Cov kab mob uas kis los ntawm yoov tshaj cum tseem yog ib qho teeb meem loj heev rau kev noj qab haus huv thoob ntiaj teb. Kev tiv thaiv kab mob ntawm cov kab mob xws li Culex pipiens pallens, rau cov tshuaj tua kab ib txwm ua rau qhov teeb meem no hnyav zuj zus. Hauv txoj kev tshawb fawb no, ntau cov thiophene-isoquinolinone hybrids tshiab tau tsim, tsim, thiab soj ntsuam raws li cov kab mob tua kab. Ntawm cov tshuaj sib xyaw ua ke, cov derivatives 5f, 6, thiab 7 tau qhia txog kev ua haujlwm tua kab mob tseem ceeb tiv thaiv Culex pipiens pallens larvae nrog LC₅₀ tus nqi ntawm 0.3, 0.1, thiab 1.85 μg / mL, raws li. Qhov tseem ceeb, tag nrho kaum ob thiophene-isoquinolinone derivatives tau qhia txog kev lom ntau dua li cov tshuaj tua kab organophosphate chlorpyrifos (LC₅₀ = 293.8 μg / mL), lees paub qhov kev lom ntau dua ntawm cov tshuaj no. Qhov nthuav yog, cov tshuaj synthetic intermediate 1a (ib qho thiophene semiester) tau pom tias muaj zog tshaj plaws (LC₅₀ = 0.004 μg/mL), thiab txawm hais tias tseem tsis tau zoo tag nrho, nws lub zog tseem tshaj qhov ntawm txhua qhov kawg derivatives. Kev tshawb fawb txog tsiaj txhu tau qhia txog cov tsos mob neurotoxicity muaj zog, qhia txog kev ua haujlwm cholinergic tsis zoo. Molecular docking thiab molecular dynamics simulations tau lees paub qhov kev soj ntsuam no, qhia txog kev sib cuam tshuam tshwj xeeb nrog acetylcholinesterase (AChE) thiab nicotinic acetylcholine receptor (nAChR), qhia txog qhov ua tau ob-action mechanism. Kev suav ntawm Density functional theory (DFT) ntxiv tau lees paub ntxiv txog cov khoom siv hluav taws xob zoo thiab reactivity ntawm cov tshuaj nquag. Qhov sib txawv ntawm cov qauv thiab qhov muaj zog siab tas li ntawm cov tshuaj no tuaj yeem txo qhov kev pheej hmoo ntawm kev tiv thaiv hla thiab pab txhawb cov tswv yim tswj kev tiv thaiv los ntawm kev sib hloov lossis kev sib xyaw ua ke. Zuag qhia tag nrho, cov txiaj ntsig no qhia tau tias thiophene-isoquinolinone hybrids yog qhov kev xaiv zoo rau kev tsim cov kab tua kab tom ntej uas tsom mus rau txoj kev neurophysiological ntawm cov kab vectors.
Cov yoov tshaj cum yog cov kab mob sib kis tau zoo tshaj plaws, kis tau ntau yam kab mob txaus ntshai thiab ua rau muaj kev hem thawj loj rau kev noj qab haus huv thoob ntiaj teb. Cov tsiaj xws li Culex pipiens, Aedes aegypti, thiab Anopheles gambiae yog cov tsiaj uas paub zoo txog kev kis cov kab mob, cov kab mob me me, thiab cov kab mob parasitic, ua rau muaj ntau lab tus neeg mob thiab ntau tus neeg tuag txhua xyoo. Piv txwv li, Culex pipiens yog tus kab mob loj ntawm cov kab mob arboviruses xws li kab mob West Nile thiab kab mob St. Louis encephalitis, nrog rau cov kab mob parasitic xws li kab mob malaria avian. Cov kev tshawb fawb tsis ntev los no kuj tau qhia tias Culex pipiens ua lub luag haujlwm tseem ceeb hauv kev kis thiab kis cov kab mob tsis zoo xws li Bacillus cereus thiab Staphylococcus warwickii, uas ua rau cov zaub mov tsis huv thiab ua rau cov teeb meem kev noj qab haus huv pej xeem hnyav dua. Kev hloov pauv tau yooj yim, kev ciaj sia, thiab kev tiv thaiv ntawm cov yoov tshaj cum rau cov txheej txheem tswj hwm ua rau lawv nyuaj rau tswj hwm thiab ua rau muaj kev hem thawj tas mus li.
Cov tshuaj tua kab yog ib qho cuab yeej tseem ceeb hauv kev tswj cov yoov tshaj cum, tshwj xeeb tshaj yog thaum muaj kab mob sib kis los ntawm cov yoov tshaj cum. Ntau hom tshuaj tua kab, suav nrog pyrethroids, organophosphates, thiab carbamates, siv dav dav los txo cov yoov tshaj cum thiab kev kis kab mob. Txawm li cas los xij, kev siv cov tshuaj no dav dav thiab ntev mus ntev tau ua rau muaj kev txhawj xeeb txog kev noj qab haus huv ntawm ib puag ncig thiab pej xeem, suav nrog kev cuam tshuam rau lub ecosystem, cov teebmeem tsis zoo rau cov tsiaj tsis yog lub hom phiaj, thiab kev loj hlob sai ntawm kev tiv thaiv tshuaj tua kab hauv cov yoov tshaj cum.11, 12, 13, 14Qhov kev tiv thaiv no ua rau txo qis qhov ua tau zoo ntawm ntau cov tshuaj tua kab ib txwm muaj, qhia txog qhov xav tau kev daws teeb meem tshuaj tshiab nrog cov txheej txheem tshiab los tawm tsam cov kev hem thawj no.11, 12, 13, 14Yuav kom daws tau cov teeb meem loj no, cov kws tshawb fawb tab tom tig mus rau lwm txoj hauv kev xws li kev tswj hwm biocontrol, kev tsim kho caj ces, thiab kev tswj hwm vector integrated (IVM). Cov txheej txheem no qhia txog kev cog lus rau kev tswj hwm yoov tshaj cum kom ruaj khov thiab mus sij hawm ntev. Txawm li cas los xij, thaum muaj kev sib kis thiab xwm txheej ceev, cov txheej txheem tshuaj lom neeg tseem ceeb rau kev teb sai.
Isoquinoline alkaloids yog cov tshuaj heterocyclic uas muaj nitrogen tseem ceeb uas tau muab faib dav hauv lub nceeg vaj cog qoob loo, suav nrog cov tsev neeg xws li Amaryllidaceae, Rubiaceae, Magnoliaceae, Papaveraceae, Berberidaceae, thiab Menispermaceae.30 Cov kev tshawb fawb yav dhau los tau lees paub tias isoquinoline alkaloids muaj ntau yam kev ua ub no thiab cov yam ntxwv ntawm cov qauv, suav nrog kev tua kab, tiv thaiv kab mob ntshav qab zib, tiv thaiv qog, tiv thaiv kab mob fungal, tiv thaiv kev o, tiv thaiv kab mob, tiv thaiv kab mob parasitic, antioxidant, antiviral, thiab neuroprotective effects.
Hauv txoj kev tshawb fawb no, cov nqi χ² rau txhua lub tebchaw tau qis dua qhov tseem ceeb, thiab cov nqi p tau siab dua 0.05. Cov txiaj ntsig no lees paub qhov kev ntseeg tau ntawm LC₅₀ kwv yees thiab qhia tau tias qhov kev rov qab los ntawm qhov tshwm sim tuaj yeem piav qhia txog kev sib raug zoo ntawm cov tshuaj-kev teb. Yog li ntawd, LC₅₀ cov nqi thiab cov ntsuas tshuaj lom (TIs) xam raws li cov tshuaj nquag tshaj plaws (1a) yog qhov ntseeg tau heev thiab tsim nyog rau kev sib piv cov teebmeem tshuaj lom.
Txhawm rau soj ntsuam qhov kev sib cuam tshuam ntawm 12 cov tshuaj thiophene-isoquinolinone derivatives tshiab thiab lawv cov precursor 1a nrog ob lub hom phiaj tseem ceeb ntawm cov kab tsuag - acetylcholinesterase (AChE) thiab nicotinic acetylcholine receptor (nAChR) - peb tau ua qhov kev ua qauv molecular docking. Cov hom phiaj no tau raug xaiv raws li cov tsos mob neurotoxic pom hauv cov kab tsuag tuag, qhia txog kev cuam tshuam ntawm cov neuronal signaling. Ntxiv mus, qhov zoo sib xws ntawm cov khoom no rau organophosphates thiab neonicotinoids txhawb nqa qhov kev xaiv zoo tshaj plaws ntawm cov hom phiaj no, vim tias organophosphates thiab neonicotinoids ua rau lawv muaj cov teebmeem lom los ntawm kev txwv AChE thiab ua kom nAChR ua haujlwm, raws li.
Ntxiv mus, ntau cov tshuaj (xws li 1a, 2, 5a, 5b, 5e, 5f, thiab 7) cuam tshuam nrog SER280. Cov seem SER280 koom nrog kev tsim cov qauv siv lead ua ke thiab tau khaws cia rau hauv cov qauv rov ua dua ntawm BT7. Qhov kev sib txawv ntawm cov hom kev sib cuam tshuam no qhia txog kev hloov pauv ntawm cov tshuaj no hauv qhov chaw nquag, nrog SER280 thiab GLU359 muaj peev xwm ua haujlwm ua qhov chaw hloov pauv hauv qab cov xwm txheej docking. Kev sib cuam tshuam ntau zaus pom ntawm cov khoom siv hluavtaws thiab cov seem tseem ceeb xws li GLU359 thiab SER280, uas yog cov khoom ntawm SER-HIS-GLU catalytic triad paub hauv tib neeg acetylcholinesterase (AChE), txhawb nqa qhov kev xav tias cov tshuaj no yuav muaj cov teebmeem inhibitory rau AChE los ntawm kev khi rau cov chaw tseem ceeb catalytic.29,61,64
Qhov tseem ceeb, cov tshuaj 6 thiab nws cov precursor 1a tau qhia txog kev ua haujlwm muaj zog tshaj plaws tiv thaiv cov kab mob hauv bioassay, qhia txog cov nqi LC₅₀ qis tshaj plaws ntawm cov tshuaj hauv cov koob. Ntawm qib molecular, cov tshuaj 6 qhia txog kev sib cuam tshuam tseem ceeb nrog chlorpyrifos ntawm qhov chaw GLU359, thaum cov tshuaj 1a sib tshooj nrog BT7 rov ua dua los ntawm kev sib txuas hydrogen rau SER280. Ob qho tib si GLU359 thiab SER280 muaj nyob rau hauv cov qauv crystallographic binding thawj ntawm BT7 thiab yog cov khoom ntawm cov catalytic triplet ntawm acetylcholinesterase (SER-HIS-GLU), qhia txog qhov tseem ceeb ntawm kev sib cuam tshuam no hauv kev tswj hwm kev ua haujlwm inhibitory ntawm cov tshuaj (Daim duab 10).
Qhov kev pom zoo sib xws ntawm cov chaw khi ntawm BT7 derivatives (suav nrog cov neeg ib txwm thiab cov uas tau rov ua dua tshiab BT7) thiab chlorpyrifos, tshwj xeeb tshaj yog ntawm cov residues tseem ceeb rau kev ua haujlwm catalytic, qhia tau zoo heev txog ib qho kev sib koom ua ke ntawm kev txwv ntawm cov tshuaj no. Zuag qhia tag nrho, cov txiaj ntsig no lees paub qhov muaj peev xwm tseem ceeb ntawm thiophene-isoquinolinone derivatives ua cov tshuaj acetylcholinesterase inhibitors muaj zog heev vim lawv cov kev sib cuam tshuam thiab kev sib raug zoo ntawm lub cev.
Ib qho kev sib raug zoo ntawm cov txiaj ntsig ntawm molecular docking thiab cov txiaj ntsig ntawm larval bioassay ntxiv lees paub tias acetylcholinesterase (AChE) thiab nicotinic acetylcholine receptor (nAChR) yog cov hom phiaj neurotoxic tseem ceeb ntawm cov synthesized thiophene-isoquinolinone derivatives. Txawm hais tias cov txiaj ntsig docking muab cov ntaub ntawv tseem ceeb ntawm receptor-ligand affinity, nws yuav tsum tau lees paub tias lub zog khi ib leeg tsis txaus los piav qhia tag nrho cov txiaj ntsig tua kab hauv vivo. Qhov sib txawv ntawm LC₅₀ tus nqi ntawm cov tshuaj uas muaj cov yam ntxwv docking zoo sib xws yuav yog vim muaj cov yam ntxwv xws li kev ruaj khov ntawm metabolic, kev nqus, bioavailability, thiab kev faib tawm hauv cov kab.⁶⁰,⁶⁴Txawm li cas los xij, qhov kev tsim qauv zoo, kev sib raug zoo ntawm cov receptors uas tau sim los ntawm kev siv computer simulation, thiab kev ua haujlwm ntawm lub cev muaj zog txhawb nqa qhov kev xav tias AChE thiab nAChRs yog cov neeg sawv cev tseem ceeb ntawm kev ua rau muaj kev lom neurotoxicity.
Xaus lus, cov thiophene-isoquinolinone hybrids uas tau tsim los muaj cov yam ntxwv tseem ceeb thiab cov yam ntxwv ua haujlwm uas sib xws nrog cov tshuaj tua kab mob neuroactive. Lawv lub peev xwm los khi rau acetylcholinesterase (AChE) thiab nicotinic acetylcholine receptors (nAChRs) tau zoo los ntawm kev sib txuas lus sib txuas lus qhia txog lawv lub peev xwm ua cov tshuaj tua kab mob ob lub hom phiaj. Lub tshuab ob lub hom phiaj no tsis yog tsuas yog ua kom cov tshuaj tua kab mob zoo dua xwb tab sis kuj muab lub tswv yim zoo rau kev kov yeej cov txheej txheem tiv thaiv uas twb muaj lawm, ua rau cov tshuaj no cog lus rau kev tsim cov tshuaj tua kab mob tiam tom ntej.
Cov kev sim ua qauv molecular dynamics (MD) yog siv los ua pov thawj thiab txuas ntxiv cov txiaj ntsig molecular docking, muab kev ntsuam xyuas ntau dua thiab nyob ntawm lub sijhawm ntawm kev sib cuam tshuam ligand-target nyob rau hauv cov xwm txheej physiologically tiag tiag. Txawm hais tias molecular docking tuaj yeem muab cov ntaub ntawv tseem ceeb ntawm cov haujlwm khi thiab affinities, nws yog tus qauv static thiab tsis tuaj yeem suav nrog kev ywj pheej ntawm receptor, solvent dynamics, lossis kev hloov pauv ntawm lub sijhawm hauv kev sib cuam tshuam molecular. Yog li ntawd, MD simulations yog ib txoj hauv kev tseem ceeb rau kev ntsuam xyuas kev ruaj khov, kev sib cuam tshuam robustness, thiab kev hloov pauv conformational hauv ligands thiab proteins dhau sijhawm.60, 62, 71
Raws li lawv cov khoom khi zoo dua rau acetylcholinesterase (AChE) piv rau nicotinic acetylcholine receptor (nAChR), peb tau xaiv lub molecule niam txiv 1a (nrog tus nqi LC₅₀ qis tshaj plaws) thiab cov thiophene-isoquinoline compound 6 uas nquag tshaj plaws rau kev sim molecular dynamics (MD). Lub hom phiaj yog los soj ntsuam seb lawv cov kev sib txuas hauv AChE qhov chaw nquag puas tseem ruaj khov dhau 100 ns ntawm kev sim thiab los sib piv lawv cov kev coj cwj pwm khi nrog chlorpyrifos thiab rebound cocrystallized AChE inhibitor BT7.
Kev sim ua qauv ntawm cov qauv molecular suav nrog kev hloov pauv ntawm cov hauv paus ntsiab lus (RMSD) los ntsuas qhov ruaj khov ntawm cov khoom sib xyaw; kev hloov pauv ntawm cov hauv paus ntsiab lus (RMSF) los kawm txog kev hloov pauv ntawm cov khoom seem; thiab kev tshuaj xyuas kev sib cuam tshuam ntawm ligand-acceptor los txiav txim siab qhov ruaj khov ntawm cov hydrogen bonds, kev sib cuag hydrophobic, thiab kev sib cuam tshuam ntawm ionic (Cov Ntaub Ntawv Ntxiv). Txawm hais tias cov nqi RMSD thiab RMSF rau txhua tus ligands tseem nyob hauv qhov ruaj khov, qhia tias tsis muaj kev hloov pauv tseem ceeb hauv AChE-ligand complex (Daim Duab 12), cov kev ntsuas no ib leeg tsis txaus los piav qhia tag nrho qhov sib txawv ntawm cov pawg sib txuas ntawm cov tshuaj.
Lub sijhawm tshaj tawm: Lub Kaum Ob Hlis-15-2025