Mutagenic Study of Benzimidazole Derivatives with (+S9) and without (−S9) Metabolic Activation

Abstract

Benzimidazole derivatives have a diverse range of biological activities, including antiulcer, antihypertensive, antiviral, antifungal, anti-inflammatory, and anticancer. Despite these activities, previous studies have revealed that some of the derivatives can induce mutations. This study aimed to screen for potential mutagenic activities of novel benzimidazole derivatives 1–4 using the Ames test and to study their structure–activity relationship (SAR). An Ames test was carried out on two strains of Salmonella typhimurium (TA98 and TA100) in the absence and presence of metabolic activation. Genetic analysis was performed prior to the Ames test to determine the genotypes of the bacterial tester strains. Both bacterial strains showed dependency on histidine with the presence of rfa mutation, uvrB deletion, and plasmid pKM101. Further, all derivatives tested showed no mutagenic activity in the absence of metabolic activation in both tester strains. However, in the presence of metabolic activation, compound 1 appeared to induce mutation at 2.5 µg/plate when tested against the TA98 strain. These results suggest that the absence of the -OH group at the ortho-position over the phenyl ring might be the cause of increased mutagenic activity in compound 1. Additionally, the presence of mutagenic activity in compound 1 when it was metabolically activated indicates that this compound is a promutagen.

Virtual Screening of Benzimidazole Derivatives as Potential Triose Phosphate Isomerase Inhibitors with Biological Activity against Leishmania mexicana

“…Benzimidazole is an aromatic heterocyclic compound with a wide range of biological activities [ 17 ] as an antiviral [ 18 ], an anthelmintic [ 19 ], an antimicrobial [ 20 ], an antiparasitic [ 21 ], and others [ 22 , 23 ]. Hybrids of benzimidazole and pentamidine derivatives have been tested against L. mexicana [ 24 ].…”

Evaluation of novel compounds as anti-bacterial or anti-virulence agents

“…The Ames test uses a number of Salmonella strains that carry mutations in various genes in the histidine operon that are involved in histidine synthesis meaning that these strains are unable to synthesize histidine (histidine-dependent), and therefore unable to grow and form colonies on agar media without histidine ( Figure 3 ) ( Mortelmans and Zeiger, 2000 ). In the presence of the mutagenic chemicals, these mutant, histidine-dependent bacterial strains revert to their original state and restore their ability to produce histidine, which is why the test is often referred to as a “reversion test” ( Figure 3 ) ( Azahar et al., 2019 ). As a positive result of the test, the growth of bacterial colonies is observed on agar plates with low concentration of histidine.…”

“…Ames assay consists of Salmonella typhimurium strains and so it is not a perfect model for human cells ( Vijay et al., 2018 ). Some chemicals display the mutagenicity only after being metabolized by enzymes that belong to the cytochrome P450 family and these enzymes are not present in bacterial cells ( Azahar et al., 2019 ). To overcome this issue, the assay is performed with S9-based metabolic activation system ( Figure 3 ).…”

Recent progress of research on anti‐tumor agents using benzimidazole as the structure unit

“…The unique structural features of benzimidazole and the wide range of biological activities of its derivatives make it preferred in drug discovery (Gaba et al, 2014). Introduced benzimidazole as the dominant skeleton is wildly used in drug design which can promote the biological activities, such as antiulcer anti‐inflammatory, anti‐hypertensive, anti‐tumor, antiviral, and antifungal (Azahar et al, 2019; Kale et al, 2016; Wu et al, 2020). Benzimidazole, as the one of the earliest nitrogen‐containing heterocyclic compounds ever found, has a flat ring system in which benzene rings are thickly combined on the 4, 5th position of the imidazole ring (Alzhrani et al, 2021).…”