Zvirwere zvinotapurirwa nehumhutu zvichiri dambudziko guru rehutano hweveruzhinji pasi roseKuramba kuri kuita zvirwere, zvakaita seCulex pipiens pallens, nemishonga yezvipembenene yechinyakare kuri kuwedzera dambudziko iri. Muchidzidzo ichi, mhando itsva dzemishonga yethiophene-isoquinoline yakagadzirwa, yakagadzirwa, uye yakaongororwa semishonga inogona kuurawa. Pakati pemishonga yakagadzirwa, mishonga ye5f, 6, uye 7 yakaratidza kushanda kwakakosha kwekuuraya mabuu eCulex pipiens pallens ine LC₅₀ values ye0.3, 0.1, uye 1.85 μg/mL, zvichiteerana. Zvinonyanya kukosha kuti mishonga yethiophene-isoquinoline gumi nemaviri yakaratidza kuurawa kwakanyanya kupfuura mishonga yezvipembenene inonzi organophosphate chlorpyrifos (LC₅₀ = 293.8 μg/mL), zvichiratidza kuurawa kwakanyanya kwemishonga iyi. Zvinofadza kuti, synthetic intermediate 1a (thiophene semiester) yakaratidza simba guru (LC₅₀ = 0.004 μg/mL), uye kunyange zvazvo isati yanyatsogadziriswa, simba rayo rakapfuura rezvinhu zvose zvinobuda mumasero. Zvidzidzo zvemakemikari zvakaratidza zviratidzo zvakasimba zve neurotoxicity, zvichiratidza kusashanda zvakanaka kwe cholinergic. Kuisa mamolecular docking uye molecular dynamics simulations zvakasimbisa izvi, zvichiratidza kudyidzana kwakasimba ne acetylcholinesterase (AChE) uye nicotinic acetylcholine receptor (nAChR), zvichiratidza kuti panogona kuva ne dual-action mechanism. Density functional theory (DFT) calculations zvakasimbisawo hunyanzvi hwakanaka hwemagetsi uye reactivity ye active compounds. Kusiyana kwechimiro uye simba rakawanda rinogara riripo reiyi series ye compounds zvinogona kuderedza njodzi yekusagona kuyambuka uye kuita kuti nzira dzekudzivirira kusagona kupindirana dzishande kuburikidza nekutenderera kana kusanganiswa kwe compound. Zvose izvi zvinoratidza kuti thiophene-isoquinoline hybrids isarudzo yakanaka yekuvandudza larvicides yechizvarwa chinotevera ichinanga nzira dze neurophysiological dzezvipembenene.
Umhutu huri pakati pezvirwere zvinotapukira zvinobudirira, zvichiparadzira utachiona hwakasiyana-siyana hune njodzi uye zvichiisa njodzi huru kuhutano hweveruzhinji pasi rose. Mhando dzakadai seCulex pipiens, Aedes aegypti, uye Anopheles gambiae dzinozivikanwa zvikuru nekuparadzira mavhairasi, mabhakitiriya, uye tupukanana, zvichikonzera mamiriyoni ezvirwere uye kufa kwakawanda gore rega rega. Semuenzaniso, Culex pipiens inokonzera mavhairasi akadai seWest Nile virus neSt. Louis encephalitis virus, pamwe nezvirwere zvetupukanana zvakaita seavian malaria. Ongororo ichangoburwa yakaratidzawo kuti Culex pipiens ine basa guru mukupararira kwebhakitiriya inokuvadza senge Bacillus cereus neStaphylococcus warwickii, iyo inosvibisa chikafu uye inowedzera matambudziko ehutano hweveruzhinji. Kugona kuchinjika kwakanyanya, kurarama, uye kuramba kweumhutu nzira dzekudzora kunoita kuti zviome kudzora uye zvinopa njodzi inogara iripo.
Mishonga yekuuraya zvipembenene inoshandiswa zvakanyanya mukudzivirira umhutu, kunyanya panguva yekupararira kwezvirwere zvinotapuriranwa neumhutu. Marudzi akasiyana-siyana emishonga yekuuraya zvipembenene, anosanganisira pyrethroids, organophosphates, uye carbamates, anoshandiswa zvakanyanya kuderedza kuwanda kweumhutu uye kutapurirana kwezvirwere. Zvisinei, kushandiswa kwakapararira uye kwenguva refu kwemakemikari aya kwakakonzera kunetseka kukuru kwezvakatipoteredza nehutano hweveruzhinji, kusanganisira kukanganiswa kwezvakatipoteredza, migumisiro inokuvadza pamarudzi asiri emhuka, uye kukurumidza kukura kwekusagona kudzivirira zvipembenene muhuwandu hweumhutu.11,12,13,14Kusagona kushandisa mishonga iyi kunoderedza zvakanyanya kushanda kwemishonga yakawanda yezvipembenene yechinyakare, zvichiratidza kudiwa kukuru kwemishonga mitsva ine nzira itsva dzekuita kuti ibudirire kurwisa njodzi idzi dziri kuchinja.11,12,13,14Kuti vagadzirise matambudziko aya akakomba, vaongorori vari kushandisa dzimwe nzira dzakadai se biocontrol, genetic engineering, uye integrated vector management (IVM). Nzira idzi dzinoratidza vimbiso yekudzora umhutu kwenguva refu uye kwenguva refu. Zvisinei, panguva yezvirwere zvematenda uye njodzi, nzira dzemakemikari dzinoramba dzichikosha kuti vanhu vakurumidze kupindura.
Maalkaloid eIsoquinoline ndiwo macompounds akakosha ane nitrogen akapararira zvakanyanya muhushe hwezvirimwa, kusanganisira mhuri dzakadai seAmaryllidaceae, Rubiaceae, Magnoliaceae, Papaveraceae, Berberidaceae, uye Menispermaceae.30 Ongororo dzakapfuura dzakasimbisa kuti maalkaloid eisoquinoline ane mabasa akasiyana-siyana ehupenyu uye maumbirwo awo, anosanganisira zvipembenene, chirwere cheshuga, tumor, antifungal, anti-inflammatory, antibacterial, antiparasitic, antioxidant, antiviral, uye neuroprotective effects.
Muchidzidzo ichi, χ² values yemakomputa ese aive pasi pe critical threshold, uye p values yaive pamusoro pe0.05. Mhedzisiro iyi inosimbisa kuvimbika kwefungidziro dzeLC₅₀ uye inoratidza kuti probabilistic regression inogona kutsanangura zvinobudirira hukama hwakaonekwa hwedose-response. Nokudaro, LC₅₀ values uye toxicity indices (TIs) dzakaverengerwa zvichibva pane inonyanya kushanda (1a) dzakavimbika zvikuru uye dzakakodzera kuenzanisa migumisiro yechepfu.
Kuti tiongorore kudyidzana kwe12 thiophene-isoquinoline derivatives itsva yakagadzirwa uye precursor 1a yavo ine zvinangwa zviviri zvakakosha zve mosquito neuronal targets—acetylcholinesterase (AChE) uye nicotinic acetylcholine receptor (nAChR)—takaita molecular docking modeling. Zvinangwa izvi zvakasarudzwa zvichibva pazviratidzo zve neurotoxic zvakaonekwa mu larval death assays, zvichiratidza kusashanda zvakanaka kwe neuronal signaling. Uyezve, kufanana kwemaumbirwo emakomichi aya ne organophosphates ne neonicotinoids kunotsigirawo sarudzo yakasarudzwa yezvinangwa izvi, sezvo organophosphates ne neonicotinoids dzichishandisa migumisiro yadzo ine chepfu nekudzivisa AChE uye kuita kuti nAChR ishande, zvichiteerana.
Uyezve, macompounds akati wandei (anosanganisira 1a, 2, 5a, 5b, 5e, 5f, uye 7) anoshanda pamwe chete neSER280. MaSER280 residues anobatanidzwa mukugadzira magadzirirwo ekristaro uye anochengetwa mukugadzirwa kweBT7. Kusiyana uku kwemaitiro ekudyidzana kunoratidza kugona kwemakemikari aya munzvimbo inoshanda, neSER280 neGLU359 zvinogona kushanda senzvimbo dzeanchor dzinochinjika pasi pemamiriro ekuisa docking. Kudyidzana kwakawanda kunoonekwa pakati pezvinhu zvakagadzirwa uye ma key residues akadai seGLU359 neSER280, izvo zviri zvikamu zveSER-HIS-GLU catalytic triad inozivikanwa muhuman acetylcholinesterase (AChE), zvinotsigirawo pfungwa yekuti macompounds aya anogona kuita mhedzisiro yakasimba paAChE nekusunga kunzvimbo dzakakosha dzecatalytic.29,61,64
Zvinonyanya kukosha kuti compound 6 ne precursor 1a yayo yakaratidza kushanda nesimba pakurwisa mabuu mu bioassay, zvichiratidza LC₅₀ values yakaderera pakati pemakomponi ari mu series. Padanho remamorekuru, compound 6 inoratidza kushanda kwakakosha ne chlorpyrifos panzvimbo yeGLU359, nepo compound 1a ichipindirana ne re-doped BT7 kuburikidza ne hydrogen bond kuSER280. GLU359 neSER280 zvese zviripo mu original crystallographic binding conformation yeBT7 uye zvikamu zve conserved catalytic triplet ye acetylcholinesterase (SER–HIS–GLU), zvichiratidza kukosha kwebasa rekudyidzana uku mukuchengetedza inhibitory activity yemakomponi (Mufananidzo 10).
Kufanana kwakaonekwa munzvimbo dzinobatanidza zvinhu zvinogadzirwa neBT7 (kusanganisira BT7 yemuno neyakagadziriswazve) uye chlorpyrifos, kunyanya pazvisaririra zvakakosha pakuita catalytic activity, zvinoratidza zvakasimba kuti pane nzira yakajairika yekudzivirira pakati pezvinhu izvi. Zvose, izvi zvinosimbisa kugona kukuru kwezvinobva mu thiophene-isoquinolinone se acetylcholinesterase inhibitors ine simba guru nekuda kwekudyidzana kwadzo kwakachengetedzwa uye kwakakosha pahupenyu.
Kubatana kwakasimba pakati pemhedzisiro ye molecular docking uye mhedzisiro ye larval bioassay kunosimbisa zvakare kuti acetylcholinesterase (AChE) uye nicotinic acetylcholine receptor (nAChR) ndizvo zvinonyanya kukonzera chepfu muuropi zve synthesized thiophene-isoquinoline derivatives. Kunyangwe mhedzisiro ye docking ichipa ruzivo rwakakosha pamusoro pe receptor-ligand affinity, zvinofanirwa kuzivikanwa kuti simba rekubatanidza chete harina kukwana kutsanangura zvizere kushanda kwezvipembenene mumuviri. Kusiyana muLC₅₀ values pakati pemakemikari ane hunhu hwakafanana hwe docking kunogona kukonzerwa nezvinhu zvakaita sekugadzikana kwe metabolic, kunyudzwa, kuwanikwa kwe bioavailability, uye kugoverwa muzvipembenene.⁶⁰,⁶⁴Zvisinei, dhizaini yekuvaka ine musoro, hukama hwepamusoro hwemareceptors hwakatevedzerwa nekushandisa komputa, uye kushanda kwakasimba kwehupenyu zvinotsigira zvakasimba maonero ekuti AChE ne nAChRs ndizvo zvinonyanya kukonzera chepfu yeuropi inoonekwa.
Mukupedzisa, hybrids dzethiophene-isoquinoline dzakagadzirwa dzine zvinhu zvakakosha zvekuvaka uye zvinoshanda zvinoenderana nemishonga yezvipembenene inozivikanwa yeneuroactive. Kukwanisa kwadzo kubatana zvinobudirira neacetylcholinesterase (AChE) uye nicotinic acetylcholine receptors (nAChRs) kuburikidza nenzira dzekudyidzana dzinowedzera simba radzo semishonga yezvipembenene ine chinangwa chedual-target. Iyi nzira mbiri haingobatsiri chete kuuraya zvipembenene asiwo inopa nzira yakanaka yekukunda nzira dziripo dzekudzivirira utsi, zvichiita kuti mishonga iyi ive netariro yekuvandudza mishonga yekudzivirira utsi yechizvarwa chinotevera.
Kutevedzera maMolecular dynamics (MD) kunoshandiswa kusimbisa nekuwedzera mhedzisiro yekuisa maMolecular docking, zvichipa kuongororwa kuri nani uye kunoenderana nenguva kwekudyidzana kwe ligand-target pasi pemamiriro ezvinhu chaiwo e physiologically. Kunyangwe kutevedzera maMolecular docking kuchigona kupa ruzivo rwekutanga rwakakosha pamusoro penzvimbo dzinogona kubatana uye hukama, i static model uye haigone kutsanangura kuchinjika kwereceptor, solvent dynamics, kana kuchinja kwenguva mukudyidzana kwemaMolecular. Nokudaro, kutevedzera maMD inzira yakakosha yekuwedzera yekuongorora kugadzikana kwakaoma, kusimba kwekudyidzana, uye shanduko dzechimiro mumaLigands nemaProtein nekufamba kwenguva.60,62,71
Zvichibva pahunhu hwavo hwepamusoro hwekusungana neacetylcholinesterase (AChE) zvichienzaniswa nenicotinic acetylcholine receptor (nAChR), takasarudza molekyuru yekutanga 1a (ine kukosha kwakaderera kweLC₅₀) uye thiophene-isoquinoline compound inonyanya kushanda 6 yekuenzanisa mamorekuru (MD). Chinangwa chaive chekuongorora kana kubatana kwavo munzvimbo inoshanda yeAChE kwakaramba kwakagadzikana pamusoro pe100 ns yekuenzanisa uye kuenzanisa maitiro avo ekubatanidza neaya echlorpyrifos uye rebound cocrystallized AChE inhibitor BT7.
Kutevedzera maMolecular dynamics kwaisanganisira root mean square deviation (RMSD) yekuongorora kugadzikana kwakazara kwecomplex; root mean square deviation of fluctuations (RMSF) yekudzidza kuchinjika kweresidue; uye kuongororwa kwekudyidzana kweligand-acceptor kuti uone kugadzikana kwehydrogen bonds, hydrophobic contacts, uye ionic interactions (Supplementary Data). Kunyangwe RMSD neRMSF values dzema ligands ese dzakaramba dziri mukati me range yakagadzikana, zvichiratidza kuti hapana shanduko huru muAChE-ligand complex (Mufananidzo 12), aya ma parameter chete haana kukwana kutsanangura zvizere mutsauko mukubatana pakati pemakomputa.
Nguva yekutumira: Zvita-15-2025