Synthetic Research Of Nitazoxanid And Design,Synthesis,Preliminary Biological Study Of Nitazoxanid Derivatives

Nitazoxanid(NTZ)is a broad-spectrum antimicrobial drug and has a significant therapeutic effect against parasites,bacteria,viruses and other epidemical diseases,such as AIDS,chronic hepatitis,cancer and so on.Given NTZ can treat a variety of diseases with good efficacy and safety,market demand and the application prospect of NTZ is good.It is necessary to develop an efficient route with high productivity and low cost,leading to potential economic and social benefits.In this paper,based on previously reported method,a novel one-step synthesis of NTZ was proposed by using the reaction reagents of trimethoxyphosphine,iodine and various bases.The reaction solvent,temperature the proportioning of material and other conditions were systematacially optimized,and ultimately the most optimal route was identified.The yield was 76%.Similar with NTZ.many NTZ derivates have been reported to display a wide spectrum of anti-infective activities with significantly inhibitory potencies against parasite,viruses and intestinal anaerobic bacteria.Since NTZ was validated as a pyruvate-ferredoxin oxidoreductase(PFOR)inhibitor,novel NTZ derivatives are expected to be developed as PFOR inhibitors.In this thesis,two novel series of NTZ derivates(series ? and ?)were designed and synthesized according to drug design strategies and computer-based desining protocol.The preliminary in vitro antibacterial and antiparasitic bioevaluations were also investigated.The structure-activity relationship(SAR)was subsequently explored and several compounds,XQH-3-6.XQH-3-7 and XQH-2-92,were identified to display excellent antibacterial activities,while compounds XQH-2-88,XQH-2-92 and XQH-2-96 displayed decent anti-T.gondii activities.These compounds might be used as potential leads in further exploration so as to find compounds with improved druggable potency,better safety and decreased toxicity.