He raruraru nui tonu ngā mate e ahu mai ana i te namu ki te hauora tūmatanui o te aoKo te tipu haere o te ātete o ngā kaikawe mate, pērā i te Culex pipiens pallens, ki ngā patu pepeke tuku iho ka nui ake te kino o tēnei raruraru. I roto i tēnei rangahau, i hangaia, i hangaia, ā, i aromatawaihia he raupapa o ngā ranu thiophene-isoquinolinone hou hei patu pepeke pea. I roto i ngā matū i hangaia, ko ngā momo 5f, 6, me te 7 i whakaatu i te kaha patu pepeke nui ki ngā torongū Culex pipiens pallens me ngā uara LC₅₀ o te 0.3, 0.1, me te 1.85 μg/mL, ia. He mea nui, ko ngā momo thiophene-isoquinolinone tekau mā rua katoa i whakaatu i te paitini nui atu i te patu pepeke organophosphate tohutoro chlorpyrifos (LC₅₀ = 293.8 μg/mL), e whakaū ana i te paitini pai ake o ēnei matū. He mea whakamīharo, ko te takawaenga hanga 1a (he thiophene semiester) i whakaatu i te kaha teitei rawa (LC₅₀ = 0.004 μg/mL), ā, ahakoa kāore anō kia tino arotauhia, i nui ake tōna kaha i ngā hua whakamutunga katoa. I whakaatuhia e ngā rangahau koiora tikanga ngā tohu kaha o te paitini neuro, e kī ana he ngoikore te mahi cholinergic. I whakaūhia tēnei kitenga e te hononga ngota ngota me ngā whakatauira hihiri ngota ngota, e whakaatu ana i ngā taunekeneke kaha motuhake me te acetylcholinesterase (AChE) me te kaiwhiwhi acetylcholine nicotinic (nAChR), e kī ana he tikanga mahi-rua pea. Nā ngā tataunga ariā mahi matotoru (DFT) i whakaū anō i ngā āhuatanga hiko pai me te tauhohenga o ngā matū hohe. Ko te kanorau hanganga me te kaha teitei tonu o tēnei raupapa matū ka whakaiti i te mōrearea o te ātete whakawhiti me te whakahaere i ngā rautaki whakahaere ātete mā te hurihanga matū, te whakakotahitanga rānei. I te nuinga, e tohu ana ēnei hua he kōwhiringa whai hua ngā ranu thiophene-isoquinolinone mō te whakawhanaketanga o ngā patu pepeke o te whakatupuranga e whai ake nei e aro ana ki ngā ara neurophysiological o ngā kawe pepeke.
Ko ngā waeroa kei roto i ngā kaikawe tino whai hua o ngā mate pāwera, e horapa ana i te whānuitanga o ngā mate kino, ā, he tūmomo mōrearea nui ki te hauora o te marea o te ao. Ko ngā momo pēnei i a Culex pipiens, Aedes aegypti, me Anopheles gambiae e mōhiotia whānuitia ana mō te kawe i ngā huaketo, ngā huakita, me ngā pirinoa, e mate ai ngā miriona me te maha o ngā mate i ia tau. Hei tauira, ko Culex pipiens te kaikawe matua o ngā arbovirus pēnei i te huaketo West Nile me te huaketo St. Louis encephalitis, tae atu ki ngā mate pirinoa pēnei i te avian malaria. Kua whakaatuhia hoki e ngā rangahau tata nei he mahi nui tā Culex pipiens i roto i te kawe me te tuku i ngā huakita kino pēnei i a Bacillus cereus me Staphylococcus warwickii, e poke ana i te kai me te whakanui ake i ngā raruraru hauora o te marea. Ko te kaha urutau, te oranga, me te ātete o ngā waeroa ki ngā tikanga whakahaere ka uaua ai te whakahaere, ā, ka noho hei tūmomo mōrearea tonu.
He taputapu matua ngā patu pepeke matū hei whakahaere i ngā waeroa, inā koa i ngā wā e horapa ana ngā mate e kawea mai ana e te waeroa. He maha ngā momo patu pepeke, tae atu ki ngā pyrethroid, ngā organophosphate, me ngā carbamates, e whakamahia whānuitia ana hei whakaiti i ngā taupori waeroa me te horapa o ngā mate. Heoi, ko te whakamahinga whānui me te whakamahinga roa o ēnei matū kua arahi ki ngā āwangawanga nui ki te taiao me te hauora tūmatanui, tae atu ki te whakararuraru i te rauropi, ngā pānga kino ki ngā momo kāore i te whainga, me te tere o te whanaketanga o te ātete patu pepeke i roto i ngā taupori waeroa.11,12,13,14Ka tino whakaitihia te whai huatanga o ngā patu pepeke tuku iho e tēnei ātete, e whakaatu ana i te hiahia nui mō ngā otinga matū auaha me ngā tikanga mahi hou hei ārai i ēnei tūmomo riri e whanake haere ana.11,12,13,14Hei whakatika i ēnei wero nui, kei te tahuri ngā kairangahau ki ngā rautaki rerekē pērā i te whakahaere koiora, te hangarau ira, me te whakahaere whāwhā whakauru (IVM). E whakaatu ana ēnei huarahi i te pūmanawa mō te whakahaere namu pumau, roa hoki. Heoi, i ngā wā o ngā mate urutā me ngā āhuatanga ohorere, he mea nui tonu ngā tikanga matū mō te urupare tere.
He mea nui ngā pūhui heterocyclic kei roto he hauota, ā, kua horapa whānuitia i roto i te ao tipu, tae atu ki ngā whānau pēnei i a Amaryllidaceae, Rubiaceae, Magnoliaceae, Papaveraceae, Berberidaceae, me Menispermaceae.30 Kua whakaūtia e ngā rangahau o mua he maha ngā mahi koiora me ngā āhuatanga hanganga o ngā pūhui isoquinoline, tae atu ki te patu pepeke, te ārai mate huka, te ārai pukupuku, te ārai harore, te ārai mumura, te ārai huakita, te ārai parataiao, te ārai ārai huaketo, me ngā pānga tiaki roro.
I roto i tēnei rangahau, ko ngā uara χ² mō ngā pūhui katoa i raro iho i te paepae matua, ā, ko ngā uara p i runga ake i te 0.05. E whakaū ana ēnei hua i te pono o ngā whakatau tata LC₅₀, ā, e whakaatu ana ka taea e te whakatau tata tūponotanga te whakaahua pai i te whanaungatanga horopeta-tauhohenga kua kitea. Nō reira, ko ngā uara LC₅₀ me ngā taupū paitini (TI) i tatauhia i runga i te pūhui tino hohe (1a) he tino pono, ā, he pai mō te whakataurite i ngā pānga paitini.
Hei aromatawai i ngā taunekeneke o ngā 12 thiophene-isoquinolinone derivatives hou i hangaia me tō rātou precursor 1a me ngā whāinga matua e rua o te neuron namu—acetylcholinesterase (AChE) me te nicotinic acetylcholine receptor (nAChR)—i whakahaerehia e mātou te tauira hononga ngota. I tīpakohia ēnei whāinga i runga i ngā tohu neurotoxic i kitea i roto i ngā whakamātautau mate torongū, e tohu ana i te ngoikore o te tohu neuron. Hei tāpiri, ko te hanganga ōrite o ēnei matū ki ngā organophosphates me ngā neonicotinoids e tautoko ana i te kōwhiringa pai o ēnei whāinga, i te mea ka puta ngā pānga paitini o ngā organophosphates me ngā neonicotinoid mā te aukati i te AChE me te whakahohe i te nAChR.
Hei tāpiri atu, he maha ngā matū (tae atu ki te 1a, 2, 5a, 5b, 5e, 5f, me te 7) e taunekeneke ana ki te SER280. Kei roto ngā toenga SER280 i te hanga i ngā hanganga hanganga tioata, ā, e tiakina ana i roto i te hanganga kua tāruatia o te BT7. E whakaatu ana tēnei kanorau o ngā momo taunekeneke i te urutau o ēnei matū i roto i te pae hohe, me te SER280 me te GLU359 e mahi pea hei pae punga urutau i raro i ngā tikanga taunga. Ko ngā taunekeneke auau i kitea i waenga i ngā matū hangai me ngā toenga matua pērā i te GLU359 me te SER280, he wāhanga o te toru catalytic SER-HIS-GLU e mōhiotia ana i roto i te acetylcholinesterase tangata (AChE), e tautoko ana i te whakapae ka taea e ēnei matū te whakamahi i ngā pānga aukati kaha ki te AChE mā te herea ki ngā pae nui catalytic.29,61,64
He mea nui, ko te matū 6 me tōna mua 1a i whakaatu i te kaha tino kaha ki ngā torongū i roto i te whakamātautau koiora, e whakaatu ana i ngā uara LC₅₀ iti rawa i roto i ngā matū o te raupapa. I te taumata ngota, ka whakaatu te matū 6 i te taunekeneke nui ki ngā chlorpyrifos i te pae GLU359, i te mea ka taupatupatu te matū 1a ki te BT7 kua tāpirihia anō mā te here hauwai ki SER280. Kei roto a GLU359 me SER280 i te hanganga here tioata taketake o BT7, ā, he wāhanga o te toru whakapūmau o te acetylcholinesterase (SER–HIS–GLU), e whakaatu ana i te hiranga mahi o ēnei taunekeneke ki te pupuri i te mahi aukati o ngā matū (Pikitia 10).
Ko te āhua ōrite i kitea i roto i ngā pae here i waenga i ngā matū BT7 (tae atu ki te BT7 taketake me te BT7 kua hangaia anō) me ngā chlorpyrifos, inā koa i ngā toenga e tino hira ana mō te mahi whakatere, e whakaatu ana i tētahi tikanga noa mō te aukati i waenga i ēnei pūhui. I te nuinga, e whakaū ana ēnei hua i te kaha nui o ngā matū thiophene-isoquinolinone hei aukati acetylcholinesterase tino kaha nā ō rātou taunekeneke e tiakina ana, e whai pānga ana ki te koiora.
Nā te hononga kaha i waenga i ngā hua o te hononga ngota ngota me ngā hua o te whakamātautau koiora torongū, ka whakaū anō ko te acetylcholinesterase (AChE) me te kaiwhiwhi acetylcholine nicotinic (nAChR) ngā whāinga neurotoxic matua o ngā thiophene-isoquinolinone derivatives kua hangaia. Ahakoa he nui ngā kōrero a ngā hua hononga mō te hononga o te kaiwhiwhi-ligand, me mārama kāore e ranea te kaha here anake hei whakamārama katoa i te whai huatanga o te patu pepeke i roto i te tinana ora. Ko ngā rerekētanga o ngā uara LC₅₀ i waenga i ngā matū he rite ngā āhuatanga hononga, tera pea nā ngā āhuatanga pēnei i te pumau o te pākia, te mimiti, te wātea o te koiora, me te tohatoha i roto i ngā pepeke.⁶⁰,⁶⁴Heoi, ko te hoahoa hanganga whaitake, te kaha o te hononga ki ngā kaiwhakawhiwhi e whakaatahia ana e te whakaata rorohiko, me te kaha o te mahi koiora e tautoko ana i te tirohanga ko AChE me nAChR ngā takawaenga matua o te paitini roro kua kitea.
Hei whakamutunga, ko ngā ranunga thiophene-isoquinolinone kua hangaia he mea hanga ki ngā āhuatanga matua o te hanganga me te mahi e hototahi ana ki ngā patu pepeke neuroactive e mōhiotia ana. Ko tō rātou kaha ki te here pai ki te acetylcholinesterase (AChE) me ngā kaiwhakawhiwhi acetylcholine nicotinic (nAChRs) mā roto i ngā tikanga taunekeneke tautoko e whakaatu ana i tō rātou kaha hei patu pepeke whainga-rua. Ehara i te mea ka whakarei ake tēnei tikanga rua i te whai huatanga o te patu pepeke engari ka whakarato hoki i tētahi rautaki whai hua mō te wikitoria i ngā tikanga ātete o nāianei, e hanga ana i ēnei matū hei kaitono whai hua mō te whanaketanga o ngā kaihoko whakahaere namu o te whakatupuranga e whai ake nei.
Ka whakamahia ngā whakatauira hihiri ngota (MD) hei whakamana me te whakawhānui i ngā hua o te hononga ngota, e whakarato ana i tētahi aromatawai pono ake, ā, e whakawhirinaki ana ki te wā, o ngā taunekeneke ligand-target i raro i ngā āhuatanga tūturu ā-tinana. Ahakoa ka taea e te hononga ngota te whakarato i ngā mōhiohio tuatahi whai hua mō ngā tūranga here me ngā hononga pea, he tauira pumau, ā, kāore e taea te whakamārama i te ngāwari o te kaiwhakawhiwhi, te hihiri whakarewa, te rerekētanga wā rānei i roto i ngā taunekeneke ngota. Nō reira, he tikanga tāpiri nui ngā whakatauira MD mō te aromatawai i te pumau matatini, te pakari o te taunekeneke, me ngā huringa āhua o ngā ligand me ngā pūmua i roto i te wā.60,62,71
I runga i ō rātou āhuatanga here pai ki te acetylcholinesterase (AChE) ki te whakataurite ki te kaiwhakawhiwhi acetylcholine nicotinic (nAChR), i tīpakohia e mātou te ngota matua 1a (me te uara LC₅₀ iti rawa) me te matū thiophene-isoquinoline 6 tino kaha mō ngā whakatauira hihiri ngota (MD). Ko te whāinga he aromatawai mēnā i noho pumau tonu tō rātou āhua here i roto i te pae kaha AChE i roto i te 100 ns o te whakatauira me te whakataurite i ō rātou whanonga here ki te whanonga o te chlorpyrifos me te aukati AChE kua whakakōkiritia anōtia BT7.
Ko ngā whakatauira hihiri ngota i whakaurua ko te pūtake toharite tapawhā rerekētanga (RMSD) hei aromatawai i te pumau o te matatini whānui; te pūtake toharite tapawhā rerekētanga o ngā piki me ngā heke (RMSF) hei ako i te ngāwari o ngā toenga; me te tātari taunekeneke ligand-accepter hei whakatau i te pumau o ngā here hauwai, ngā hononga hydrophobic, me ngā taunekeneke ionic (Raraunga Tāpiri). Ahakoa i noho tonu ngā uara RMSD me te RMSF mō ngā ligand katoa i roto i te awhe pumau, e tohu ana kāore he huringa āhua nui i roto i te matatini AChE-ligand (Pikitia 12), kāore i te rawaka ēnei tawhā anake hei whakamārama katoa i ngā rerekētanga o te papatipu here i waenga i ngā pūhui.
Wā tuku: Hakihea-15-2025
