana nezibulala-zinambuzane eningini lomiyane.11,12,13,14Lokhu kumelana kunciphisa kakhulu ukusebenza kahle kwezibulala-zinambuzane eziningi zendabuko, kugqamisa isidingo esiphuthumayo sezixazululo zamakhemikhali ezintsha ezinezindlela ezintsha zokusebenza ukuze kulwiwe ngempumelelo nalezi zinsongo ezishintshayo.11,12,13,14Ukuze babhekane nalezi zinselele ezinkulu, abacwaningi baphendukela emasu ahlukile njengokulawulwa kwezinto eziphilayo, ubunjiniyela bezakhi zofuzo, kanye nokuphathwa kwe-vector okuhlanganisiwe (i-IVM). Lezi zindlela zibonisa isithembiso sokulawulwa komiyane okusimeme nokwesikhathi eside. Kodwa-ke, ngesikhathi sezifo eziwumshayabhuqe nezimo eziphuthumayo, izindlela zamakhemikhali zihlala zibalulekile ekuphenduleni ngokushesha.
Ama-alkaloid e-Isoquinoline ayizinto ezibalulekile eziqukethe i-nitrogen ezisatshalaliswa kabanzi embusweni wezitshalo, okuhlanganisa imindeni efana ne-Amaryllidaceae, i-Rubiaceae, i-Magnoliaceae, i-Papaveraceae, i-Berberidaceae, kanye ne-Menispermaceae.30 Izifundo zangaphambilini ziqinisekisile ukuthi ama-alkaloid e-isoquinoline anemisebenzi eyahlukahlukene yezinto eziphilayo kanye nezici zesakhiwo, okuhlanganisa ukubulala izinambuzane, ukulwa nesifo sikashukela, ukulwa nomdlavuza, ukubulala amagciwane, ukulwa nokuvuvukala, ukulwa namagciwane, ukulwa nezilokazane, ukulwa ne-antioxidant, ukulwa namagciwane, kanye nokuvikela imizwa.
Kulolu cwaningo, amanani angu-χ² azo zonke izinhlanganisela ayengaphansi komkhawulo obalulekile, kanti amanani e-p ayengaphezu kuka-0.05. Le miphumela iqinisekisa ukuthembeka kwezilinganiso ze-LC₅₀ futhi ikhombisa ukuthi ukuhlehla okungenzeka kungachaza ngempumelelo ubudlelwano obubonwe phakathi komthamo nempendulo. Ngakho-ke, amanani e-LC₅₀ kanye nezinkomba zobuthi (ama-TI) ezibalwe ngokusekelwe kunhlanganisela esebenzayo kakhulu (1a) zithembeke kakhulu futhi zifanelekile ukuqhathanisa imiphumela yobuthi.
Ukuze sihlole ukusebenzisana kwezinhlobo ezingu-12 ze-thiophene-isoquinolinone ezisanda kuhlanganiswa kanye ne-precursor 1a yazo enezinhloso ezimbili ezibalulekile ze-mosquito neuronal—i-acetylcholinesterase (AChE) kanye ne-nicotinic acetylcholine receptor (nAChR)—senze i-molecular docking modeling. Lezi zinhloso zikhethwe ngokusekelwe ezimpawini ezinobuthi be-neurological ezibonwe ekuhlolweni kokufa kwe-larval, okubonisa ukuphazamiseka kwesignali ye-neuronal. Ngaphezu kwalokho, ukufana kwesakhiwo kwalezi zinhlanganisela ne-organophosphates kanye ne-neonicotinoids kusekela kakhulu ukukhetha okuthandwayo kwalezi zinhloso, njengoba ama-organophosphates kanye ne-neonicotinoids enza imiphumela yawo enobuthi ngokuvimbela i-AChE kanye nokusebenzisa i-nAChR, ngokulandelana.
Ngaphezu kwalokho, ama-compound amaningana (kufaka phakathi i-1a, 2, 5a, 5b, 5e, 5f, kanye ne-7) asebenzisana ne-SER280. Ama-residue e-SER280 ahilelekile ekwakheni ukwakheka kwesakhiwo sekristalu futhi agcinwa ekubunjweni kabusha kwe-BT7. Lokhu kuhlukahluka kwezindlela zokuxhumana kugqamisa ukuzivumelanisa nezimo kwala ma-compound endaweni esebenzayo, kanti i-SER280 kanye ne-GLU359 kungenzeka zisebenze njengezindawo ze-anchor eziguquguqukayo ngaphansi kwezimo zokufaka idokhi. Ukusebenzisana okuvamile okubonwa phakathi kwezinto ezisetshenziswayo kanye nama-residue ayisihluthulelo njenge-GLU359 kanye ne-SER280, okuyizingxenye ze-SER-HIS-GLU catalytic triad eyaziwayo ku-acetylcholinesterase yabantu (AChE), kusekela ngokwengeziwe umbono wokuthi la ma-compound angase abe nemiphumela enamandla yokuvimbela ku-AChE ngokubopha ezindaweni ezibalulekile ze-catalytic.29,61,64
Okuphawulekayo ukuthi i-compound 6 kanye ne-precursor yayo i-1a kubonise umsebenzi onamandla kakhulu ngokumelene nezibungu ku-bioassay, kubonisa amanani aphansi kakhulu e-LC₅₀ phakathi kwamakhemikhali ochungechungeni. Ezingeni lama-molecule, i-compound 6 ibonisa ukusebenzisana okubalulekile nama-chlorpyrifos endaweni ye-GLU359, kuyilapho i-compound 1a ihlangana ne-BT7 ephinde yafakwa ngesibopho se-hydrogen ku-SER280. Zombili i-GLU359 ne-SER280 zikhona ekuhlanganisweni kokuqala kwe-crystallographic kwe-BT7 futhi ziyizingxenye ze-acetylcholinesterase egciniwe (SER–HIS–GLU), okugqamisa ukubaluleka kokusebenza kwalokhu kusebenzisana ekugcineni umsebenzi wokuvimbela wamakhemikhali (Isithombe 10).
Ukufana okubonwe ezindaweni zokubopha phakathi kwe-BT7 derivatives (kufaka phakathi i-BT7 yemvelo kanye ne-reinstated) kanye ne-chlorpyrifos, ikakhulukazi kuma-residues abalulekile emsebenzini we-catalytic, kusikisela kakhulu indlela evamile yokuvimbela phakathi kwala ma-compounds. Sekukonke, le miphumela iqinisekisa amandla abalulekile e-thiophene-isoquinolinone derivatives njenge-acetylcholinesterase inhibitors enamandla kakhulu ngenxa yokusebenzisana kwawo okugcinwe futhi okuhlobene ne-biology.
Ubudlelwano obuqinile phakathi kwemiphumela yokufakwa kwama-molecule kanye nemiphumela yokuhlolwa kwe-larval bioassay buqinisekisa ukuthi i-acetylcholinesterase (AChE) kanye ne-nicotinic acetylcholine receptor (nAChR) yizona zinhloso eziyinhloko ze-neurotoxic ze-thiophene-isoquinoline derivatives ezenziwe. Nakuba imiphumela yokufakwa kwama-docking inikeza ulwazi olubalulekile mayelana nokuhambisana kwe-receptor-ligand, kufanele kuqashelwe ukuthi amandla okubopha ewodwa awanele ukuchaza ngokugcwele ukusebenza kahle kokubulala izinambuzane emzimbeni. Umehluko kumanani e-LC₅₀ phakathi kwamakhemikhali anezimpawu ezifanayo zokufakwa kwama-docking ungase ubangelwe yizici ezifana nokuzinza kwe-metabolic, ukumuncwa, ukutholakala kwe-bioavailability, kanye nokusatshalaliswa kwezinambuzane.⁶⁰,⁶⁴Kodwa-ke, ukwakheka okunengqondo, ukuzwelana okuphezulu kwama-receptor okulingiswe ngokulingisa ikhompyutha, kanye nomsebenzi onamandla webhayoloji kusekela kakhulu umbono wokuthi ama-AChE nama-nAChR yiwona abangela ubuthi obubonakalayo be-neurotoxicity.
Ekuphetheni, ama-hybrid e-thiophene-isoquinoline ahlanganisiwe anezici ezibalulekile zesakhiwo nokusebenza ezihambisana kakhulu nemithi yokubulala izinambuzane eyaziwayo ye-neuroactive. Amandla awo okubopha ngempumelelo ku-acetylcholinesterase (AChE) kanye nama-receptor e-nicotinic acetylcholine (nAChRs) ngokusebenzisa izindlela zokuxhumana ezihambisanayo aqokomisa amandla awo njengemithi yokubulala izinambuzane eqondiswe kabili. Le ndlela yokwelapha ekabili ayigcini nje ngokuthuthukisa ukusebenza kahle kokubulala izinambuzane kodwa futhi ihlinzeka nesu elithembisayo lokunqoba izindlela zokumelana ezikhona, okwenza lezi zinhlanganisela zibe yizithako ezithembisayo zokuthuthukiswa kwemithi yokulawula omiyane yesizukulwane esilandelayo.
Ukulingisa kwe-Molecular Dynamics (MD) kusetshenziselwa ukuqinisekisa nokwandisa imiphumela yokubeka ama-molecule, okuhlinzeka ngokuhlolwa okungokoqobo nokuncike esikhathini kokuxhumana kwe-ligand-target ngaphansi kwezimo ezingokoqobo zemvelo. Nakuba ukufaka ama-molecule kunganikeza ulwazi olubalulekile lokuqala mayelana nezikhundla zokubopha kanye nokuhlobana okungenzeka, kuyimodeli engaguquki futhi ayikwazi ukubheka ukuguquguquka kwe-receptor, i-solvent dynamics, noma ukuguquguquka kwesikhathi ekusebenzisaneni kwama-molecule. Ngakho-ke, ukulingisa kwe-MD kuyindlela ebalulekile ehambisanayo yokuhlola ukuzinza okuyinkimbinkimbi, ukuqina kokuxhumana, kanye nezinguquko zesimo kuma-ligand namaprotheni ngokuhamba kwesikhathi.60,62,71
Ngokusekelwe ezimpahleni zabo zokubopha eziphakeme kakhulu ku-acetylcholinesterase (AChE) uma kuqhathaniswa ne-nicotinic acetylcholine receptor (nAChR), sikhethe i-molecule yomzali i-1a (enenani eliphansi kakhulu le-LC₅₀) kanye ne-thiophene-isoquinoline compound 6 esebenzayo kakhulu yokulingisa ama-molecular dynamics (MD). Umgomo kwakuwukuhlola ukuthi ukwakheka kwabo kokubopha endaweni esebenzayo ye-AChE kuhlala kuzinzile ngaphezu kwama-ns ayi-100 okulingisa kanye nokuqhathanisa ukuziphatha kwabo kokubopha nokwe-chlorpyrifos kanye ne-rebound cocrystallized AChE inhibitor BT7.
Ukulingisa kwe-molecular dynamics kufaka phakathi i-root mean square deviation (RMSD) ukuhlola ukuzinza okuyinkimbinkimbi okujwayelekile; i-root mean square deviation of fluctuations (RMSF) yokufunda ukuguquguquka kwe-residue; kanye nokuhlaziywa kokuxhumana kwe-ligand-acceptor ukuze kunqunywe ukuzinza kwezibopho ze-hydrogen, ukuxhumana kwe-hydrophobic, kanye nokusebenzisana kwe-ionic (Idatha Engeziwe). Nakuba amanani e-RMSD kanye ne-RMSF awo wonke ama-ligand ahlala ngaphakathi kobubanzi obuzinzile, okubonisa ukuthi akukho zinguquko ezibalulekile zesakhiwo ku-AChE-ligand complex (Isithombe 12), la mapharamitha wodwa awanele ukuchaza ngokugcwele umehluko ekuhlanganiseni phakathi kwamakhemikhali.
Isikhathi sokuthunyelwe: Disemba 15-2025