Synthesis and Antiproliferative activity in vitro of Amidino Substituted 2-phenylbenzazoles

Livio Racané,Grace Karminski-Zamola,Kristina Butković,Marijeta Kralj,Irena Martin-Kleiner,Marijana Hranjec

doi:10.5562/cca3531

Livio Racané, Grace Karminski-Zamola + Show 4 more

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https://doi.org/10.5562/cca3531

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Abstract

Within this work we describe the synthesis of versatile substituted 2-phenyl benzothiazole 3–10 and 2-phenylbenzimidazole 12–19 derivatives bearing amidino groups. Furthermore, the synthesized compounds were explored for their antiproliferative activity in vitro on three cancer cell lines. Tested compounds showed moderate to strong antiproliferative activity. Furthermore, the type of the attached amidino group on benzazole nuclei has the significant impact on the antiproliferative activity only within benzimidazole derivatives with 2-imidazolinyl substituted derivatives being more active in comparison to amidino substituted analogues. All obtained results revealed that this type of benzothiazole derivatives have a great potential for further optimization and development of more efficient potential antiproliferative agents.

Highlights

As a continuation of our scientific research based on the biologically active amidino substituted benazazoles, we present the design and synthesis of 2-phenyl substituted benzothiazole and benzimidazole derivatives bearing two types of amidino groups, either unsubstituted or cyclic amidine
The mentioned compounds were synthesized to explore their antiproliferative activity in vitro on several cancer cells while results were compared to standard antiproliferative agent etoposide
Our mail goal was to study SAR and the influence of the type of substituent placed at the phenyl ring, the type of the benzazole nuclei as well as the type of the amidino group placed at the heteroaromatic nuclei on the antiproliferative activity

Summary

Introduction

D UE to their biological importance based on a broad spectrum of biological features, benzimidazole and benzothiazole derivatives are nowadays important and well-known privileged building structural motifs in medicinal and pharmaceutical chemistry.[1,2] These nitrogen and sulphur-containing heterocycles become unavoidable substructures in the rational design of novel drugs.[3,4] These derivatives has been proven to possess important role in the structure of various biologically important natural and synthetic molecules, while among their versatile pharmacological features, the most important ones are antimicrobial,[5,6] antitumor,[7,8] antiviral,[9] anti-inflammanory,[10] antihistaminic,[11] antioxidant,[12,13] etc. We have published several papers which describe the antiproliferative activity and potential of versatile benzothiazole and benzimidazole derivatives substituted with carboxamido, amino, halogeno, cyano, amidino, amino or nitro groups placed at different positions on the mentioned scaffold. The most significant biological importance was observed with amidino substituted benzazoles bearing different types of amidine substituents suchlike unsubstituted, isopropyl, morpholinyl or imidazolinyl.[16] Obtained results revealed that the most significant influence and the enhancement of the antiproliferative activity in vitro showed benzazole derivatives substituted with cyclic amidino substituent, namely 2-imidazolinyl group with IC50 values in submicromolar range of concentrations (Fig. 1).[17,18] Interestingly, some of the tested derivatives showed selectivity towards cancer cells as well as very low cytotoxicity against normal fibroblasts

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