Synthesis and histone deacetylases inhibitory activity of pyrimidine‐based 1,3,4‐oxadiazoles DOI

Virginija Jakubkienė,

I. Labalaukyte,

Markus Schweipert

et al.

Journal of Heterocyclic Chemistry, Journal Year: 2024, Volume and Issue: 61(9), P. 1426 - 1438

Published: July 9, 2024

Abstract The histone deacetylases (HDACs) are being explored as a promising therapeutic target for the treatment of various diseases. Here, synthesis series pyrimidine‐based 1,3,4‐oxadiazoles, in which oxadiazole scaffold is attached to pyrimidine ring via methyleneoxy spacer, described and their HDAC inhibitory activity studied. compounds were synthesized by sequence reactions involving O ‐alkylation 2‐(methylthio)pyrimidin‐4(3 H )‐ones with ethyl 2‐bromoethanoate followed oxidation 2‐methylthio group, displacement obtained 2‐methylsulfonyl group amines, hydrazinolysis (2‐amino‐substituted pyrimidin‐4‐yloxy)acetates give corresponding hydrazides cyclization under ‐ethyl xanthate or carbonyldiimidazole 1,3,4‐oxadiazole‐2(3 )‐thiones 1,3,4‐oxadiazol‐2(3 )‐one, correspondingly. In addition, two converted into ( N 3)‐morpholinomethyl derivatives Mannich reaction formaldehyde morpholine. yields intermediates ranged from moderate excellent. characterized 1 13 C NMR spectra HRMS data, purity was controlled TLC. 1,3,4‐oxadiazoles (18 compounds) tested inhibitors HDAC4 HDAC8 isoforms compared that Vorinostat. Most oxadiazolethiones containing methyl at position 6 moiety found be more selective towards HDAC8, while propyl active against HDAC4. Among compounds, 5‐((2‐(dibutylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3 )‐thione 48 ) have strongest isoform (IC 50 = 4.2 μM vs. IC 59 Vorinostat) 5‐((2‐(cyclopentylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3 most potent inhibitor 6.8 μM).

Language: Английский

Indole Derivatives: A Versatile Scaffold in Modern Drug Discovery—An Updated Review on Their Multifaceted Therapeutic Applications (2020–2024) DOI Creative Commons

Xingyou Mo,

Devendra Pratap Rao,

Kirandeep Kaur

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(19), P. 4770 - 4770

Published: Oct. 9, 2024

Indole derivatives have become an important class of compounds in medicinal chemistry, recognized for their wide-ranging biological activities and therapeutic potential. This review provides a comprehensive overview recent advances the evaluation indole-based last five years, highlighting roles cancer treatment, infectious disease management, anti-inflammatory therapies, metabolic disorder interventions, neurodegenerative management. shown significant efficacy targeting diverse pathways, making them valuable scaffolds designing new drugs. Notably, these demonstrated ability to combat drug-resistant cells pathogens, breakthrough field, offer promising options chronic diseases such as diabetes hypertension. By summarizing key findings exploring underlying mechanisms, this underscores potential indole addressing major healthcare challenges, thereby instilling hope optimism field modern medicine.

Language: Английский

Citations

9
A Comprehensive Computational Approach for Identifying Estrogen Receptor Alpha Inhibitors in Breast Cancer Treatment: Integrating Biophysical Analysis and In Vitro Validation DOI Open Access
Perwez Alam,

Mohammed Faiz Arshad,

Indrakant K. Singh

et al.

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(10)

Published: March 1, 2025

Abstract Breast cancer is a major global health issue, with estrogen receptor alpha (ERα) being key therapeutic target. This study utilized computational drug discovery to identify potential ERα inhibitors from the DrugLib library, aiming develop novel treatments. Through MtiOpenScreen webserver, virtual screening Lipinski filter identified 1500 compounds docking scores between −12.4 and −9.1 kcal/mol. Three promising (Tradipitant, Flezelastine, Zaldaride) were selected for further analysis, including re‐docking, molecular dynamics (MD) simulations, Molecular mechanics generalized Born surface area solvation (MM/GBSA), free energy landscape (FEL) analysis. These demonstrated strong inhibitory against ERα, showing stable binding in receptor's pocket. MMGBSA calculations confirmed favorable energies, whereas FEL analysis provided insights into dynamic stability of inhibitor‐ERα complexes. Isothermal titration calorimetry (ITC) their constants thermodynamic profiles. Additionally, anticancer activity was assessed using MTT assays on ERα‐specific MCF‐7 cell line, comparable efficacy Doxorubicin. The study's experimental findings establish basis these compounds' development as breast treatment.

Language: Английский

Citations

0
Electrochemical synthesis of electron and hole transporters via C–F bond cleavage as a new approach to the coupling of para substituted (pentafluorophenyl)-1,3,4-oxadiazoles DOI
Matej Uhliar, Dániel Végh, Vladimı́r Lukeš

et al.

Electrochimica Acta, Journal Year: 2025, Volume and Issue: 527, P. 146229 - 146229

Published: April 18, 2025

Language: Английский

Citations

0
Indoles as promising Therapeutics: A review of recent drug discovery efforts DOI

Naik Jui Pravin,

Rohini S. Kavalapure, Shankar G. Alegaon

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 154, P. 108092 - 108092

Published: Dec. 25, 2024

Language: Английский

Citations

1
Azole Derivatives: Cutting‐Edge Agents in Cancer Therapy DOI
Anuradha Mehra, Amit Mittal, Rekha Sangwan

et al.

ChemistrySelect, Journal Year: 2024, Volume and Issue: 9(43)

Published: Nov. 1, 2024

Abstract Monocyclic 5‐membered heterocycles including imidazoles, thiazoles, oxazoles, and their related compounds have gained significant attention in medicinal chemistry because of potent anticancerous activity. These small heterocyclic molecules possess versatile properties, biological activity, absorption, distribution, metabolism, excretion, chemical diversity that give them immense potential as anticancer agents. It is also a fact inherent characteristic azoles to combine with many through hydrogen bond, stacking, hydrophobic interaction makes effective against almost all cancer types. In the present paper author discusses way which connected structure monocyclic activity namely ability these intercalate DNA, inhibit some enzymes interfere cellular signaling pathways. Interestingly, several azole derivatives been seen be preclinical efficacy studies well clinical trials are considered overcoming problem resistance side effects common As synthetic progresses, structural system has diversified development pharmacology become more specific. This helped enhancing formation new class improved selectivity efficacy. Furthermore, comprehensive review explains how computational structure‐activity relationship (SAR) approaches applied design future‐generation compounds. light facts, this article designed broad overview current state azole‐based agents an attempt further assert its therapeutic promise spur attempts at infusing said into therapeutics fray. The discoveries made study may allow radical different approaches, could lead targeted treatment cancer.

Language: Английский

Citations

1
Synthesis and histone deacetylases inhibitory activity of pyrimidine‐based 1,3,4‐oxadiazoles DOI

Virginija Jakubkienė,

I. Labalaukyte,

Markus Schweipert

et al.

Journal of Heterocyclic Chemistry, Journal Year: 2024, Volume and Issue: 61(9), P. 1426 - 1438

Published: July 9, 2024

Abstract The histone deacetylases (HDACs) are being explored as a promising therapeutic target for the treatment of various diseases. Here, synthesis series pyrimidine‐based 1,3,4‐oxadiazoles, in which oxadiazole scaffold is attached to pyrimidine ring via methyleneoxy spacer, described and their HDAC inhibitory activity studied. compounds were synthesized by sequence reactions involving O ‐alkylation 2‐(methylthio)pyrimidin‐4(3 H )‐ones with ethyl 2‐bromoethanoate followed oxidation 2‐methylthio group, displacement obtained 2‐methylsulfonyl group amines, hydrazinolysis (2‐amino‐substituted pyrimidin‐4‐yloxy)acetates give corresponding hydrazides cyclization under ‐ethyl xanthate or carbonyldiimidazole 1,3,4‐oxadiazole‐2(3 )‐thiones 1,3,4‐oxadiazol‐2(3 )‐one, correspondingly. In addition, two converted into ( N 3)‐morpholinomethyl derivatives Mannich reaction formaldehyde morpholine. yields intermediates ranged from moderate excellent. characterized 1 13 C NMR spectra HRMS data, purity was controlled TLC. 1,3,4‐oxadiazoles (18 compounds) tested inhibitors HDAC4 HDAC8 isoforms compared that Vorinostat. Most oxadiazolethiones containing methyl at position 6 moiety found be more selective towards HDAC8, while propyl active against HDAC4. Among compounds, 5‐((2‐(dibutylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3 )‐thione 48 ) have strongest isoform (IC 50 = 4.2 μM vs. IC 59 Vorinostat) 5‐((2‐(cyclopentylamino)‐6‐propylpyrimidin‐4‐yloxy)methyl)‐1,3,4‐oxadiazole‐2(3 most potent inhibitor 6.8 μM).

Language: Английский

Citations

0