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17 pages, 1523 KiB

Open AccessArticle

Design and Synthesis of Pyridyl and 2-Hydroxyphenyl Chalcones with Antitubercular Activity

by Kelphina Aziafor, Ketan Ruparelia, Brandon Moulds, Mire Zloh, Tanya Parish and Federico Brucoli

Molecules 2024, 29(19), 4539; https://doi.org/10.3390/molecules29194539 - 24 Sep 2024

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Abstract

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl-(14), pyrene-1-yl (20)- and biphenyl-4-yl ( [...] Read more.

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl-(14), pyrene-1-yl (20)- and biphenyl-4-yl (21) moieties were found to be the most potent of the series inhibiting the growth of M. tuberculosis H37Rv with IC₉₀ values ranging from 8.9–28 µM. Aryl chalcones containing a 3-methoxyphenyl A-ring and either p-Br-phenyl (25) or p-Cl-phenyl (26) B-rings showed an IC₉₀ value of 28 µM. Aryl-chalcones were generally less toxic to HepG2 cells compared to pyridyl-chalcones. Dose-dependent antiproliferative activity against MDA468 cells was observed for trimethoxy-phenyl (16) and anthracene-9-yl (19) pyridyl-chalcones with IC₅₀ values of 0.7 and 0.3 µM, respectively. Docking studies revealed that chalone 20 was predicted to bind to the M. tuberculosis protein tyrosine phosphatases B (PtpB) with higher affinity compared to a previously reported PtpB inhibitor. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 2nd Edition)

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13 pages, 3217 KiB

Open AccessArticle

A Novel Compound from the Phenylsulfonylpiperazine Class: Evaluation of In Vitro Activity on Luminal Breast Cancer Cells

by Fernanda Cardoso da Silva, Ana Clara Cassiano Martinho, Helen Soares Valença Ferreira, Raoni Pais Siqueira, Vinicius Marques Arruda, Joyce Ferreira da Costa Guerra, Maria Laura dos Reis de Souza, Emanuelly Silva Landin, Celso de Oliveira Rezende Júnior and Thaise Gonçalves de Araújo

Molecules 2024, 29(18), 4471; https://doi.org/10.3390/molecules29184471 - 20 Sep 2024

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Abstract

Breast cancer (BC) is the most common cancer in women, and is characterized by its histological and molecular heterogeneity. Luminal BC is an estrogen receptor-positive subtype, with varied clinical courses. Although BC patients are eligible for hormone therapy, both early and late relapses [...] Read more.

Breast cancer (BC) is the most common cancer in women, and is characterized by its histological and molecular heterogeneity. Luminal BC is an estrogen receptor-positive subtype, with varied clinical courses. Although BC patients are eligible for hormone therapy, both early and late relapses still occur, and thus there is a demand for new cytotoxic and selective treatment strategies for these patients. In the present study, inspired by the structure of phenylsulfonylpiperazine, a series of 20 derivatives were tested in bioassays against MCF7, MDA-MB-231 and MDA-MB-453 BC cells to discover new hit compounds. After 48 h of treatment, 12 derivatives impaired cell viability and presented significant IC₅₀ values against at least one of the tumor lineages. Overall, the luminal BC cell line MCF7 was more sensitive to treatments. Compound 3, (4-(1H-tetrazol-1-yl)phenyl)(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)methanone, was the most promising, with IC₅₀ = 4.48 μM and selective index (SI) = 35.6 in MCF7 cells. Compound 3 also presented significant antimigratory and antiproliferative activities against luminal BC cells, possibly by affecting the expression of genes involved in the epithelial–mesenchymal transition mechanism, upregulating E-Cadherin transcripts (CDH1). Our findings suggest that phenylsulfonylpiperazine derivatives are potential candidates for the development of new therapies, especially those targeting luminal BC. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 2nd Edition)

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16 pages, 3434 KiB

Open AccessArticle

Assessment of the Lipophilicity of Indole Derivatives of Betulin and Their Toxicity in a Zebrafish Model

by Zuzanna Rzepka, Katarzyna Bober-Majnusz, Justyna Magdalena Hermanowicz, Ewa Bębenek, Elwira Chrobak, Arkadiusz Surażyński and Dorota Wrześniok

Molecules 2024, 29(18), 4408; https://doi.org/10.3390/molecules29184408 - 16 Sep 2024

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Abstract

There are scientific studies indicating that the attachment of an indole moiety to the triterpene scaffold can lead to increased anticancer potential. Lipophilicity is one of the factors that may influence biological properties and is therefore an important parameter to determine for newly [...] Read more.

There are scientific studies indicating that the attachment of an indole moiety to the triterpene scaffold can lead to increased anticancer potential. Lipophilicity is one of the factors that may influence biological properties and is therefore an important parameter to determine for newly obtained compounds as drug candidates. In the present study, previously synthesized 3 and/or 28-indole-betulin derivatives were evaluated for lipophilicity by reversed-phase thin-layer chromatography. The experimental values of lipophilicity (logP_TLC) were then subjected to correlation analysis with theoretical values of logP, as well as for selected physicochemical and pharmacokinetic parameters and anticancer activity. A toxicity test using zebrafish embryos and larvae was also conducted. High correlation was observed between the experimental and theoretical values of lipophilicity. We presented correlation equations and statistical parameters describing the relationships between logP_TLC and several physicochemical and ADME parameters. We also revealed the lack of correlation between the experimental values of lipophilicity and anticancer activity. Moreover, experiments on zebrafish have confirmed no toxicity of the tested compounds, which was consistent with the results of the in silico toxicity analysis. The results demonstrated, using the example of indole derivatives of betulin, the utility of lipophilicity values in the context of predicting the biological activity of new compounds. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 2nd Edition)

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11 pages, 875 KiB

Open AccessArticle

Design, Synthesis, and Acaricidal Activity of 2,5-Diphenyl-1,3-oxazoline Compounds

by Yuming Chen, Jiarui Tian, Yuhao Tan, Yuxiu Liu and Qingmin Wang

Molecules 2024, 29(17), 4149; https://doi.org/10.3390/molecules29174149 - 31 Aug 2024

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Abstract

By using a scaffold hopping/ring equivalent and intermediate derivatization strategies, a series of compounds of 2,5-diphenyl-1,3-oxazoline with substituent changes at the 5-phenyl position were prepared, and their acaricidal activity was studied. However, the synthesized 2,5-diphenyl-1,3-oxazolines showed lower activity against mite eggs and larvae [...] Read more.

By using a scaffold hopping/ring equivalent and intermediate derivatization strategies, a series of compounds of 2,5-diphenyl-1,3-oxazoline with substituent changes at the 5-phenyl position were prepared, and their acaricidal activity was studied. However, the synthesized 2,5-diphenyl-1,3-oxazolines showed lower activity against mite eggs and larvae compared to the 2,4-diphenyl-1,3-oxazolines with the same substituents. We speculate that there is a significant difference in the spatial extension direction of the substituents between the two skeletons of compounds, resulting in differences in their ability to bind to the potential target chitin synthase 1. This work is helpful in inferring the internal structure of chitin synthase binding pockets. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 2nd Edition)

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18 pages, 1425 KiB

Open AccessArticle

Trolox, Ferulic, Sinapic, and Cinnamic Acid Derivatives of Proline and GABA with Antioxidant and/or Anti-Inflammatory Properties

by Georgios Papagiouvannis, Panagiotis Theodosis-Nobelos and Eleni A. Rekka

Molecules 2024, 29(16), 3763; https://doi.org/10.3390/molecules29163763 - 8 Aug 2024

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Abstract

Degenerative conditions, such as neurodegenerative disorders (Alzheimer’s disease (AD), Parkinson’s disease (PD)) and cardiovascular diseases, are complex, multifactorial disorders whose pathophysiology has not been fully elucidated yet. As a result, the available treatment options cannot eliminate these diseases radically, but only alleviate the [...] Read more.

Degenerative conditions, such as neurodegenerative disorders (Alzheimer’s disease (AD), Parkinson’s disease (PD)) and cardiovascular diseases, are complex, multifactorial disorders whose pathophysiology has not been fully elucidated yet. As a result, the available treatment options cannot eliminate these diseases radically, but only alleviate the symptoms. Both inflammatory processes and oxidation are key factors in the development and evolution of neurodegeneration, while acetylcholinesterase inhibitors are the most used therapeutic options against AD. In this work, following the multi-targeting compound approach, we designed and synthesized a series of proline and gamma-aminobutyric acid (GABA) amides with various acidic moieties that possess an antioxidant and/or anti-inflammatory potency. Proline is the pharmacophore of nootropic drugs (e.g., piracetam) used for memory improvement, while GABA is the main inhibitory neurotransmitter in the central nervous system. The designed molecules were subjected to a preliminary screening of their bioactivity in antioxidant and anti-inflammatory assays, as well as against acetylcholinesterase. Most of the synthesized compounds could inhibit lipid peroxidation (IC₅₀ as low as 8 μΜ) and oxidative protein glycation (inhibition of up to 48%) and reduce the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH). In addition, all of the compounds were moderate inhibitors of lipoxygenase (LOX) (up to 46% at 100 μΜ) and could decrease carrageenan-induced paw edema in rats by up to 55%. Finally, some of the compounds were moderate acetylcholinesterase inhibitors (IC₅₀ as low as 219 μΜ). The results confirmed the design rationale, indicating that the compounds could be further optimized as multi-targeting molecules directed against degenerative conditions. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 2nd Edition)

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19 pages, 9630 KiB

Open AccessArticle

A Series of Novel 1-H-isoindole-1,3(2H)-dione Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: In Silico, Synthesis and In Vitro Studies

by Edward Krzyżak, Aleksandra Marciniak, Dominika Szkatuła, Klaudia A. Jankowska, Natalia Dobies and Aleksandra Kotynia

Molecules 2024, 29(15), 3528; https://doi.org/10.3390/molecules29153528 - 26 Jul 2024

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Abstract

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer’s therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in [...] Read more.

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer’s therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by ¹H NMR, ¹³C NMR, FT-IR, and ESI–MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman’s method. IC₅₀ values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC₅₀ = 1.12 μM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC₅₀ = 21.24 μM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 2nd Edition)

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22 pages, 3674 KiB

Open AccessArticle

New 3-(Dibenzyloxyphosphoryl)isoxazolidine Conjugates of N1-Benzylated Quinazoline-2,4-diones as Potential Cytotoxic Agents against Cancer Cell Lines

by Magdalena Łysakowska, Iwona E. Głowacka, Ewelina Honkisz-Orzechowska, Jadwiga Handzlik and Dorota G. Piotrowska

Molecules 2024, 29(13), 3050; https://doi.org/10.3390/molecules29133050 - 27 Jun 2024

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Abstract

In this study, a new series of cis and trans 5-substituted-3-(dibenzyloxyphosphoryl)isoxazolidines 16a–g were synthesized by the 1,3-dipolar cycloaddition reaction of N-benzyl-C-(dibenzyloxyphosphoryl)nitrone and selected N¹-allyl-N³-benzylquinazoline-2,4-diones. All the obtained trans-isoxazolidines 16a–g and [...] Read more.

In this study, a new series of cis and trans 5-substituted-3-(dibenzyloxyphosphoryl)isoxazolidines 16a–g were synthesized by the 1,3-dipolar cycloaddition reaction of N-benzyl-C-(dibenzyloxyphosphoryl)nitrone and selected N¹-allyl-N³-benzylquinazoline-2,4-diones. All the obtained trans-isoxazolidines 16a–g and the samples enriched in respective cis-isomers were evaluated for anticancer activity against three tumor cell lines. All the tested compounds exhibited high activity against the prostate cancer cell line (PC-3). Isoxazolidines trans-16a and trans-16b and diastereoisomeric mixtures of isoxazolidines enriched in cis-isomer using HPLC, namely cis-16a/trans-16a (97:3) and cis-16b/trans-16b (90:10), showed the highest antiproliferative properties towards the PC-3 cell line (IC₅₀ = 9.84 ± 3.69–12.67 ± 3.45 μM). For the most active compounds, induction apoptosis tests and an evaluation of toxicity were conducted. Isoxazolidine trans-16b showed the highest induction of apoptosis. Moreover, the most active compounds turned out safe in vitro as none affected the cell viability in the HEK293, HepG2, and HSF cellular models at all the tested concentrations. The results indicated isoxazolidine trans-16b as a promising new lead structure in the search for effective anticancer drugs. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 2nd Edition)

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16 pages, 7206 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2

by Kirti Sharma, Manjinder Singh, Pratibha Sharma, Sumesh C. Sharma, Somdutt Mujwar, Mohit Kapoor, Krishna Kumar Mishra and Tanveer A. Wani

Molecules 2024, 29(6), 1406; https://doi.org/10.3390/molecules29061406 - 21 Mar 2024

Cited by 1 | Viewed by 1650

Abstract

SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to [...] Read more.

SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The M^pro of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of β-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 M^Pro to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds KS82 and KS94 was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules KS82 and KS94 were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 2nd Edition)

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