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Herein, we describe the synthesis and application of novel phosphonic inhibitors designed to target the NS3/4A protease, which is crucial for the life cycle of hepatitis C virus. We examined the inhibitory potency of our synthesized compounds against two genotypes (1a and 1b) of NS3/4A protease and four mutant strains of HCV. The most potent inhibitors displayed k2/KI values of 79 850 M−1s−1 and 60 850 M−1s−1 against genotype 1a and 1b protease, respectively. Further in vitro evaluation of the most potent inhibitors revealed that vastly reduced HCV replication. Cellular toxicity, plasma stability, reactivity with selected human proteases as well the stability of inhibitor-protease complex and its intracellular availability are also discussed.The synthesis of novel irreversible phosphonic inhibitors of HCV NS3/4A protease is described.The inhibitory potency of synthesized compounds has been demonstrated.The selectivity of synthesized compounds has been evaluated.The most potent inhibitor 54R showed k2/Ki value of 79 850 M−1s−1.The obtained inhibitors reduced replication of HCV genotypes 1b and 2a.