Synthesis, Antitumor and Antiviral In Vitro Activities of New Benzotriazole-Dicarboxamide Derivatives.

Roberta Ibba,Tinuccia Dettori,Ilenia Delogu,Sandra Piras,Antonio Carta,Paola Caria,Paola Corona,Giuseppina Sanna,Gabriella Collu,Federico Riu,Roberta Loddo

doi:10.3389/fchem.2021.660424

Roberta Ibba, Tinuccia Dettori + Show 9 more

Open Access

https://doi.org/10.3389/fchem.2021.660424

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Abstract

Cancer and viral infections continue to threaten humankind causing death worldwide. Hence, the discovery of new anticancer and antiviral agents still represents a major scientific goal. Heterocycles designed to mimic the chemical structure of natural pyrimidines and purines have been designed over the years, exerting their activity acting as false substrates on several different targets. We reported a series of bis-benzotriazole-dicarboxamide derivatives which inhibit viral helicase of poliovirus, and hence we planned structure modifications to obtain different series of new dicarboxamides. Here, the synthesis and characterization of 56 new compounds: 31 bis-benzotriazole dicarboxamides and 25 mono-substituted acidic derivatives are reported. The synthesized compounds were tested for their antiviral and antitumor activity. Mostly, compounds 4a, 4c and 4d showed antiviral activity against tested Picornaviruses, Coxsackievirus B5 and Poliovirus-1. Likewise, four derivatives (3b, 3d, 4d, 9b) showed notable antiproliferative activity inhibiting cell growth in two distinct antitumor screenings. Compound 3b was selected as the antitumor lead compound for the wide range of activity and the potency proved. The lead compound was proved to induce apoptosis in SK-MES1 tumor cells, in a dose-dependent manner.

Highlights

Among the various diseases that affect humankind, cancer and viral infections remain great threats to human health worldwide
BT derivatives may mimic purine ring acting as antimetabolites interfering with purine metabolism but may bind the enzymes that naturally interact with purines, mimicking the natural substrate, resulting in potential antitumor (Al-Soud et al, 2003), antibacterial (Sanna et al, 1992; Carta et al, 2011; Ochal et al, 2013), antifungal (Patel et al, 2010) or antiviral (Borowski et al, 2003) agents
From a selection of representatives that were subjected to an antitumor in vitro assay, four of them (3b, 3d, 4d and 9b) resulted as the most interesting for their CC50 values that mostly turned out to be in the micromolar range

Summary

Introduction

Among the various diseases that affect humankind, cancer and viral infections remain great threats to human health worldwide. 5-fluorouracil is a well-known example; it is a widely used anticancer agent which acts as antimetabolite It was proved active against several viruses such as foot and mouth disease virus (Pariente et al, 2003; Agudo et al, 2009), herpes simplex virus (Dragún et al, 1990), poliovirus (Cooper, 1964). Purine-like antimetabolites enter the metabolic pathway acting as false substrates or mimicking the natural building blocks of RNA and DNA (De Clercq, 2013) For these features, besides humancell targets, viral enzymes involved in RNA and DNA synthesis, such as RNA-dependent-RNA-polymerases (RdRp) (Furuta et al, 2017), helicases (Carta et al, 2007), proteases (Kneller et al, 2019), may be targeted by this class of derivatives.

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