Regioselective C-H Functionalization of the Six-Membered Ring of the 6,5-Fused Heterocyclic Systems: An Overview

Faarasse, Soukaina; Brahmi, Nabil El; Guillaumet, Gérald; Kazzouli, Saı̈d El

doi:10.3390/molecules26195763

Cited by 8 publications

(4 citation statements)

References 124 publications

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“…In fact, the 6,5-fused heterocyclic systems X, Y, and Z share a number of common features, such as the presence of pyrimidine, amino, and amide groups. According to the literature, there is evidence that 6,5-fused heterocyclic compounds exhibit a wide range of biological activity, including antiprotozoal activity [52,53]. In addition, the involvement of amino [54], amide [55], and pyrimidine [56,57] moieties in potent antiprotozoal hit compounds is indubitable.…”

Section: Resultsmentioning

confidence: 99%

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Dize,

Tali,

Ngansop

et al. 2024

Future Pharmacology

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Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effects on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to >61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM), amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth of P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski’s rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blockers and DHFR inhibitors.

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Section: Resultsmentioning

confidence: 99%

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Dize,

Tali,

Ngansop

et al. 2024

Future Pharmacology

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“…[ 13 ] Furthermore, preferred conditions for C─H activation involve using a phosphine‐free palladium catalyst, [ 4 ] polar coordinating solvents like dimethyl sulfoxide (DMSO), DMAc, dimethylformamide (DMF), n ‐methyl‐2‐pyrrolidone (NMP), and hexafluoroisopropanol (HFIP), [ 3 , 13 , 14 ] and the addition of quaternary ammonium salts ( n ‐Bu 4 NX) to facilitate the formation of anionic palladium species. [ 3 , 10 ] Additionally, incorporating substoichiometric amounts of additives such as Pivalic acid (PivOH), [ 4 , 15 ] silver carbonate (Ag 2 CO 3 ), [ 16 ] and copper(I) chloride (CuCl), [ 17 , 18 ] has been shown to assist the C─H activation process. However, these conditions have been specifically effective in promoting the activation of the C─OTf bond.…”

Section: Introductionmentioning

confidence: 99%

Regio‐ and Chemoselective Palladium‐Catalyzed Additive‐Free Direct C─H Functionalization of Heterocycles with Chloroaryl Triflates Using Pyrazole‐Alkyl Phosphine Ligands

Gu,

2024

Advanced Science

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A series of new pyrazole‐alkyl phosphine ligands with varying cycloalkyl ring sizes that enable additive‐free regio‐ and chemoselective C─H arylation of heterocycles are reported. Excellent α/β selectivity of various heterocycles such as benzo[b]thiophene, thiophene, furan, benzofuran, and thiazole can be achieved using these ligands, along with excellent chemoselectivity of C─Cl over C─OTf of chloroaryl triflates. Mechanistic studies supported by both experimental findings and density functional theory calculations indicate that the pyrazole phosphine ligands with optimal ring sizes allow the reaction to proceed with a lower energy barrier via a concerted metalation–deprotonation pathway.

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“…On the other hand, cross-coupling reactions can join a wide range of organic molecules, including aryl halides, vinyl halides, aryl triflates, boronic acids or boronates, alkynes, and alkyl halides, to form a new molecule with a carbon–carbon bond. There are numerous publications, such as articles and reviews, that discuss C–H activation and cross-coupling reactions [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. These reactions have been extensively studied and widely used in organic synthesis, making them a popular research topic in chemistry.…”

Section: Introductionmentioning

confidence: 99%

Unlocking the Potential of Deep Eutectic Solvents for C–H Activation and Cross-Coupling Reactions: A Review

et al. 2023

Self Cite

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Green chemistry principles have underpinned the development of deep eutectic solvents (DESs). In this brief overview, we discuss the potential of DESs as a greener alternative to volatile organic solvents for cross-coupling and C–H activation reactions in organic chemistry. DESs offer numerous benefits, such as easy preparation, low toxicity, high biodegradability, and the potential to replace volatile organic compounds. The ability of DESs to recover the catalyst-solvent system enhances their sustainability. This review highlights recent advances and challenges in utilizing DESs as a reaction media, as well as the impact of physicochemical properties on the reaction process. Several types of reactions are studied to highlight their effectiveness at promoting C–C bond formation. Aside from demonstrating the success of DESs in this context, this review also discusses the limitations and future prospects of DESs in organic chemistry.

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Regioselective C-H Functionalization of the Six-Membered Ring of the 6,5-Fused Heterocyclic Systems: An Overview

Cited by 8 publications

References 124 publications

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Regio‐ and Chemoselective Palladium‐Catalyzed Additive‐Free Direct C─H Functionalization of Heterocycles with Chloroaryl Triflates Using Pyrazole‐Alkyl Phosphine Ligands

Unlocking the Potential of Deep Eutectic Solvents for C–H Activation and Cross-Coupling Reactions: A Review

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