Imikhiqizo

Inhlanganisela (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3- i-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide iyinhlanganisela eyinkimbinkimbi futhi ecaciswe kakhulu enezinhlelo zokusebenza ezahlukahlukene ucwaningo lwezemithi nokuthuthukiswa kwezidakamizwa.Le nhlanganisela ingeyekilasi elibizwa ngokuthi i-azabicyclohexane carboxamides, eyaziwa ngokuba nomsebenzi obalulekile webhayoloji.Kuyinhlanganisela ye-chiral, equkethe ama-stereocenters ahlukene, aboniswa yigama elithi (1R,2S,5S).Ukuba khona kobubele kubalulekile njengoba kungaba nomthelela omkhulu ezintweni eziphilayo zenkomponi kanye nokusebenzisana nezinto ezihlosiwe zebhayoloji.Okunye okungase kube khona ukusetshenziswa kwalesi sithako njengokuhloswe ngaso ukuklama nokuhlanganisa izidakamizwa zenoveli.Isakhiwo sayo esiyingqayizivele kanye ne-stereochemistry kunikeza amathuba ezifundo zobudlelwano bomsebenzi wesakhiwo (SAR) kanye nokwenza kahle okuholayo.Abacwaningi bemithi bangashintsha izifunda ezihlukahlukene ze-molecule ukuze baphenye ukuthi lezi zinguquko zikuthinta kanjani ukusebenzisana kwayo nezinto ezihlosiwe zebhayoloji, njengama-enzyme, ama-receptors, noma izithuthi.Lolu lwazi lungase lusetshenziselwe ukwakha imithi enamandla kakhulu futhi ekhethiwe yezifo ezihlukahlukene. Ngaphezu kwalokho, ukwakheka kwenhlanganisela kuphakamisa ukuthi ingaba namandla njenge-protease inhibitor.Ama-protease ama-enzyme adlala indima ebalulekile ezinqubweni ezihlukahlukene zebhayoloji futhi abandakanyeka ezifweni ezinjengomdlavuza, i-HIV, kanye nokuphazamiseka kokuvuvukala.Ukucushwa okuqondile namaqembu asebenzayo alesi sakhi sikwenza kube ikhandidethi elithembisayo lokuthuthukisa ama-protease inhibitors anamandla athuthukisiwe nokukhetha.Ukwengeza, ukuba khona kwe-compound yeqembu le-cyano kanye nendandatho ye-pyrrolidine kubonisa ukuthi ingase ibe nomsebenzi wokulwa nokutheleleka kwebhaktheriya noma ukukhunta.Ukuguqulwa kwesakhiwo kungenziwa ukuze kuthuthukiswe izakhiwo zayo ze-antibacterial noma i-antifungal futhi kuholele ekuthuthukisweni kwama-antimicrobial agents amasha.Ngaphezu kwalokho, ukuba khona kweqembu le-trifluoroacetyl kusho ukuthi i-compound ingaba namandla njenge-prodrug.Imikhiqizo ayizinhlanganisela ezingasebenzi noma ezingasasebenzi kangako ezingaguqulwa zibe ifomu elisebenzayo ngaphakathi emzimbeni.Iqembu le-trifluoroacetyl lingasebenza njengeqembu elivikela isifihla-buso elingagoqeka ukuze likhulule i-molecule yomuthi esebenzayo endaweni efiselekayo yokwenza.Leli su lingathuthukisa i-bioavailability yomuthi, ukunyibilika, noma ukulethwa ezicutshini ezithile. Ekugcineni, inhlanganisela (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin -3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1. I-0]hexane-2-carboxamide inesithembiso njengenhlanganisela ebalulekile ocwaningweni lwezemithi nasekuthuthukisweni kwezidakamizwa.Isakhiwo sayo esiyinkimbinkimbi, i-stereochemistry, kanye namaqembu asebenzayo anikeza amathuba amaningi okuklama kanye nokuhlanganiswa kwezidakamizwa zenoveli, ukuhlola ukuvinjelwa kwe-protease, ukuthuthukisa ama-antimicrobial agents, nokusebenzisa amasu e-prodrug.Ucwaningo olwengeziwe nokuhlola imisebenzi yalo yebhayoloji namandla ekhemisi kungase kuholele ekuphumeleleni ezindaweni ezihlukahlukene zokwelapha.