Preclinical in vitro screening of newly synthesised amidino substituted benzimidazoles and benzothiazoles

Abstract

Newly synthesised benzimidazole/benzotiazole derivatives bearing amidino, namely 3,4,5,6-tetrahydropyrimidin-1-ium chloride, substituents have been evaluated for their potential antitumor activity in vitro. Compounds and standard drugs (doxorubicin, staurosporine and vandetanib) were tested on three human lung cancer cell lines A549, HCC827 and NCI-H358. We tested compounds in MTS citotoxicity assay and in BrdU proliferative assay performed on 2 D and 3 D assay format. Because benzmidazole scaffold is similar to natural purines, we tested the most active compounds for ability to induce cell apoptosis of A549 by binding to DNA in comparison with doxorubicin and saturosporine. Additionally, the ADME properties of the most active benzothiazole/benzimidazole and non-active compounds were determined to see if the different ADME properties are the cause of different activity in 2 D and 3 D assays, as well as to see if the tested active compounds have drug like properties and potency for further profilation. ADME characterisation included solubility, lipophilicity, permeability, metabolic stability and binding to plasma proteins. In general, the benzothiazole derivatives were more active in comparison to their benzimidazole analogues. The exception was 2-phenyl substituted benzimidazole 6a being active with very pronounced activity especially towards HCC827 cells. All active compounds have similar mode of action on A549 cell line as standard compound doxorubicin, which binds to nucleic acids with the DNA double helix. Tested active benzothiazole compounds were characterised by moderate to good solubility, good metabolic stability, low permeability and high binding to plasma proteins. One tested active benzimidazole derivative showed ADME properties, but lower lipophilicity resulted in low PPB and higher metabolic instability. In addition, no significant difference was observed in ADME profile between active and non-active compounds.

Synthesis, antiproliferative and antitrypanosomal activities, and DNA binding of novel 6-amidino-2-arylbenzothiazoles

“…Amidino-substituted 2-aminothiophenoles ( 7–9 ) were prepared from 6-cyanobenzothiazole by the Pinner method, as previously reported 45 , 46 . To study the influence of the type of the hydrophilic amidino substituents, non-substituted amidino, imidazolino and pyrimidino moieties were introduced at C-6 of benzothiazole scaffold.…”

“…Synthesis of main precursors for the synthesis of targeted benzothiazoles, namely 4-(prop-2-yn-1-yloxy)benzaldehyde ( 2 ) 41 , 4-[(1-phenyl-1 H -1,2,3-triazol-4-yl)methoxy]benzaldehyde ( 3a ) 41 , 4-{[1-(4-chlorophenyl)-1 H -1,2,3-triazol-4-yl]methoxy}benzaldehyde ( 3b ) 41 , 4-{[1-(4-methoxyphenyl)-1 H -1,2,3-triazol-4-yl]methoxy}benzaldehyde ( 3c ) 38 , 4-[(1-benzyl-1 H -1,2,3-triazol-4-yl)methoxy]benzaldehyde ( 3d ) 41 , (1-phenyl-1 H -1,2,3-triazol-4-yl)methanol ( 5a ) 42 , [1-(4-chlorophenyl)-1 H -1,2,3-triazol-4-yl]methanol ( 5b ) 41 , [1-(4-methoxyphenyl)-1 H -1,2,3-triazol-4-yl]methanol ( 5c ) 42 , (1-benzyl-1 H -1,2,3-triazol-4-yl)methanol ( 5d ) 43 , 1-phenyl-1 H -1,2,3-triazole-4-carbaldehyde ( 6a ) 44 , 1-(4-chlorophenyl)-1 H -1,2,3-triazole-4-carbaldehyde ( 6b ) 41 , 1-(4-methoxyphenyl)-1 H -1,2,3-triazole-4-carbaldehyde ( 6c ) 42 , 1-benzyl-1 H -1,2,3-triazole-4-carbaldehyde ( 6d ) 43 , 2-amino-5-amidiniumbenzenethiolate ( 7 ) 45 , 2-amino-5-(4,5-dihydro-1 H -imidazol-3-ium-2-yl)benzenethiolate hydrate ( 8 ) 45 and 2-amino-5-(3,4,5,6-tetrahydropyrimidin-1-ium-2-yl)benzenethiolate ( 9 ) 46 was carried out according to the previously published experimental procedures.…”

Benzimidazole based derivatives as anticancer agents: Structure activity relationship analysis for various targets

“…Racane et al [87] synthesized 3,4,5,6‐tetrahydropyran‐midin‐1‐ium chloride bearing novel derivatives of 1 H ‐benzimidazole and screened them for their anti‐carcinogenic activity against (A549, HCC827, and NCI‐H358) human lung cancer cell lines with doxorubicin, vandetanib and staurosporine. The studies displayed that a few compounds induced apoptosis in A459 cell lines.…”

Design, synthesis, biological evaluation and QSAR analysis of novel N-substituted benzimidazole derived carboxamides

“…In our previous work, we described the design, synthesis, computational analysis and biological activity of multipurpose benzimidazole derivatives with significant antiproliferative, antioxidant and antimicrobial activities. We synthesised several classes of benzimidazole derivatives including amidino substituted derivatives 17 , styryl derivatives 18 , 19 , benzo[ b ]thienyl substituted derivatives 20 , tricyclic 21 , tetracyclic 22 and pentacyclic 23 derivatives substituted with amidino, amino and amido side chains, 2-carboxamides bearing amidino, nitro and amino substituents, 24 acrylonitriles 25 and Schiff bases 26 . Taking into account very promising and significant biological activities displayed by recently synthesised benzimidazole derivatives, our research has been focussed on the design and optimisation of novel benzimidazoles as potential antioxidants with antitumor activity.…”