He pilikia olakino lehulehu koʻikoʻi nā maʻi i lawe ʻia e ka makikaʻO ka ulu ʻana o ke kūʻē ʻana o nā mea lawe maʻi, e like me Culex pipiens pallens, i nā insecticides kuʻuna e hoʻonui hou aku i kēia pilikia. Ma kēia haʻawina, ua hoʻolālā ʻia, synthesized, a loiloi ʻia kekahi mau hybrids thiophene-isoquinolinone hou e like me nā larvicides hiki. Ma waena o nā hui i synthesized ʻia, ua hōʻike nā derivatives 5f, 6, a me 7 i ka hana larvicidal koʻikoʻi e kūʻē i nā larvae Culex pipiens pallens me nā waiwai LC₅₀ o 0.3, 0.1, a me 1.85 μg/mL, kēlā me kēia. ʻO ka mea nui, ua hōʻike nā derivatives thiophene-isoquinolinone he ʻumikūmālua i ka ʻawaʻawa kiʻekiʻe ma mua o ka organophosphate insecticide chlorpyrifos (LC₅₀ = 293.8 μg/mL), e hōʻoia ana i ka ʻawaʻawa kiʻekiʻe o kēia mau hui. ʻO ka mea hoihoi, ua hōʻike ka synthetic intermediate 1a (kahi thiophene semiester) i ka ikaika kiʻekiʻe loa (LC₅₀ = 0.004 μg/mL), a ʻoiai ʻaʻole i hoʻomaikaʻi piha ʻia, ua ʻoi aku kona ikaika ma mua o nā derivatives hope loa. Ua hōʻike nā haʻawina biology mechanistic i nā hōʻailona neurotoxicity ikaika, e hōʻike ana i ka hana cholinergic impaired. Ua hōʻoia ka molecular docking a me nā molecular dynamics simulations i kēia ʻike, e hōʻike ana i nā pilina kikoʻī ikaika me acetylcholinesterase (AChE) a me ka nicotinic acetylcholine receptor (nAChR), e hōʻike ana i kahi ʻano hana pālua. Ua hōʻoia hou nā helu ʻana o ke kumumanaʻo hana Density (DFT) i nā waiwai uila maikaʻi a me ka reactivity o nā pūhui hana. ʻO ke ʻano like ʻole o ke ʻano a me ka ikaika kiʻekiʻe mau o kēia moʻo o nā pūhui e hōʻemi i ka pilikia o ke kū'ē ʻana a hoʻomaʻamaʻa i nā hoʻolālā hoʻokele kū'ē ma o ka hoʻololi pūhui a i ʻole ka hui pū ʻana. Ma keʻano holoʻokoʻa, hōʻike kēia mau hopena he koho hoʻohiki nā hybrids thiophene-isoquinolinone no ka hoʻomohala ʻana i nā larvicides hanauna e hiki mai ana e kuhikuhi ana i nā ala neurophysiological o nā vectors pepeke.
ʻO nā makika kekahi o nā mea lawe maʻi lele maikaʻi loa, e hoʻolaha ana i nā ʻano pathogens weliweli a hoʻoweliweli nui i ke olakino lehulehu honua. ʻO nā ʻano e like me Culex pipiens, Aedes aegypti, a me Anopheles gambiae ua ʻike nui ʻia no ka hoʻoili ʻana i nā virus, bacteria, a me nā parasites, e hoʻoulu ana i nā miliona o nā maʻi a me nā make he nui i kēlā me kēia makahiki. No ka laʻana, ʻo Culex pipiens kahi mea lawe nui o nā arboviruses e like me ka maʻi West Nile a me ka maʻi St. Louis encephalitis, a me nā maʻi parasitic e like me ka avian malaria. Ua hōʻike pū ʻia nā noiʻi hou he kuleana koʻikoʻi ko Culex pipiens i ka mea lawe a me ka hoʻoili ʻana i nā bacteria ʻino e like me Bacillus cereus lāua ʻo Staphylococcus warwickii, ka mea e haumia ai i ka meaʻai a hoʻonui i nā pilikia olakino lehulehu. ʻO ke kiʻekiʻe o ka hoʻololi ʻana, ke ola ʻana, a me ke kūʻē ʻana o nā makika i nā ʻano kaohi e paʻakikī ai ke kaohi a hoʻoweliweli mau.
He mea nui nā lāʻau pepehi kanaka kemika i ka hoʻomalu ʻana i nā makika, ʻoiai i ka wā e puka mai ai nā maʻi mai nā makika. Hoʻohana nui ʻia nā ʻano lāʻau pepehi kanaka like ʻole, me nā pyrethroids, organophosphates, a me nā carbamates, e hōʻemi i ka heluna makika a me ka laha ʻana o nā maʻi. Eia nō naʻe, ʻo ka hoʻohana nui ʻana a me ka lōʻihi o kēia mau kemika ua alakaʻi i nā hopohopo koʻikoʻi no ke kaiapuni a me ke olakino lehulehu, me ka hoʻopilikia ʻana i ka ʻōnaehana ola, nā hopena ʻino i nā ʻano ʻaʻole i hoʻolālā ʻia, a me ka ulu wikiwiki ʻana o ke kūʻē ʻana i nā lāʻau pepehi kanaka i nā heluna makika.11,12,13,14Hoʻemi nui kēia kū'ē i ka pono o nā insecticides kuʻuna he nui, e hōʻike ana i ka pono wikiwiki no nā hoʻonā kemika hou me nā ʻano hana hou e kūʻē pono ai i kēia mau hoʻoweliweli e ulu nei.11,12,13,14No ka hoʻoponopono ʻana i kēia mau pilikia koʻikoʻi, ke huli nei nā mea noiʻi i nā hoʻolālā ʻē aʻe e like me ka biocontrol, genetic engineering, a me ka hoʻokele vector i hoʻohui ʻia (IVM). Hōʻike kēia mau ʻano hana i ka hoʻohiki no ka kaohi mau ʻana i nā makika no ka wā lōʻihi. Eia nō naʻe, i ka wā o nā maʻi ahulau a me nā pilikia, he mea nui mau nā ʻano kemika no ka pane wikiwiki.
He mau mea nui nā alkaloids Isoquinoline i loaʻa ka naikokene i hoʻolaha nui ʻia ma ke aupuni o nā mea kanu, me nā ʻohana e like me Amaryllidaceae, Rubiaceae, Magnoliaceae, Papaveraceae, Berberidaceae, a me Menispermaceae.30 Ua hōʻoia nā haʻawina mua he mau hana olaola like ʻole a me nā hiʻohiʻona hoʻonohonoho like ʻole nā alkaloids isoquinoline, me ka insecticidal, antidiabetic, antitumor, antifungal, anti-inflammatory, antibacterial, antiparasitic, antioxidant, antiviral, a me nā hopena neuroprotective.
Ma kēia haʻawina, ua emi nā waiwai χ² no nā hui āpau ma mua o ka paepae koʻikoʻi, a ua emi nā waiwai p ma mua o 0.05. Hōʻoia kēia mau hopena i ka hilinaʻi o nā kuhi LC₅₀ a hōʻike i ka hiki i ka regression probabilistic ke wehewehe pono i ka pilina dose-response i ʻike ʻia. No laila, ʻo nā waiwai LC₅₀ a me nā ʻōkuhi toxicity (TIs) i helu ʻia ma muli o ka hui hana nui loa (1a) he hilinaʻi loa a kūpono no ka hoʻohālikelike ʻana i nā hopena toxicological.
No ka loiloi ʻana i nā pilina o 12 mau derivatives thiophene-isoquinolinone i hana hou ʻia a me kā lākou precursor 1a me ʻelua mau pahuhopu neuronal makika koʻikoʻi—acetylcholinesterase (AChE) a me ka nicotinic acetylcholine receptor (nAChR)—ua hana mākou i ka hoʻohālike docking molecular. Ua koho ʻia kēia mau pahuhopu ma muli o nā hōʻailona neurotoxic i ʻike ʻia i nā hoʻāʻo make larval, e hōʻike ana i ka hōʻailona neuronal i hōʻino ʻia. Eia kekahi, ʻo ke ʻano like o kēia mau hui i nā organophosphates a me nā neonicotinoids e kākoʻo hou aku i ke koho makemake ʻia o kēia mau pahuhopu, ʻoiai ʻo nā organophosphates a me nā neonicotinoids e hoʻopuka i ko lākou hopena ʻawahia ma ka pale ʻana iā AChE a me ka hoʻoulu ʻana iā nAChR.
Eia kekahi, he nui nā hui (me 1a, 2, 5a, 5b, 5e, 5f, a me 7) e launa pū me SER280. Pili nā koena SER280 i ke ʻano o ke kūkulu ʻana i nā ʻano kristal a mālama ʻia i loko o ke ʻano hou o BT7. Hōʻike kēia ʻano like ʻole o nā ʻano launa pū i ka hiki ke hoʻololi i kēia mau hui ma ke kahua hana, me SER280 a me GLU359 e lawelawe ana ma ke ʻano he mau wahi heleuma adaptive ma lalo o nā kūlana docking. ʻO nā pilina pinepine i ʻike ʻia ma waena o nā derivatives synthetic a me nā koena koʻikoʻi e like me GLU359 a me SER280, ʻo ia nā ʻāpana o ka triad catalytic SER-HIS-GLU i ʻike ʻia i loko o ka acetylcholinesterase kanaka (AChE), kākoʻo hou i ka manaʻo e hiki i kēia mau hui ke hoʻokō i nā hopena inhibitory ikaika ma AChE ma o ka nakinaki ʻana i nā wahi koʻikoʻi catalytic.29,61,64
ʻO ka mea nui, ua hōʻike ka hui 6 a me kāna mea i hana mua ʻia 1a i ka hana ikaika loa e kūʻē i nā larvae i ka bioassay, e hōʻike ana i nā waiwai LC₅₀ haʻahaʻa loa i waena o nā hui i loko o ka moʻo. Ma ka pae molekala, hōʻike ka hui 6 i kahi pilina koʻikoʻi me chlorpyrifos ma kahi GLU359, ʻoiai ʻo ka hui 1a e uhi ana me BT7 i hoʻohui hou ʻia ma o kahi pilina hydrogen iā SER280. Aia ʻo GLU359 a me SER280 i loko o ke ʻano hoʻopaʻa crystallographic mua o BT7 a he mau ʻāpana o ka triplet catalytic i mālama ʻia o acetylcholinesterase (SER-HIS-GLU), e hōʻike ana i ke koʻikoʻi o ka hana o kēia mau pilina i ka mālama ʻana i ka hana inhibitory o nā hui (Kiʻi 10).
ʻO ke ʻano like i ʻike ʻia ma nā wahi hoʻopaʻa ma waena o nā derivatives BT7 (me ka BT7 maoli a me ka BT7 i hoʻohui hou ʻia) a me nā chlorpyrifos, ʻoi aku hoʻi ma nā koena koʻikoʻi no ka hana catalytic, e hōʻike ikaika ana i kahi ʻano hana maʻamau o ka pale ʻana ma waena o kēia mau hui. Ma keʻano holoʻokoʻa, ua hōʻoia kēia mau hopena i ka hiki nui o nā derivatives thiophene-isoquinolinone ma ke ʻano he mau mea hoʻopaʻa acetylcholinesterase ikaika loa ma muli o kā lākou pilina i mālama ʻia a pili i ka biology.
ʻO ka pilina ikaika ma waena o nā hopena docking molecular a me nā hopena bioassay larval e hōʻoia hou ana ʻo acetylcholinesterase (AChE) a me ka nicotinic acetylcholine receptor (nAChR) nā pahuhopu neurotoxic mua o nā thiophene-isoquinolinone derivatives i synthesized. ʻOiai hāʻawi nā hopena docking i ka ʻike koʻikoʻi e pili ana i ka receptor-ligand affinity, pono e ʻike ʻia ʻaʻole lawa ka ikehu nakinaki wale nō e wehewehe piha i ka pono insecticidal in vivo. ʻO nā ʻokoʻa i nā waiwai LC₅₀ ma waena o nā hui me nā ʻano docking like paha ma muli o nā mea e like me ka metabolic stability, absorption, bioavailability, a me ka hoʻolaha ʻana i nā pepeke.⁶⁰,⁶⁴Eia nō naʻe, ʻo ka hoʻolālā hoʻonohonoho kūpono, ke kiʻekiʻe o ka receptor affinity i hoʻohālike ʻia e ka simulation kamepiula, a me ka hana olaola ikaika e kākoʻo ikaika i ka manaʻo ʻo AChE a me nAChRs nā mea hoʻoponopono nui o ka neurotoxicity i ʻike ʻia.
I ka hopena, loaʻa i nā hybrids thiophene-isoquinolinone i synthesized nā mea nui o ke kūkulu ʻana a me ka hana e kūlike nui me nā insecticides neuroactive i ʻike ʻia. ʻO ko lākou hiki ke hoʻopaʻa pono i ka acetylcholinesterase (AChE) a me nā nicotinic acetylcholine receptors (nAChRs) ma o nā ʻano hana launa pū e hōʻike ana i ko lākou hiki ke lilo i mau insecticides pālua-target. ʻAʻole wale kēia ʻano hana pālua e hoʻonui i ka pono o ka insecticidal akā hāʻawi pū i kahi hoʻolālā hoʻohiki no ka lanakila ʻana i nā ʻano kūʻē e kū nei, e hana ana i kēia mau hui i mau moho hoʻohiki no ka hoʻomohala ʻana i nā mea hoʻomalu makika hanauna hou.
Hoʻohana ʻia nā simulations molecular dynamics (MD) e hōʻoia a hoʻonui i nā hopena docking molecular, e hāʻawi ana i kahi loiloi ʻoi aku ka maoli a me ka manawa o nā pilina ligand-target ma lalo o nā kūlana physiologically realistic. ʻOiai hiki i ka docking molecular ke hāʻawi i ka ʻike mua waiwai nui e pili ana i nā kūlana hoʻopaʻa a me nā affinities hiki, he kumu hoʻohālike static ia a ʻaʻole hiki ke helu no ka maʻalahi o ka receptor, dynamics solvent, a i ʻole nā fluctuations temporal i nā pilina molecular. No laila, he ʻano hoʻopihapiha koʻikoʻi nā simulations MD no ka loiloi ʻana i ka paʻa paʻakikī, ka paʻa o ka pilina, a me nā loli conformational i nā ligands a me nā protein i ka hala ʻana o ka manawa.60,62,71
Ma muli o ko lākou mau waiwai hoʻopaʻa kiʻekiʻe i ka acetylcholinesterase (AChE) i hoʻohālikelike ʻia me ka nicotinic acetylcholine receptor (nAChR), ua koho mākou i ka molekole makua 1a (me ka waiwai LC₅₀ haʻahaʻa loa) a me ka hui thiophene-isoquinoline ikaika loa 6 no nā simulations molecular dynamics (MD). ʻO ka pahuhopu ka loiloi inā ua kūpaʻa ko lākou ʻano hoʻopaʻa ʻana ma ka pūnaewele hana AChE ma luna o 100 ns o ka simulation a e hoʻohālikelike i kā lākou ʻano hoʻopaʻa ʻana me ko chlorpyrifos a me ka rebound cocrystallized AChE inhibitor BT7.
ʻO nā hoʻohālikelike dynamics molecular i hoʻokomo i ke kumu aʻo ʻana i ka ʻokoʻa o ka paʻakikī holoʻokoʻa; ʻo ke kumu aʻo ʻana i ka ʻokoʻa o nā fluctuations (RMSF) e aʻo ai i ka maʻalahi o ke koena; a me ka loiloi pilina ligand-acceptor e hoʻoholo ai i ke kūpaʻa o nā pilina hydrogen, nā pilina hydrophobic, a me nā pilina ionic (ʻIkepili Hoʻohui). ʻOiai ua noho nā waiwai RMSD a me RMSF no nā ligands āpau i loko o kahi pae paʻa, e hōʻike ana ʻaʻohe loli koʻikoʻi o ka conformational i loko o ka hui AChE-ligand (Kiʻi 12), ʻaʻole lawa kēia mau palena wale nō e wehewehe piha i nā ʻokoʻa o ka nui o ka hoʻopaʻa ʻana ma waena o nā hui.
Ka manawa hoʻouna: Dec-15-2025