Therapeutic Development For Hepatitis B,Hepatocellular Carcinoma And Dengue Fever&New Methodology For C-C Bond Formation

This dissertation described three drug discovery projects, aiming for novel therapeuticsfor chronic hepatitis B virus (HBV) infection, hepatocellular carcinoma (HCC) and Denguevirus (DENV) infection, respectively; and one new carbon-carbon (C-C) bond formationmethodology for indole synthesis:1. Built on the structure of the hit HBF-0259, novel triazolo-pyrimidine inhibitors (2-1,2-3and2-4) were designed, synthesized and evaluated for HBV surface antigen (HBsAg)secretion. Extensive structure-activity relationship (SAR) study led to substantialimprovements in their inhibitory activity, with the best compound being2-3-3(EC50=1.4±0.4M, SI≥36). These HBsAg secrection inhibitors were active on drug-resistant HBVvariants. Both lead candidates,2-1-1and2-3-3, were well-tolerated in both normal and HBV-transgenic mice, and exhibited acceptable pharmacokinetics and bioavailability in maleSprague-Dawley rats.2. A comprehensive SAR investigation of diaryl substituted2-aminothiazoles has beenconducted, based on the structure of the hit HBF-0079. Both the anti-HCC activity andselectivity have been significantly improved (e.g.3-1-33and3-1-36), with better solubilityprofile. Built on3-1-33, MTX and biotin derivatives were designed and synthesized formechanism of action study. A preliminary efficacy study in mice showed that the tumorgrowth could be well inhibited by HBF-0079, with no sign of toxicity observed.3. CM-10-18is the first deoxynojirimycin (DNJ) derivative, which could protect animalsfrom death in lethal DENV infected mouse models, but the in vitro EC50of6.5μM limited itsin vivo use (dose as much as75mg/kg). Built on the structure of CM-10-18, new N-alkylatedDNJ derivatives were designed and synthesized, with analogs4-2-8,4-2-12,4-3-9,4-3-11,4-3-21,4-4-2and4-4-3possessing nanomolar anti-DENV activity (EC50=0.3-0.5μM), whilemaintaining low cytotoxicity (CC50>500μM, SI>1000). In male Sprague-Dawley rats, leadcompound4-3-11was well tolerated at a dose up to200mg/kg and displayed desirable PKprofile, with significantly improved bioavailability (F=92%).4. A variety of functionalized indoles were synthesized from N-aryl enamines viaphenyliodine diacetate (PIDA)-mediated oxidative C-C bond formation. The features of thepresent reaction include:1) facilitative preparation of substrates;2) good functional grouptolerance; and3) mild reaction conditions without transition metals.