Pharmacophore optimization of imidazole chalcones to modulate microtubule dynamics

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC50 in the submicromolar range from 0.56 ± 0.01 µM to 0.74 ± 0.02 µM. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO• radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R2 = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological β-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer’s disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer’s disease.

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“…The product yield was 0.9 g (85%). The NMR spectra were consistent with previously reported data [148].…”

Section: Synthesis Of (S)-n1-hydroxysupporting

confidence: 91%

Elaboration of the Effective Multi-Target Therapeutic Platform for the Treatment of Alzheimer’s Disease Based on Novel Monoterpene-Derived Hydroxamic Acids

Aleksandrova

Munkuev

Mozhaitsev

et al. 2023

IJMS

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“…Compound 15 was synthesized as described in [43]. Spectroscopic data were consistent with those previously reported [44].…”

Section: Synthesis Of Methyl 4-formylbenzoate 15mentioning

confidence: 54%

Hydroxamic Acids Containing a Bicyclic Pinane Backbone as Epigenetic and Metabolic Regulators: Synergizing Agents to Overcome Cisplatin Resistance

Aleksandrova,

Munkuev,

Mozhaitsev

et al. 2023

Cancers

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Multidrug resistance is the dominant obstacle to effective chemotherapy for malignant neoplasms. It is well known that neoplastic cells use a wide range of adaptive mechanisms to form and maintain resistance against antitumor agents, which makes it urgent to identify promising therapies to solve this problem. Hydroxamic acids are biologically active compounds and in recent years have been actively considered to be potentially promising drugs of various pharmacological applications. In this paper, we synthesized a number of hydroxamic acids containing a p-substituted cinnamic acid core and bearing bicyclic pinane fragments, including derivatives of (−)-myrtenol, (+)-myrtenol and (−)-nopol, as a Cap-group. Among the synthesized compounds, the most promising hydroxamic acid was identified, containing a fragment of (−)-nopol in the Cap group 18c. This compound synergizes with cisplatin to increase its anticancer effect and overcomes cisplatin resistance, which may be associated with the inhibition of histone deacetylase 1 and glycolytic function. Taken together, our results demonstrate that the use of hydroxamic acids with a bicyclic pinane backbone can be considered to be an effective approach to the eradication of tumor cells and overcoming drug resistance in the treatment of malignant neoplasms.

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“…In 2022, the group of Tillekeratne reported a new class of imidazole-based chalcones as potential antimitotic agents. 40 Thanks to promising cytotoxic activity, a comprehensive structure-activity relationship (SAR) was carried out. In-silico studies demonstrated that the series have the ability to bind to the colchicine binding site of β-tubulin.…”

Section: Template For Synthesis Thiemementioning

confidence: 99%

Recent Advances in the Chemistry and Application of SF5-Compounds

Bizet,

Abd El Sater,

Popek

et al. 2024

Synthesis

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This review article outlines the literature covering last three years on the recent developments of the SF5 chemistry. Recent synthesis methodologies of SF5-containing building blocks are reported. These methods include the synthesis of SF5Cl, its use in pentafluorosulfanylation reactions, and oxidative fluorination reactions. Moreover, the reactivity of SF5-alkynes as versatile platform to access new SF5-compounds is described. Finally, effect of SF5 moiety is highlighted according to its application in different fields such as biological/medicinal chemistry, catalysis and material sciences.

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Pharmacophore optimization of imidazole chalcones to modulate microtubule dynamics

Cited by 8 publications

References 21 publications

Elaboration of the Effective Multi-Target Therapeutic Platform for the Treatment of Alzheimer’s Disease Based on Novel Monoterpene-Derived Hydroxamic Acids

Elaboration of the Effective Multi-Target Therapeutic Platform for the Treatment of Alzheimer’s Disease Based on Novel Monoterpene-Derived Hydroxamic Acids

Hydroxamic Acids Containing a Bicyclic Pinane Backbone as Epigenetic and Metabolic Regulators: Synergizing Agents to Overcome Cisplatin Resistance

Recent Advances in the Chemistry and Application of SF5-Compounds

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