Izifo ezithwalwa yiingcongconi ziseyingxaki enkulu yempilo yoluntu kwihlabathi liphela. Ukwanda kokumelana kwezifo, njengeCulex pipiens pallens, kwizinambuzane zemveli kuyayiqinisa le ngxaki. Kolu phononongo, uthotho lwee-hybrids ezintsha ze-thiophene-isoquinoline zenziwe, zahlanganiswa, zaza zavavanywa njengee-larvicides ezinokubakho. Phakathi kwee-compounds ezidityanisiweyo, ii-derivatives 5f, 6, kunye ne-7 zibonise umsebenzi obalulekileyo wokubulala ii-larvicides ngokuchasene nee-larvicides zeCulex pipiens pallens ezinexabiso le-LC₅₀ le-0.3, 0.1, kunye ne-1.85 μg/mL, ngokulandelelana. Okuphawulekayo kukuba, zonke ii-derivatives ezilishumi elinambini ze-thiophene-isoquinolinone zibonakalise ubuthi obuphezulu kakhulu kune-chlorpyrifos ye-organophosphate insecticide (LC₅₀ = 293.8 μg/mL), eqinisekisa ubuthi obuphezulu bezi-compounds. Okunomdla kukuba, i-synthetic intermediate 1a (i-thiophene semiester) ibonakalise amandla aphezulu (LC₅₀ = 0.004 μg/mL), kwaye nangona ingekalungiswa ngokupheleleyo, amandla ayo asadlula lawo onke ama-derivatives okugqibela. Izifundo zebhayoloji zeMechanistic zityhile iimpawu ezinamandla ze-neurotoxicity, zibonisa ukusebenza okungasebenzi kakuhle kwe-cholinergic. Ukulinganisa iimolekyuli kunye nokulinganisa iimolekyuli kuqinisekisile oku kubonwayo, kutyhila ukusebenzisana okuqinileyo kunye ne-acetylcholinesterase (AChE) kunye ne-nicotinic acetylcholine receptor (nAChR), okubonisa indlela enokwenzeka yokusebenza kabini. Ubalo lwe-Density functional theory (DFT) luqinisekisile ngakumbi iipropati ze-elektroniki ezilungileyo kunye nokusebenza kwakhona kweekhompawundi ezisebenzayo. Ukwahluka kwesakhiwo kunye namandla aphezulu rhoqo kolu luhlu lweekhompawundi kunokunciphisa umngcipheko wokuxhathisa okunqamlezileyo kwaye kube lula amaqhinga okulawula ukumelana ngokujikeleza okanye ukudibana kweekhompawundi. Ngokubanzi, ezi ziphumo zibonisa ukuba ii-hybrids ze-thiophene-isoquinoline ziyindlela ethembisayo yophuhliso lwee-larvicides zesizukulwana esilandelayo ezijolise kwiindlela ze-neurophysiological zeevectors zezinambuzane.
Iingcongconi ziphakathi kwezona zibangela izifo ezisulelayo, zisasaza uluhlu olubanzi lweentsholongwane eziyingozi kwaye zibeka umngcipheko omkhulu kwimpilo yoluntu kwihlabathi liphela. Iintlobo ezifana neCulex pipiens, Aedes aegypti, kunye neAnopheles gambiae zaziwa kakhulu ngokudlulisela iintsholongwane, iibhaktheriya, kunye neeparasite, ezibangela izigidi zezifo kunye nokufa okuninzi minyaka le. Umzekelo, iCulex pipiens yi-vector enkulu ye-arboviruses efana ne-West Nile virus kunye ne-St. Louis encephalitis virus, kunye nezifo ezibangelwa ziintsholongwane ezifana ne-avian malaria. Uphando lwakutshanje lukwabonise ukuba i-Culex pipiens idlala indima ebalulekileyo kwi-vector kunye nokudluliselwa kweebhaktheriya eziyingozi ezifana ne-Bacillus cereus kunye ne-Staphylococcus warwickii, ezingcolisa ukutya kwaye zibhebhethekise iingxaki zempilo yoluntu. Ukuziqhelanisa okuphezulu, ukusinda, kunye nokuxhathisa kweengcongconi kwiindlela zokulawula kwenza kube nzima ukuzilawula kwaye zibe ngumngcipheko oqhubekayo.
Izibulali-zinambuzane ezisebenzisa iikhemikhali zizixhobo ezibalulekileyo ekulawuleni iingcongconi, ingakumbi ngexesha lokuqhambuka kwezifo ezithwalwa ziingcongconi. Iindidi ezahlukeneyo zezibulali-zinambuzane, kuquka i-pyrethroids, i-organophosphates, kunye ne-carbamates, zisetyenziswa kakhulu ukunciphisa inani leengcongconi kunye nokudluliselwa kwezifo. Nangona kunjalo, ukusetyenziswa ngokubanzi kunye nexesha elide kwezi khemikhali kukhokelele kwiinkxalabo ezinkulu zempilo yoluntu kunye nokusingqongileyo, kubandakanya ukuphazamiseka kwenkqubo yendalo, iziphumo eziyingozi kwizilwanyana ezingajoliswanga kuzo, kunye nophuhliso olukhawulezileyo lokuxhathisa izinambuzane kumaqela eengcongconi.11,12,13,14Olu xhathiso lunciphisa kakhulu ukusebenza kakuhle kwezibulali-zinambuzane ezininzi zemveli, nto leyo egxininisa imfuneko engxamisekileyo yezisombululo ezintsha zeekhemikhali ezineendlela ezintsha zokusebenza ukulwa ngempumelelo nezi ngozi zitshintshayo.11,12,13,14Ukuze bajongane nale mingeni inzima, abaphandi bajika baye kwiindlela ezahlukeneyo ezifana nolawulo lwezinto eziphilayo, ubunjineli bemfuza, kunye nolawulo oluhlanganisiweyo lwe-vector (IVM). Ezi ndlela zibonisa ithemba lolawulo lweengcongconi oluhlala ixesha elide noluzinzileyo. Nangona kunjalo, ngexesha lezifo ezibangelwa ziintsholongwane kunye neengxamiseko, iindlela zamachiza zihlala zibalulekile ekuphenduleni ngokukhawuleza.
Ii-alkaloids ze-Isoquinoline zizinto ezibalulekileyo ezine-nitrogen eziqulethe i-heterocyclic compounds ezisasazwa kakhulu kubukumkani bezityalo, kuquka iintsapho ezifana ne-Amaryllidaceae, i-Rubiaceae, i-Magnoliaceae, i-Papaveraceae, i-Berberidaceae, kunye ne-Menispermaceae.30 Izifundo zangaphambili ziqinisekisile ukuba ii-alkaloids ze-isoquinoline zinemisebenzi eyahlukeneyo yebhayoloji kunye neempawu zesakhiwo, kubandakanya ukubulala izinambuzane, ukulwa nesifo seswekile, ukulwa nethumba, ukubola, ukulwa nokuvuvukala, ukulwa neentsholongwane, ukulwa neentsholongwane, ukulwa neentsholongwane, ukulwa neentsholongwane, ukulwa neentsholongwane, kunye nokukhusela imithambo-luvo.
Kolu phononongo, amaxabiso e-χ² kuzo zonke iikhompawundi ayengaphantsi komda obalulekileyo, kwaye amaxabiso e-p ayengaphezulu kwe-0.05. Ezi ziphumo ziqinisekisa ukuthembeka koqikelelo lwe-LC₅₀ kwaye zibonisa ukuba ukuhlehla okunokwenzeka kunokuchaza ngokufanelekileyo ulwalamano olubonweyo lwedosi-impendulo. Ke ngoko, amaxabiso e-LC₅₀ kunye nee-toxicity indices (TIs) ezibalwe ngokusekelwe kwikhompawundi esebenzayo kakhulu (1a) zithembekile kakhulu kwaye zifanelekile ukuthelekisa iziphumo zetyhefu.
Ukuvavanya ukusebenzisana kwee-12 ezisandula ukwenziwa ze-thiophene-isoquinoline kunye ne-precursor 1a kunye neethagethi ezimbini eziphambili ze-mosquito neuronal—i-acetylcholinesterase (AChE) kunye ne-nicotinic acetylcholine receptor (nAChR)—senze i-molecular docking modeling. Ezi thagethi zikhethwe ngokusekelwe kwiimpawu ze-neurotoxic ezibonwe kwiimvavanyo zokufa kwe-larval, ezibonisa ukuphazamiseka kwe-neuronal signaling. Ngaphezu koko, ukufana kwesakhiwo kwezi compounds kwi-organophosphates kunye ne-neonicotinoids kuxhasa ngakumbi ukhetho olukhethiweyo lwezi thagethi, njengoko ii-organophosphates kunye ne-neonicotinoids zivelisa iziphumo zazo zetyhefu ngokuthintela i-AChE kunye nokwenza i-nAChR isebenze, ngokulandelelana.
Ngaphezu koko, iikhompawundi ezininzi (kuquka i-1a, 2, 5a, 5b, 5e, 5f, kunye ne-7) zisebenzisana ne-SER280. Iintsalela ze-SER280 zibandakanyeka ekubumbeni ukwakheka kwesakhiwo sekristale kwaye zigcinwa kwimo ephinde yakhiwa ye-BT7. Olu luhluhlu lweendlela zokusebenzisana lugxininisa ukulungelelaniswa kwezi khompawundi kwindawo esebenzayo, kunye ne-SER280 kunye ne-GLU359 ezinokuthi zisebenze njengeendawo ze-anchor eziguquguqukayo phantsi kweemeko zokumisa. Unxibelelwano oluqhelekileyo olubonwayo phakathi kwezinto ezisetyenzisiweyo kunye neentsalela eziphambili ezifana ne-GLU359 kunye ne-SER280, eziyinxalenye ye-SER-HIS-GLU catalytic triad eyaziwayo kwi-acetylcholinesterase yomntu (AChE), ixhasa ngakumbi ingcamango yokuba ezi khompawundi zinokuba neziphumo ezinamandla zokuthintela kwi-AChE ngokubophelela kwiindawo ezibalulekileyo ze-catalytic.29,61,64
Okuphawulekayo kukuba, i-compound 6 kunye ne-precursor yayo i-1a ibonise umsebenzi onamandla kakhulu ngokuchasene nee-larvae kwi-bioassay, ibonisa amaxabiso aphantsi e-LC₅₀ phakathi kwee-compounds kolu luhlu. Kwinqanaba le-molecular, i-compound 6 ibonisa ukusebenzisana okubalulekileyo ne-chlorpyrifos kwindawo ye-GLU359, ngelixa i-compound 1a idibana ne-BT7 ephinde yafakwa nge-hydrogen bond kwi-SER280. Zombini i-GLU359 kunye ne-SER280 zikhona kwi-crystallographic binding conformation yokuqala ye-BT7 kwaye ziyinxenye ye-conserved catalytic triplet ye-acetylcholinesterase (SER–HIS–GLU), igxininisa ukubaluleka kokusebenza kwezi ntsebenziswano ekugcineni umsebenzi wokuthintela wee-compounds (Umzobo 10).
Ukufana okubonwe kwiindawo zokubopha phakathi kwezinto eziphuma kwi-BT7 (kuquka i-BT7 yendalo kunye ne-BT7 ephinde yakhiwa) kunye ne-chlorpyrifos, ingakumbi kwiintsalela ezibalulekileyo kumsebenzi we-catalytic, kubonisa ngamandla indlela eqhelekileyo yokuthintela phakathi kwezi zinto zixutyiweyo. Ngokubanzi, ezi ziphumo ziqinisekisa amandla abalulekileyo ezinto eziphuma kwi-thiophene-isoquinolinone njengezithinteli ze-acetylcholinesterase ezinamandla kakhulu ngenxa yokusebenzisana kwazo okugcinweyo nokubalulekileyo kwibhayoloji.
Ulwalamano oluqinileyo phakathi kweziphumo ze-molecular docking kunye neziphumo ze-larval bioassay ziqinisekisa ngakumbi ukuba i-acetylcholinesterase (AChE) kunye ne-nicotinic acetylcholine receptor (nAChR) zezona njongo ziphambili ze-neurotoxic ze-synthesized thiophene-isoquinoline derivatives. Nangona iziphumo ze-docking zibonelela ngolwazi olubalulekileyo malunga ne-receptor-ligand affinity, kufuneka kuqatshelwe ukuba amandla okubopha edwa awanele ukuchaza ngokupheleleyo ukusebenza kwe-insecticidal in vivo. Umahluko kwixabiso le-LC₅₀ phakathi kwee-compounds ezineempawu ezifanayo ze-docking unokubangelwa zizinto ezifana nokuzinza kwe-metabolic, ukufunxwa, ukufumaneka kwe-bioavailability, kunye nokusasazwa kwizinambuzane.⁶⁰,⁶⁴Nangona kunjalo, uyilo oluqiqileyo lwesakhiwo, ukuxinana kwee-receptor eziphezulu ezilinganiswa yi-computer simulation, kunye nomsebenzi onamandla webhayoloji zixhasa kakhulu umbono wokuba ii-AChE kunye nee-nAChR zezona ziphambili kwi-neurotoxicity ebonwayo.
Ukuqukumbela, ii-hybrids ze-thiophene-isoquinoline ezidityanisiweyo zinezinto ezibalulekileyo zokwakha nokusebenzayo ezihambelana kakhulu nezibulala-zinambuzane ezaziwayo ze-neuroactive. Amandla azo okubopha ngokufanelekileyo kwi-acetylcholinesterase (AChE) kunye ne-nicotinic acetylcholine receptors (nAChRs) ngeendlela zokusebenzisana ezihambelanayo abonisa amandla azo njengezinambuzane ezijolise kabini. Le ndlela imbini ayigcini nje ngokuphucula ukusebenza kakuhle kokubulala izinambuzane kodwa ikwabonelela ngesicwangciso esithembisayo sokoyisa iindlela ezikhoyo zokuxhathisa, okwenza ezi zinto zivelisa amathuba okuphuhlisa iiarhente zokulawula iingcongconi zesizukulwana esilandelayo.
Ukulinganisa iiMolecular dynamics (MD) kusetyenziselwa ukuqinisekisa nokwandisa iziphumo ze-molecular docking, ukubonelela ngovavanyo oluchanekileyo noluxhomekeke kwixesha lokunxibelelana kwe-ligand-target phantsi kweemeko ezingokoqobo ze-physiologically. Nangona i-molecular docking inokubonelela ngolwazi olubalulekileyo lokuqala malunga nezikhundla zokubopha kunye nokunamathelana, yimodeli engaguqukiyo kwaye ayinakuchaza ukuguquguquka kwe-receptor, i-solvent dynamics, okanye ukuguquguquka kwexesha kwiintsebenziswano ze-molecular. Ke ngoko, ukulinganisa i-MD yindlela ebalulekileyo encedisayo yokuvavanya uzinzo oluntsonkothileyo, ukuqina kokunxibelelana, kunye notshintsho lwe-conformational kwi-ligands kunye neeproteni ngokuhamba kwexesha.60,62,71
Ngokusekelwe kwiipropati zabo zokubopha eziphezulu kwi-acetylcholinesterase (AChE) xa kuthelekiswa ne-nicotinic acetylcholine receptor (nAChR), sikhethe i-molecule yomzali i-1a (enexabiso eliphantsi le-LC₅₀) kunye ne-thiophene-isoquinoline compound esebenzayo kakhulu i-6 kwiimodeli ze-molecular dynamics (MD). Injongo yayikukuvavanya ukuba ukwakheka kwabo kokubopha kwindawo esebenzayo ye-AChE kuhlala kuzinzile ngaphezulu kwe-100 ns yokulinganisa kunye nokuthelekisa ukuziphatha kwabo kokubopha kunye ne-chlorpyrifos kunye ne-rebound cocrystallized AChE inhibitor BT7.
Ukulinganisa i-molecular dynamics kuquka i-root mean square deviation (RMSD) ukuvavanya uzinzo oluntsonkothileyo; i-root mean square deviation of fluctuations (RMSF) ukufunda ukuguquguquka kwe-residue; kunye nohlalutyo lwe-ligand-acceptor interaction ukumisela uzinzo lwee-hydrogen bonds, i-hydrophobic contacts, kunye nokusebenzisana kwe-ionic (Idatha eyongezelelekileyo). Nangona ixabiso le-RMSD kunye ne-RMSF kuzo zonke ii-ligands lihlale likwinqanaba elizinzileyo, libonisa ukuba akukho tshintsho lubalulekileyo kwi-AChE-ligand complex (Umfanekiso 12), ezi parameters zodwa azanele ukuchaza ngokupheleleyo umahluko kwi-binding mass phakathi kwee-compounds.
Ixesha leposi: Disemba-15-2025