Recent accomplishments on the synthetic/biological facets of pharmacologically active 1H-1,2,3-triazoles

Highlights

• The use of Click reaction for affording new hybrids with varied biological potential.

• Recently reported anti-plasmodial, anti-TB, anti-microbial and anti-proliferative triazoles.

• Structure-Activity Relationship of the synthesized hybrids along with mechanism of action.

Abstract

The continuous demand of medicinally important scaffolds has prompted the synthetic chemists to identify simple and efficient routes for their synthesis. 1H-1,2,3-triazole, obtained by highly versatile, efficacious and selective “Click Reaction” has become a synthetic/medicinal chemist’s favorite not only because of its ability to mimic different functional groups but also due to enhancement in the targeted biological activities. Triazole ring has also been shown to play a critical role in biomolecular mimetics, fragment-based drug design, and bioorthogonal methodologies. In addition, the availability of triazole containing drugs such as fluconazole, furacyclin, etizolam, voriconazole, triozolam etc. in market has underscored the potential of this biologically enriched core in expediting development of new scaffolds. The present review, therefore, is an attempt to highlight the recent synthetic/biological advancements in triazole derivatives that could facilitate the in-depth understanding of its role in the drug discovery process.

Introduction

Synthetic medicinal chemistry of biologically relevant heterocycles has been a continuous source of inspiration and attracts continuous attention of chemists and biologists all around the world. Amongst the various processes in drug development, one key step is the systemic incorporation of heterocyclic fragments with relevant physicochemical properties to obtain the fine-tuned and potent compounds [[1], [1](a), [1](b), [1](c)]. Synthetic tailoring of heterocyclic scaffolds via manipulation of polarity, hydrogen bonding and lipophilicity has led to improved pharmacological/physicochemical properties eventually leading to clinical drugs candidates or drug-like molecules [[2], [2](a), [2](b)]. Synthesizing new molecular assemblies with well-defined biological targets remains an extremely exigent task and requires refinements in conventional synthetic tactics [[3], [3](a), [3](b),4]. Click Chemistry, an approach to link substrate of choice with specific biomolecules is one of the most desirable synthetic methodologies that remains in brain and heart of most synthetic organic chemist. Huisgen’s 1,3-cycloaddition, a reaction between an azide and alkyne to afford 1,2,3-triazole, is considered as a revolutionary work in the field of azole chemistry [5]. This was further accelerated by the Nobel laureate K. Barry Sharpless (Nobel prize laureate in chemistry, 2001) who referred, to this 1,3-dipolar cycloaddition as “the cream of the crop” of “Click Chemistry” [[6], [7], [8]]. The term “Click Chemistry” as a class of biocompatible reactions was initially coined by K. B. Sharpless in 1998 and fully explained in 2001 [5,6]. According to Sharpless et. al., click chemistry has been associated with various attributes that include simple reaction conditions, wide scope, high yields, insensitivity to oxygen and water, use of either no solvent or water and easily removable solvents, strongly exothermic by virtue of stabilized product, no by-products and simple product isolation [[9], [10], [10](a), [10](b), [11]]. These salient features resemble the salient aspects of chemical biology and hence click chemistry has played a key role in total synthesis of natural product [12].

Triazoles synthesized by means of click reaction consist of five-membered ring with two carbon and three nitrogen atoms, and can be divided into two categories viz. 1,2,3- and 1,2,4-triazoles as depicted in Fig. 1 [13]. In 2001, Meldal and Sharpless research laboratories individually synthesized regioselective 1,4-disubtituted 1,2,3-triazoles using Cu(I) salts as a catalyst. On the other hand, Ru/Rh catalyzed 1,3-dipolar cycloaddition afforded the corresponding 1,4-isomer [14]. In recent years, Cu (I) promoted azide-alkyne cycloaddition (CuAAC) has proven to be a powerful tool for the affording new pharmacologically active entities [[12], [13], [14], [15]]. Triazole containing scaffolds exhibit numerous pharmacological properties such as anti-microbial, anti-cancer, anti-malarial, anti-bacterial, anti-alzheimer and anti-tubercular activities [[16], [17], [17](a), [17](b), [18]]. The advent of pharmaceutical compounds possessing 1,2,3-triazole core including anticancer carboxyamidotriazole (CAI), anti-bacterial Tazobactum, antibiotic Cefatrizine, has led the way for the development of 1,2,3-triazole containing compounds. A list of drugs containing 1,2,3-triazole core is depicted in Fig. 2 [19].

Triazoles are considered as the fundamental building blocks and can be employed as bio-isosters for modifying active molecules [20]. Triazole may act as the bio-isosters of functional groups such as amide, ester and carboxylic acid and can mimic the various amino acids [21]. Molecular Hybridization (MH) is considered as a strategy in drug design and development involving amalgamation of pharmacophoric moieties of different bio-active molecules to produce a hybrid compound with improved affinity and efficacy compared to the parent drugs. The approach has resulted in scaffolds with modified selectivity, dual modes of action and low incidence of side effects. The emergence of click reaction has further revolutionized the concept of MH as it is one of the straight-forward methods of coalescing two pharmacophores to yield the desired hybrid in high yields without the formation of any side-products using simple purification techniques.

Keeping in view of the biological importance of triazoles, the present review entails the recent developments (2017–2019) in synthetic/medicinal attributes of 1H-1,2,3-triazole containing heterocycles and has been further categorized on the basis of their biological activities into following sections:

• Anti-proliferative 1H-1,2,3-triazoles

• Anti-plasmodial/malarial 1H-1,2,3-triazoles

• Anti-mycobacterial/tubercular 1H-1,2,3-triazoles

• Anti-microbial 1H-1,2,3-triazoles