Polysubstituted pyrazoles, part 5. Synthesis of new 1-(4-chlorophenyl)-4-hydroxy-1 H-pyrazole-3-carboxylic acid hydrazide analogs and some derived ring systems. A novel class of potential antitumor and anti-HCV agents

Abstract

A novel series of 1-(4-chlorophenyl)-4-hydroxy-1 H-pyrazole-3-carboxylic acid hydrazide analogs and some derived 4-substituted-1,2,4-triazolin-3-thiones, 2-substituted-1,3,4-thiadiazole and 2-substituted-1,3,4-oxadiazoles has been synthesized. Ten of the newly synthesized compounds were selected by the National Cancer Institute (NCI)-in vitro-disease oriented antitumor screening to be evaluated for their antitumor activity. Seven compounds, namely 7a– c, 9, 11, 13 and 14, exhibited potential and broad spectrum antitumor activity against most of the tested subpanel tumour cell lines (GI 50<100 μM). Compounds 14 (GI 50, TGI, and LC 50 MG-MID values of 0.08, 15.8 and 64.6 μM, respectively) and 11 (GI 50, TGI, and LC 50 MG-MID values of 0.20, 11.7 and 87.1 μM, respectively) proved to be the most active members in this study with potential activity against all the tested subpanel tumour cell lines and particular effectiveness on the leukaemia subpanel at both the GI 50 (0.03 and 0.09 μM, respectively) and the TGI levels (35.2 and 28.1 μM, respectively). Moreover, compound 14 exhibited a super sensitivity profile towards about 26 different cancer cell lines with GI 50 values lying in the nanomolar concentration range (GI 50 values<0.01 μM). In addition, compounds 2– 5, 6a– d, 7a, 8– 11, 12a, 13, 14 were investigated for their in vitro effect on the replication of hepatitis-C virus (HCV) in HepG2 hepatocellular carcinoma cell line infected with the virus using the reverse transcription–polymerase chain reaction (RT-PCR) technique. The results revealed that compounds 2 and 5 were capable of inhibiting the replication of both the HCV RNA (+) and (−) strands at 10–100 μg mL −1 concentration range.