Discovery of Imidazo[2,1-b]thiazole HCV NS4B Inhibitors Exhibiting Synergistic Effect with Other Direct-Acting Antiviral Agents

Abstract

The design, synthesis, and SAR studies of novel inhibitors of HCV NS4B based on the imidazo[2,1-b]thiazole scaffold were described. Optimization of potency with respect to genotype 1b resulted in the discovery of two potent leads 26f (EC50 = 16 nM) and 28g (EC50 = 31 nM). The resistance profile studies revealed that 26f and 28g targeted HCV NS4B, more precisely the second amphipathic α helix of NS4B (4BAH2). Cross-resistance between our 4BAH2 inhibitors and other direct-acting antiviral agents targeting NS3/4A, NS5A, and NS5B was not observed. For the first time, the synergism of a series of combinations based on 4BAH2 inhibitors was evaluated. The results demonstrated that our 4BAH2 inhibitor 26f was synergistic with NS3/4A inhibitor simeprevir, NS5A inhibitor daclatasvir, and NS5B inhibitor sofosbuvir, and it could also reduce the dose of these drugs at almost all effect levels. Our study suggested that favorable effects could be achieved by combining 4BAH2 inhibitors such as 26f with these approved drugs and that new all-oral antiviral combinations based on 4BAH2 inhibitors were worth developing to supplement or even replace current treatment regimens for curing HCV infection.

Promising Anti-Hepatitis C Virus Compounds from Natural Resources

“…This quercetin analog exerted potent inhibition of HCV NS5B RdRp activity through chelation of magnesium ions at the active site [59]. Other derivatives such as imidazo derivatives were also potent inhibitors of HCV [60,61]. Compound 5o, an imidazo[1,2-α] [1,8]naphthyridine derivative, revealed promising pharmacokinetics in rat at the concentration of 100 mg/kg [60].…”

A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 In order to confirm NS4B as the target for the imidazo[2,1-b]thiazole chemotype, the new hit compounds 34 and 37 were tested against a panel of representative resistant replicons of NS4B as well as of NS3/4A, NS5A, and NS5B. 111 The tested compounds resulted still active against mutants for NS3/4A, NS5A, and NS5B. In the context of NS4B mutants, 34 and 37 were active against the replicons carriyng the typical mutations reported for clemizole (i.e.…”

Synthesis and antibacterial activity of novel 3-substituted 1-(2-methyl-5-nitrophenyl)-5-oxopyrrolidine derivatives

“…Pyrrolidinone derivatives are widely known for their biological activities such as antimicrobial [1], antiviral [2], etc. Furthermore, thiazole is an important pharmacophore associated with varied biological activities including antimicrobial [3], antiviral [4]. In the view of this interesting pharmacological content we have decided to design and synthesize the molecular framework of new pyrrolidinone derivatives with heterocyclic or acyclic fragments and investigate their antibacterial activity.…”