1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships.

The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pKa, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Comprehensive review on the anti-bacterial activity of 1,2,3-triazole hybrids.

Triazole derivatives and their antiplasmodial and antimalarial activities.

The 1,2,3-triazole ring as a bioisostere in medicinal chemistry

The aza-alkylation reaction at indole's C3 position allows the introduction of a differently substituted aminomethyl group, with the formation of a new stereogenic centre. The reaction involves essentially three different partners: an indole, aldehyde and amine. The formation of the reactive iminium species can be catalyzed by metals, Bronsted acids, Lewis acids or organocatalysts. The stereoselective reaction is feasible with satisfactory outcomes. This review summarizes the recent (2000–2019) meaningful papers in which the in-depth study and exploitation of this reactivity are reported.

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Catalytic C3 aza-alkylation of indoles.

Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin-inspired derivatives. The modest bioactivity and the apparent absence of interaction with α-tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α-tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p-Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules.

Synthesis of Thicolchicine-Based Conjugates: Investigation towards Bivalent Tubulin/Microtubules Binders

This review summarizes the main strategies aimed at the total synthesis of vincamine and congeners. Then, our contribution in this field is presented: we describe (+)-vincamine semi-synthesis using tabersonine as starting material. Characterization and quantification of the main impurities are discussed, and HPLC conditions, structural elucidation and NMR data of four of them are reported.

Vincamine by synthesis and semi-synthesis

The piperidine ring is a widespread motif in several natural bioactive alkaloids of both vegetal and marine origin. In the last years, a diversity-oriented synthetic (DOS) approach, aimed at the generation of a library of piperidine-based derivatives, was developed in our research group, employing commercially available 2-piperidine ethanol as a versatile precursor. Here, we report the exploration of another ramification of our DOS approach, that led us to the stereoselective total synthesis of (–)-anaferine, a bis-piperidine alkaloid present in Withania somnifera extract. This natural product was obtained in 9% overall yield over 13 steps, starting from a key homoallylic alcohol previously synthesised in our laboratory. Therefore, the collection of piperidine-derivatives accessible from 2-piperidine ethanol was enriched with a new, diverse scaffold.

https://www.mdpi.com/1420-3049/25/5/1057/pdf

Elisa Bonandi

Papers

The 1,2,3-triazole ring as a bioisostere in medicinal chemistry

Catalytic C3 aza-alkylation of indoles.

Synthesis of Thicolchicine-Based Conjugates: Investigation towards Bivalent Tubulin/Microtubules Binders

Vincamine by synthesis and semi-synthesis

Total Synthesis of (–)-Anaferine: A Further Ramification in a Diversity-Oriented Approach