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

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.

Design, Synthesis, and Antiviral Activities of New Benzotriazole-Based Derivatives

“… Previously reported benzotriazole-based compounds with biological activities, BTZ1 [ 41 ], BTZ2 [ 42 ], BTZ3 [ 43 ], BTZ4 [ 44 ], BTZ5 [ 46 ], BTZ6 [ 47 ], BTZ7 [ 48 ]. …”

“…Benzo[ d ][1,2,3]triazole (benzotriazole, BTZ) nucleus is a bicyclic scaffold frequently used in drug design for its proved endowment with a wide range of biological properties [ 38 ], including antibacterial and antiprotozoal [ 39 ], antimycotic [ 40 ], antimycobacterial [ 41 , 42 ], antitumor [ 43 , 44 , 45 ], and antiviral [ 46 , 47 , 48 , 49 , 50 ] activities, as reported in Figure 1 .…”

“…Aiming to expand the structure-analysis knowledge on these types of molecules, in this work, we present new derivatives obtained through the manipulation of our previously developed hit compounds. Notably, we previously observed that the introduction of a methylene spacer on the not active N1,N4 -bis(4-(5,6-dichloro-1 H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)succinimide derivative (A, Figure 3 ) successfully led to N1,N4 -bis(4-((5,6-dichloro-1 H -benzo[ d ][1,2,3]triazol-1-yl)methyl)phenyl)succinimide derivative (B, Figure 3 ), which was active on CVB at micromolar concentration (EC 50 = 23 μM) [ 43 ].…”

Advances in synthesis and biological activities of benzotriazole analogues: A micro review

“…Benzotriazole (BTZ) based compounds are unique nitrogencontaining heterocycles that have attracted significant attention from medicinal chemists as a promising class of bioactive heterocyclic products with numerous biological properties [1][2][3]. The focal attention on BTZ is in the pharmaceutical industry, as suitably substituted BTZ derivatives can have a wide range of biological features, including antibacterial [4], antitumor and antiviral [5], antiprotozoal [6], anti-proliferative [7], choleretic [8], plant growth regulator [9] and anti-inflammatory [10] activity.…”

Methylene-Tethered Arylsulfonation and Benzotriazolation of Aryl/Heteroaryl C–H Bonds with DMSO as a One-Carbon Surrogate

“…On the other hand, aryl sulfonyl and benzotriazole motifs are fertile synthetic intermediates . Importantly, aryl sulfones and benzotriazoles exhibited various biological properties, including antifungal, anti-inflammatory, antibacterial, and are nontoxic in nature, due to which these scaffolds have drawn immense attention of synthetic and medicinal chemists . Inspired by the significance of imidazopyridine, aryl sulfone, and benzotriazole, we envisioned that connecting these structural motifs through dimethyl sulfoxide (DMSO) activation would deliver novel chemotypes for drug discovery.…”