Synthesis, Molecular Modeling, and Biological Evaluation of Novel Benzimidazole Derivatives as Inhibitors of Hepatitis C Virus RNA Replication

Abstract

In this study, synthesis and docking studies of a series of new benzimidazole derivatives linked to substituted pyrimidines either through the methylenethio linkage or its bioisosteric methylene amino bridge were carried out. All the synthesized compounds were evaluated for their hepatitis C virus (HCV) RNA replication-inhibitory activity. Compounds 4d, 4f, and 4h were found to be more potent than VX-950 (IC 50/ Key words synthesis; benzimidazole; pyrimidine; hepatitis C virus; viral RNA replication inhibitor As estimated by WHO, 170 million persons worldwide are infected with hepatitis C virus (HCV) which causes chronic liver disease. HCV is a positive stranded RNA virus and is a member of the Flaviviridae family of viruses.1,2) Combined therapy of HCV infections with pegylated alpha interferon (IFN-α) and ribavirin is only effective in 50-60% of infected individuals and is associated with serious side effects such as depression, flu-like symptoms, fatigue and hemolytic anemia caused by ribavirin. 3,4)There is an unmet need for potent and selective inhibitors of HCV replication. Significant research efforts are currently directed towards targeting viral enzymes especially NS3-4A serine protease [5][6][7][8] and NS5B RNA-dependent RNA polymerase which are both required for virus propagation. 9-11)The NS3-4A serine protease has been an attractive target in the development of new antivirals with activities against HCV since it is essential for viral replication.9-11) The serine protease activity of NS3 in complex with the NS4A cofactor is responsible for the proteolytic cleavage at four junctions of the HCV polyprotein precursor: NS3-NS4A (self cleavage), NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B. 7,[12][13][14][15][16][17] Crystal structure of the serine protease domain of the NS3, with its essential cofactor NS4A, 18,19) revealed that the NS3-4A complex adopts a chymotrypsin/trypsin-like fold with structurally conserved regions typical of small chymotrypsin-like proteases. 20,21) The N-terminal region of NS3-4A (residues 1-93 of NS3 and residues 21-34 of NS4A) contains an eightstranded β-barrel motif, with one of the strands contributed by the NS4A cofactor.20) The C-terminal region (residues 94-175) contains a six-stranded-barrel that ends with a helix. The active site (His: 57, Asp: 81, and Ser: 139) is located between these two regions and is formed by a shallow solvent exposed pocket to which the inhibitors bind in an extended conformation. 18-21)Sofosbuvir (GS-7977), a uridine nucleotide analogue, and an inhibitor of HCV NS5B polymerase is effective against HCV genotypes 1, 2, 3, 4, and 6. Sofosbuvir, especially in interferon-free combinations, represents a very promising option in the treatment of chronic hepatitis C. 22)Currently, different anti-HCV treatments depend on the inhibition of HCV NS3-4A serine protease. Telaprevir (VX-950), boceprevir and BILN 2061 (Fig. 1) are examples of well known HCV NS3-4A serine protease inhibtors. 23,24) Telaprevir, a small molecule peptidomimetic, forms a covalent but revers...

Synthesis, crystal structure, and ADME prediction studies of novel imidazopyrimidines as antibacterial and cytotoxic agents

“…For the synthesis of the target compounds 6a–u , a series of 2‐imino‐4‐oxo‐6‐(un)substituted‐phenyl‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitriles 4a–d were first synthesized by one‐pot reaction of guanidine hydrochloride ( 1 ), ethyl cyanoacetate ( 2 ), and aromatic aldehydes 3a–d in the presence of anhydrous K 2 CO 3 to give the corresponding 2‐imino‐4‐oxo‐6‐(un)substituted‐phenyl‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitriles 4a–d . [ 28 ] Compounds 4a–d were subsequently reacted with different 2‐bromoacetophenones 5a–i under basic conditions to give the corresponding cyclized products 6a–u in good yields under mild reaction conditions (Scheme 1).…”

“…The starting 2‐imino‐4‐oxo‐6‐substituted‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitriles 4 and 2‐imino‐6‐substituted‐2,3‐dihydropyrimidin‐4(1 H )‐ones 8 were synthesized according to the previously reported procedure. [ 21,28 ]…”

“…Meanwhile, Kamal et al [ 27 ] demonstrated the promising anticancer activity of some benzimidazole–imidazopyrimidine conjugates such as compound X against different cell lines. On the basis of this background and as a continuation of our efforts in the synthesis of new chemotherapeutic agents, [ 20,21,23,24,28,29 ] the main aim of this study is to synthesize a novel series of polyfunctionalized imidazopyrimidines 6 and 9 (Figure 2) that could provide other chemotherapeutic opportunities in drug discovery. The synthesized compounds were evaluated for their antibacterial activity against some Gram‐positive (+) and Gram‐negative (−) bacteria.…”

Synthesis of some benzimidazole derivatives endowed with 1,2,3-triazole as potential inhibitors of hepatitis C virus

“…The organic phase was washed with water, dried over anhydrous Na 2 SO 4 and concentrated. The crude product was purified by column chromatography using CH 2 Cl 2 /methanol (9:1) as an eluent to give pure products (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

“…Derivatives of bis-benzimidazolemethane were discovered to be highly potent, reversible and selective serine protease inhibitors (6,7). Furthermore, by replacing the 2-methylbenzimidazole moiety of this compound with 2-pyrimidomethylenethio moiety or its bioisosteric 2-pyrimidomethyleneamino group was shown to have a positive impact on the inhibitory activity against HCV (8). Moreover, several 2-substituted benzimidazoles showed good antiviral activity (9, 10).…”