Matenda ofalitsidwa ndi udzudzu akadali vuto lalikulu la thanzi la anthu padziko lonse lapansiKukana kwa tizilombo toyambitsa matenda, monga Culex pipiens pallens, ku mankhwala ophera tizilombo achikhalidwe kukuwonjezera vutoli. Mu kafukufukuyu, mitundu yatsopano ya thiophene-isoquinoline hybrids idapangidwa, kupangidwa, ndikuyesedwa ngati mankhwala ophera tizilombo omwe angathe kukhala larvicides. Pakati pa mankhwala ophera tizilombo, zotumphukira 5f, 6, ndi 7 zidawonetsa mphamvu yayikulu yophera tizilombo motsutsana ndi mphutsi za Culex pipiens pallens zokhala ndi LC₅₀ values ya 0.3, 0.1, ndi 1.85 μg/mL, motsatana. Chodziwika bwino n'chakuti, zotumphukira zonse khumi ndi ziwiri za thiophene-isoquinoline zidawonetsa poizoni wambiri kuposa mankhwala ophera tizilombo a organophosphate chlorpyrifos (LC₅₀ = 293.8 μg/mL), zomwe zikutsimikizira poizoni wapamwamba wa mankhwala awa. Chochititsa chidwi n'chakuti, synthetic intermediate 1a (thiophene semiester) inasonyeza mphamvu yapamwamba kwambiri (LC₅₀ = 0.004 μg/mL), ndipo ngakhale kuti sinakonzedwe bwino, mphamvu yake inali yoposa ya zotumphukira zonse zomaliza. Maphunziro a zamoyo zamakina adawonetsa zizindikiro zolimba za poizoni wa mitsempha, zomwe zikusonyeza kuti ntchito ya cholinergic yasokonekera. Kuyika ma molecular docking ndi ma molecular dynamics simulations adatsimikizira izi, zomwe zikuwonetsa kuyanjana kwamphamvu ndi acetylcholinesterase (AChE) ndi nicotinic acetylcholine receptor (nAChR), zomwe zikusonyeza njira yotheka yogwirira ntchito ziwiri. Kuwerengera kwa density functional theory (DFT) kunatsimikiziranso mphamvu zamagetsi ndi reactivity ya mankhwala ogwira ntchito. Kusiyanasiyana kwa kapangidwe kake ndi mphamvu yayikulu yokhazikika ya mndandanda wa mankhwala awa kungachepetse chiopsezo cha kukana kudutsana ndikuthandizira njira zowongolera kukana kudzera mu kuzungulira kwa mankhwala kapena kuphatikiza. Ponseponse, zotsatirazi zikusonyeza kuti ma hybrid a thiophene-isoquinolineone ndi njira yabwino kwambiri yopangira ma larvicides a m'badwo wotsatira omwe akulunjika njira za neurophysiological za tizilombo toyambitsa matenda.
Udzudzu ndi m'gulu la tizilombo toyambitsa matenda tomwe timayambitsa matenda opatsirana, kufalitsa mitundu yosiyanasiyana ya tizilombo toyambitsa matenda toopsa komanso kuopseza thanzi la anthu padziko lonse lapansi. Mitundu monga Culex pipiens, Aedes aegypti, ndi Anopheles gambiae imadziwika kwambiri pofalitsa mavairasi, mabakiteriya, ndi tizilombo toyambitsa matenda, zomwe zimayambitsa matenda ambirimbiri komanso imfa zambiri pachaka. Mwachitsanzo, Culex pipiens ndi tizilombo toyambitsa matenda tomwe timayambitsa matenda monga kachilombo ka West Nile ndi kachilombo ka St. Louis encephalitis, komanso matenda ena monga malungo a mbalame. Kafukufuku waposachedwapa wasonyezanso kuti Culex pipiens imagwira ntchito yofunika kwambiri pa tizilombo toyambitsa matenda komanso kufalitsa mabakiteriya owopsa monga Bacillus cereus ndi Staphylococcus warwickii, omwe amadetsa chakudya ndikuwonjezera mavuto azaumoyo wa anthu. Kusinthasintha kwakukulu, kupulumuka, komanso kukana kwa udzudzu ku njira zowongolera kumapangitsa kuti zikhale zovuta kuzilamulira ndipo zimakhala zoopsa kwambiri.
Mankhwala ophera tizilombo ndi chida chofunikira kwambiri polimbana ndi udzudzu, makamaka panthawi ya kufalikira kwa matenda opatsirana ndi udzudzu. Mitundu yosiyanasiyana ya mankhwala ophera tizilombo, kuphatikizapo pyrethroids, organophosphates, ndi carbamates, amagwiritsidwa ntchito kwambiri kuti achepetse kuchuluka kwa udzudzu ndi kufalikira kwa matenda. Komabe, kugwiritsa ntchito mankhwala amenewa kwa nthawi yayitali kwadzetsa nkhawa zazikulu pazachilengedwe ndi thanzi la anthu, kuphatikizapo kusokonekera kwa chilengedwe, zotsatirapo zoyipa pa mitundu yosafunikira, komanso kukula mwachangu kwa kukana mankhwala ophera tizilombo m'magulu a udzudzu.11,12,13,14Kukana kumeneku kumachepetsa kwambiri mphamvu ya mankhwala ambiri ophera tizilombo, zomwe zikusonyeza kufunika kwachangu kwa njira zatsopano zopangira mankhwala okhala ndi njira zatsopano zothanirana ndi zoopsa zomwe zikusintha.11,12,13,14Pofuna kuthana ndi mavuto akuluakuluwa, ofufuza akugwiritsa ntchito njira zina monga biocontrol, genetic engineering, ndi integrated vector management (IVM). Njirazi zikusonyeza kuti pali chiyembekezo choteteza udzudzu kwa nthawi yayitali komanso kosatha. Komabe, panthawi ya miliri ndi zadzidzidzi, njira zamankhwala zimakhalabe zofunika kwambiri kuti anthu azitha kuchitapo kanthu mwachangu.
Ma alkaloid a Isoquinoline ndi mankhwala ofunikira okhala ndi nayitrogeni omwe amapezeka kwambiri m'minda, kuphatikiza mabanja monga Amaryllidaceae, Rubiaceae, Magnoliaceae, Papaveraceae, Berberidaceae, ndi Menispermaceae.30 Kafukufuku wakale watsimikizira kuti ma alkaloid a isoquinoline ali ndi zochita zosiyanasiyana zamoyo komanso kapangidwe kake, kuphatikiza mankhwala ophera tizilombo, oletsa matenda a shuga, oletsa chotupa, oletsa bowa, oletsa kutupa, oletsa mabakiteriya, oletsa parasitic, oletsa antioxidant, oletsa mavairasi, komanso oteteza mitsempha.
Mu kafukufukuyu, ma values a χ² a ma compounds onse anali pansi pa critical threshold, ndipo ma values a p anali pamwamba pa 0.05. Zotsatirazi zikutsimikizira kudalirika kwa kuyerekezera kwa LC₅₀ ndipo zikuwonetsa kuti kubwerezabwereza kwa probabilistic kumatha kufotokoza bwino ubale womwe wawonedwa pakati pa mlingo ndi mayankho. Chifukwa chake, ma values a LC₅₀ ndi ma toxic indices (TIs) owerengedwa kutengera compound yogwira ntchito kwambiri (1a) ndi odalirika kwambiri ndipo ndi oyenera kuyerekeza zotsatira za poizoni.
Kuti tiwone momwe zinthu 12 zopangidwa ndi thiophene-isoquinoline zomwe zapangidwa kumene komanso precursor 1a zimagwirira ntchito limodzi ndi zolinga ziwiri zazikulu za neuronal za udzudzu—acetylcholinesterase (AChE) ndi nicotinic acetylcholine receptor (nAChR)—tinachita chitsanzo cha molecular docking. Zolinga izi zinasankhidwa kutengera zizindikiro za neurotoxic zomwe zimawonedwa mu mayeso a imfa ya mphutsi, zomwe zikusonyeza kuti zizindikiro za neuronal sizikuyenda bwino. Kuphatikiza apo, kufanana kwa kapangidwe ka mankhwala awa ndi organophosphates ndi neonicotinoids kumathandiziranso kusankha komwe kumakonda kwa zolinga izi, chifukwa organophosphates ndi neonicotinoids zimakhala ndi zotsatirapo zake zoopsa poletsa AChE ndikuyambitsa nAChR, motsatana.
Kuphatikiza apo, mankhwala angapo (kuphatikizapo 1a, 2, 5a, 5b, 5e, 5f, ndi 7) amalumikizana ndi SER280. Zotsalira za SER280 zimakhudzidwa popanga mawonekedwe a kristalo ndipo zimasungidwa mu mawonekedwe obwezeretsedwa a BT7. Kusiyanasiyana kwa njira zolumikizirana kumeneku kukuwonetsa kusinthasintha kwa mankhwala awa pamalo ogwirira ntchito, ndipo SER280 ndi GLU359 zitha kukhala ngati malo olumikizirana osinthika pansi pa mikhalidwe yolowera. Kuyanjana pafupipafupi komwe kumachitika pakati pa zotumphukira zopangidwa ndi zotsalira zazikulu monga GLU359 ndi SER280, zomwe ndi zigawo za SER-HIS-GLU catalytic triad yodziwika bwino mu acetylcholinesterase ya anthu (AChE), kumathandiziranso lingaliro lakuti mankhwala awa akhoza kukhala ndi mphamvu zoletsa AChE pomangirira kumalo ofunikira kwambiri.29,61,64
Chodziwika bwino n'chakuti, compound 6 ndi precursor 1a yake yawonetsa ntchito yamphamvu kwambiri motsutsana ndi mphutsi mu bioassay, kuwonetsa ma values otsika kwambiri a LC₅₀ pakati pa ma compounds omwe ali mu mndandandawu. Pa mulingo wa mamolekyulu, compound 6 ikuwonetsa kuyanjana kofunikira ndi chlorpyrifos pamalo a GLU359, pomwe compound 1a imalumikizana ndi re-doped BT7 kudzera mu hydrogen bond ku SER280. GLU359 ndi SER280 zonse zilipo mu crystallographic binding conformation yoyambirira ya BT7 ndipo ndi zigawo za conserved catalytic triplet ya acetylcholinesterase (SER–HIS–GLU), kuwonetsa kufunika kwa kuyanjana kumeneku pakusunga ntchito yoletsa ya ma compounds (Chithunzi 10).
Kufanana komwe kwawonedwa pakati pa zinthu zomangira pakati pa zinthu zotumphukira za BT7 (kuphatikiza BT7 yachilengedwe ndi yopangidwanso) ndi chlorpyrifos, makamaka pa zotsalira zofunika kwambiri pa ntchito yothandiza anthu, kukusonyeza kwambiri kuti pali njira yodziwika bwino yoletsa pakati pa zinthuzi. Ponseponse, zotsatirazi zikutsimikizira kuthekera kwakukulu kwa zinthu zotumphukira za thiophene-isoquinolinone ngati zoletsa zamphamvu kwambiri za acetylcholinesterase chifukwa cha kuyanjana kwawo kosungidwa komanso kofunikira pazamoyo.
Kugwirizana kwakukulu pakati pa zotsatira za ma molekyulu ndi zotsatira za larval bioassay kumatsimikiziranso kuti acetylcholinesterase (AChE) ndi nicotinic acetylcholine receptor (nAChR) ndiye zolinga zazikulu za neurotoxic za thiophene-isoquinoline derivatives yopangidwa. Ngakhale zotsatira za docking zimapereka chidziwitso chofunikira pa receptor-ligand affinity, ziyenera kudziwika kuti mphamvu yomangirira yokha siyokwanira kufotokoza mokwanira mphamvu yopha tizilombo m'thupi. Kusiyana kwa LC₅₀ values pakati pa mankhwala omwe ali ndi makhalidwe ofanana a docking kungakhale chifukwa cha zinthu monga kukhazikika kwa kagayidwe kachakudya, kuyamwa, kupezeka kwa bioavailability, ndi kufalikira kwa tizilombo.⁶⁰,⁶⁴Komabe, kapangidwe kake kabwino, kuyanjana kwakukulu kwa ma receptor komwe kumayesedwa ndi kuyerekezera kwa makompyuta, komanso mphamvu yamphamvu ya zamoyo zimatsimikizira kwambiri lingaliro lakuti AChE ndi nAChRs ndiye omwe amayambitsa poizoni wa mitsempha womwe wawonedwa.
Pomaliza, ma hybrid a thiophene-isoquinoline opangidwa ali ndi zinthu zofunika kwambiri zomwe zimagwirizana ndi mankhwala ophera tizilombo omwe amadziwika kuti ndi neuroactive. Kutha kwawo kumalumikizana bwino ndi acetylcholinesterase (AChE) ndi nicotinic acetylcholine receptors (nAChRs) kudzera mu njira zolumikizirana zophatikizana kukuwonetsa kuthekera kwawo ngati mankhwala ophera tizilombo okhala ndi zolinga ziwiri. Njira ziwirizi sizimangowonjezera mphamvu yopha tizilombo komanso zimapereka njira yabwino yogonjetsera njira zomwe zilipo kale zopewera udzudzu, zomwe zimapangitsa kuti mankhwalawa akhale abwino kwambiri pakupanga mankhwala oletsa udzudzu a m'badwo wotsatira.
Ma simulation a Molecular dynamics (MD) amagwiritsidwa ntchito kutsimikizira ndikuwonjezera zotsatira za ma molecular docking, kupereka kuwunika koyenera komanso kodalira nthawi ya kuyanjana kwa ligand-target pansi pa mikhalidwe yeniyeni ya thupi. Ngakhale kuti ma molecular docking angapereke chidziwitso chofunikira choyambirira pa malo omwe angagwirizanitse ndi ma affinities, ndi chitsanzo chosasinthika ndipo sichingathe kufotokoza kusinthasintha kwa receptor, solvent dynamics, kapena kusinthasintha kwa nthawi pakuyanjana kwa ma molecular. Chifukwa chake, ma simulation a MD ndi njira yofunika kwambiri yowonjezerapo poyesa kukhazikika kovuta, kulimba kwa kuyanjana, komanso kusintha kwa mawonekedwe a ma ligand ndi mapuloteni pakapita nthawi.60,62,71
Kutengera ndi mphamvu zawo zomangira bwino kwambiri ku acetylcholinesterase (AChE) poyerekeza ndi nicotinic acetylcholine receptor (nAChR), tinasankha molekyulu yoyamba 1a (yomwe ili ndi LC₅₀ value yotsika kwambiri) ndi thiophene-isoquinoline compound 6 yogwira ntchito kwambiri pa ma simulation a molecular dynamics (MD). Cholinga chinali kuwunika ngati mawonekedwe awo omangira mu AChE active site akhalabe okhazikika pa 100 ns ya simulation ndikuyerekeza machitidwe awo omangira ndi a chlorpyrifos ndi rebound cocrystallized AChE inhibitor BT7.
Ma simulation a ma molecular dynamics anaphatikizapo root mean square deviation (RMSD) kuti aone kukhazikika kwa zovuta zonse; root mean square deviation of fluctuations (RMSF) kuti aphunzire kusinthasintha kwa zotsalira; ndi kusanthula kwa ligand-acceptor interaction kuti azindikire kukhazikika kwa ma hydrogen bonds, hydrophobic contacts, ndi ionic interactions (Supplementary Data). Ngakhale kuti ma RMSD ndi RMSF values a ma ligands onse anakhalabe mkati mwa range yokhazikika, kusonyeza kuti palibe kusintha kwakukulu kwa conformational mu AChE-ligand complex (Chithunzi 12), magawo awa okha sakwanira kufotokoza mokwanira kusiyana kwa ma binding mass pakati pa ma compounds.
Nthawi yotumizira: Disembala-15-2025