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21 pages, 2869 KiB

Open AccessArticle

2-Alkyl-Substituted-4-Amino-Thieno[2,3-d]Pyrimidines: Anti-Proliferative Properties to In Vitro Breast Cancer Models

by Ivan Iliev, Anelia Mavrova, Denitsa Yancheva, Stefan Dimov, Galya Staneva, Alexandrina Nesheva, Iana Tsoneva and Biliana Nikolova

Molecules 2023, 28(17), 6347; https://doi.org/10.3390/molecules28176347 - 30 Aug 2023

Viewed by 1068

Abstract

Thienopyrimidines are structural analogs of quinazolines, and the creation of new 2-alkyl derivatives of ethyl 4-aminothienopyrimidine-6-carboxylates for the study of their anti-proliferative properties is of great pharmacological interest. Some 2-alkyl-4-amino-thieno[2,3-d]pyrimidines 2–5 were synthesized, and their cyto- and phototoxicity against [...] Read more.

Thienopyrimidines are structural analogs of quinazolines, and the creation of new 2-alkyl derivatives of ethyl 4-aminothienopyrimidine-6-carboxylates for the study of their anti-proliferative properties is of great pharmacological interest. Some 2-alkyl-4-amino-thieno[2,3-d]pyrimidines 2–5 were synthesized, and their cyto- and phototoxicity against BALB 3T3 cells were established by an in vitro 3T3 NRU test. The obtained results indicate that the tested compounds are not cytotoxic or phototoxic, and that they are appropriate to be studied for their anti-proliferative and anti-tumor properties. The anti-proliferative potential of the compounds was investigated on MCF-7 and MDA-MB-231 cancer cells, as well as a MCF-10A cell line (normal human mammary epithelial cells). The most toxic to MCF-7 was thienopyrimidine 3 with IC₅₀ 13.42 μg/mL (IC₅₀ 0.045 μM), followed by compound 4 (IC₅₀ 28.89 μg/mL or IC₅₀ 0.11 μM). The thienopyrimidine 4 revealed higher selectivity to MCF-7 and lower activity (IC₅₀ 367 μg/mL i.e., 1.4 μM) than compound 3 with MCF-10A cells. With respect to MDA-MB-231 cells, ester 2 manifested the highest effect with IC₅₀ 52.56 μg/mL (IC₅₀ 0.16 μM), and 2-ethyl derivative 4 revealed IC₅₀ 62.86 μg/mL (IC₅₀ 0.24 μM). It was estimated that the effect of the substances on the cell cycle progression was due to cell cycle arrest in the G2 stage for MDA-MB-231, while arrest in G1 was detected for the estrogen (ER)-positive MCF-7 cell line. The tested compound’s effects on the change of the zeta potential in the tumorigenic cells utilized in this study were determined. The calculation which we performed of the physicochemical properties and pharmacokinetic parameters influencing the biological activity suggested high intestinal absorption, as well as drug-likeness. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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18 pages, 7151 KiB

Open AccessArticle

Evaluation of Biological Activities of Twenty Flavones and In Silico Docking Study

by Meriam Belaiba, Sarah Aldulaijan, Sabri Messaoudi, Manef Abedrabba, Adnene Dhouib and Jalloul Bouajila

Molecules 2023, 28(6), 2419; https://doi.org/10.3390/molecules28062419 - 07 Mar 2023

Cited by 5 | Viewed by 2118

Abstract

This work aimed to evaluate the biological activities of 20 flavones (M1 to M20) and discuss their structure–activity relationships. In vitro assays were established to assess their numerous biological activities (anti-α-amylase, anti-acetylcholinesterase, anti-xanthine oxidase, anti-superoxide dismutase, and anticancer cell lines (HCT-116, MCF7, OVCAR-3, [...] Read more.

This work aimed to evaluate the biological activities of 20 flavones (M1 to M20) and discuss their structure–activity relationships. In vitro assays were established to assess their numerous biological activities (anti-α-amylase, anti-acetylcholinesterase, anti-xanthine oxidase, anti-superoxide dismutase, and anticancer cell lines (HCT-116, MCF7, OVCAR-3, IGROV-1, and SKOV-3 cells lines)). An in silico docking study was also established in order to find the relationship between the chemical structure and the biological activities. In vitro tests revealed that M5 and M13 were the most active in terms of anti-α-amylase activity (IC₅₀ = 1.2 and 1.4 µM, respectively). M17 was an inhibitor of xanthine oxidase (XOD) and performed better than the reference (allopurinol), at IC₅₀ = 0.9 µM. M7 presented interesting anti-inflammatory (IC₅₀ = 38.5 µM), anti-supriode dismutase (anti-SOD) (IC₅₀ = 31.5 µM), and anti-acetylcholinesterase (IC₅₀ = 10.2 µM) activities. Those abilities were in concordance with its high scavenging activity in antioxidant ABTS and DPPH assays, at IC₅₀ = 6.3 and 5.2 µM, respectively. Selectivity was detected regarding cytotoxic activity for those flavones. M1 (IC₅₀ = 35.9 µM) was a specific inhibitor to the MCF7 cancer cell lines. M3 (IC₅₀ = 44.7 µM) and M15 (IC₅₀ = 45.6 µM) were particularly potent for the OVCAR-3 cell line. M14 (IC₅₀ = 4.6 µM) contributed more clearly to inhibiting the colon cancer cell line (HCT116). M7 (IC₅₀ = 15.6 µM) was especially active against the ovarian SKOV human cancer cell line. The results of the biological activities were supported by means of in silico molecular docking calculations. This investigation analyzed the contribution of the structure–activity of natural flavones in terms of their biological properties, which is important for their future application against diseases. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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16 pages, 1398 KiB

Open AccessArticle

Undescribed Metabolites from an Actinobacteria Acrocarpospora punica and Their Anti-Inflammatory Activity

by Ming-Der Wu and Ming-Jen Cheng

Molecules 2022, 27(22), 7982; https://doi.org/10.3390/molecules27227982 - 17 Nov 2022

Cited by 2 | Viewed by 997

Abstract

In an effort to explore bioactive anti-inflammatory compounds from natural Actinobacteria resources from all over Taiwan and various ecological environments, an active strain of Acrocarpospora punica was collected at Taitung County in Taiwan, prepared from soil origin. A bioassay-guided fractionation of the BuOH [...] Read more.

In an effort to explore bioactive anti-inflammatory compounds from natural Actinobacteria resources from all over Taiwan and various ecological environments, an active strain of Acrocarpospora punica was collected at Taitung County in Taiwan, prepared from soil origin. A bioassay-guided fractionation of the BuOH extract of a culture broth of a new strain of the actinomycete Acrocarpospora punica led to the isolation of five previously undescribed compounds: acrocarpunicains A–F (1–6). The structures were elucidated by 1D and 2D Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Furthermore, the isolated compounds were subjected to in vitro testing to evaluate their anti-inflammatory activity. Of these isolates, acrocarpunicains A (1), B (2), C (3) and F (6) showed NO inhibitory activity with IC₅₀ values of 9.36 ± 0.25, 10.11 ± 0.47, 5.15 ± 0.18, and 27.17 ± 1.87 μM, stronger than the positive control, quercetin (IC₅₀ = 35.95 ± 2.34 μM). To the best of our knowledge, this is the first report on azaphilone and phenanthrene-type metabolites from the genus Acrocarpospora. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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13 pages, 8334 KiB

Open AccessArticle

Synthesis, In Vitro Anti-Microbial Analysis and Molecular Docking Study of Aliphatic Hydrazide-Based Benzene Sulphonamide Derivatives as Potent Inhibitors of α-Glucosidase and Urease

by Shoaib Khan, Shahid Iqbal, Mazloom Shah, Wajid Rehman, Rafaqat Hussain, Liaqat Rasheed, Hamad Alrbyawi, Ayed A. Dera, Mohammed Issa Alahmdi, Rami Adel Pashameah, Eman Alzahrani and Abd-ElAziem Farouk

Molecules 2022, 27(20), 7129; https://doi.org/10.3390/molecules27207129 - 21 Oct 2022

Cited by 12 | Viewed by 1598

Abstract

A unique series of sulphonamide derivatives was attempted to be synthesized in this study using a new and effective method. All of the synthesized compounds were verified using several spectroscopic methods, including FTIR, ¹H-NMR, ¹³C-NMR, and HREI-MS, and their binding interactions [...] Read more.

A unique series of sulphonamide derivatives was attempted to be synthesized in this study using a new and effective method. All of the synthesized compounds were verified using several spectroscopic methods, including FTIR, ¹H-NMR, ¹³C-NMR, and HREI-MS, and their binding interactions were studied using molecular docking. The enzymes urease and α-glucosidase were evaluated against each derivative (1–15). When compared to their respective standard drug such as acarbose and thiourea, almost all compounds were shown to have excellent activity. Among the screened series, analogs 5 (IC₅₀ = 3.20 ± 0.40 and 2.10 ± 0.10 µM) and 6 (IC₅₀ = 2.50 ± 0.40 and 5.30 ± 0.20 µM), emerged as potent molecules when compared to the standard drugs acarbose (IC₅₀ = 8.24 ± 0.08 µM) and urease (IC₅₀ = 7.80 ± 0.30). Moreover, an anti-microbial study also demonstrated that analogs 5 and 6 were found with minimum inhibitory concentrations (MICs) in the presence of standard drugs streptomycin and terinafine. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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19 pages, 4446 KiB

Open AccessArticle

New Triazinoindole Bearing Benzimidazole/Benzoxazole Hybrids Analogs as Potent Inhibitors of Urease: Synthesis, In Vitro Analysis and Molecular Docking Studies

by Sundas Mumtaz, Shahid Iqbal, Mazloom Shah, Rafaqat Hussain, Fazal Rahim, Wajid Rehman, Shoaib Khan, Obaid-ur-Rahman Abid, Liaqat Rasheed, Ayed A. Dera, Hanan A. Al-ghulikah, Sana Kehili, Eslam B. Elkaeed, Hamad Alrbyawi and Mohammed Issa Alahmdi

Molecules 2022, 27(19), 6580; https://doi.org/10.3390/molecules27196580 - 04 Oct 2022

Cited by 12 | Viewed by 1968

Abstract

Twenty-four analogs based on triazinoindole bearing benzimidazole/benzoxazole moieties (1–25) were synthesized. Utilizing a variety of spectroscopic methods, including ¹H-, ¹³C-NMR, and HREI-MS, the newly afforded compounds (1–25) were analyzed. The synthesized analogs were [...] Read more.

Twenty-four analogs based on triazinoindole bearing benzimidazole/benzoxazole moieties (1–25) were synthesized. Utilizing a variety of spectroscopic methods, including ¹H-, ¹³C-NMR, and HREI-MS, the newly afforded compounds (1–25) were analyzed. The synthesized analogs were tested against urease enzyme (in vitro) as compared to the standard thiourea drug. All triazinoindole-based benzimidazole/benzoxazole analogs (1–25) exhibited moderate to excellent inhibition profiles, having IC₅₀ values of 0.20 ± 0.01 to 36.20 ± 0.70 μM when evaluated under the positive control of thiourea as a standard drug. To better understand the structure–activity relationship, the synthesized compounds were split into two groups, “A” and “B.” Among category “A” analogs, analogs 8 (bearing tri-hydroxy substitutions at the 2,4,6-position of aryl ring C) and 5 (bearing di-hydroxy substitutions at the 3,4-position of aryl ring C) emerged as the most potent inhibitors of urease enzyme and displayed many times more potency than a standard thiourea drug. Besides that, analog 22 (which holds di-hydroxy substitutions at the 2,3-position of the aryl ring) and analog 23 (bearing ortho-fluoro substitution) showed ten-fold-enhanced inhibitory potential compared to standard thiourea among category “B” analogs. Molecular docking studies on the active analogs of each category were performed; the results obtained revealed that the presence of hydroxy and fluoro-substitutions on different positions of aryl ring C play a pivotal role in binding interactions with the active site of the targeted urease enzyme. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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25 pages, 3425 KiB

Open AccessArticle

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments

by Salma M. Khirallah, Heba M. M. Ramadan, Ahmed Shawky, Safa H. Qahl, Roua S. Baty, Nada Alqadri, Amnah Mohammed Alsuhaibani, Mariusz Jaremko, Abdul-Hamid Emwas and Essa M. Saied

Molecules 2022, 27(19), 6271; https://doi.org/10.3390/molecules27196271 - 23 Sep 2022

Cited by 14 | Viewed by 2167

Abstract

Inflammation is the main cause of several autoimmune diseases, including type I diabetes, rheumatoid arthritis, bullous pemphigoid, paraneoplastic pemphigoid, and multiple sclerosis. Currently, there is an urgent demand for the discovery of novel anti-inflammatory drugs with potent activity but also safe for long-term [...] Read more.

Inflammation is the main cause of several autoimmune diseases, including type I diabetes, rheumatoid arthritis, bullous pemphigoid, paraneoplastic pemphigoid, and multiple sclerosis. Currently, there is an urgent demand for the discovery of novel anti-inflammatory drugs with potent activity but also safe for long-term application. Toward this aim, the present study reported the design, synthesis, and characterization of a set of novel 1,3-disubstituted-2-thiohydantoins derivatives. The anti-inflammatory activity of synthesized compounds was assessed against murine leukemia cell line (RAW264.7) by evaluating the cytotoxicity activity and their potency to prevent nitric oxide (NO) production. The results revealed that the synthesized compounds possess a considerable cytotoxic activity together with the ability to reduce the NO production in murine leukemia cell line (RAW264.7). Among synthesized compounds, compound 7 exhibited the most potent cytotoxic activity with IC₅₀ of 197.68 μg/mL, compared to celecoxib drug (IC₅₀ value 251.2 μg/mL), and demonstrated a significant ability to diminish the NO production (six-fold reduction). Exploring the mode of action responsible for the anti-inflammatory activity revealed that compound 7 displays a significant and dose-dependent inhibitory effect on the expression of pro-inflammatory cytokines IL-1β. Furthermore, compound 7 demonstrated the ability to significantly reduce the expression of the inflammatory cytokines IL-6 and TNF-α at 50 μg/mL, as compared to Celecoxib. Finally, detailed molecular modelling studies indicated that compound 7 exhibits a substantial binding affinity toward the binding pocket of the cyclooxygenase 2 enzyme. Taken together, our study reveals that 1,3-disubstituted-2-thiohydantoin could be considered as a promising scaffold for the development of potent anti-inflammatory agents. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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19 pages, 4442 KiB

Open AccessArticle

Efficacy of 2-Hydroxyflavanone in Rodent Models of Pain and Inflammation: Involvement of Opioidergic and GABAergic Anti-Nociceptive Mechanisms

by Faiz Ali Khan, Gowhar Ali, Khista Rahman, Yahya Khan, Muhammad Ayaz, Osama F. Mosa, Asif Nawaz, Syed Shams ul Hassan and Simona Bungau

Molecules 2022, 27(17), 5431; https://doi.org/10.3390/molecules27175431 - 25 Aug 2022

Cited by 12 | Viewed by 1520

Abstract

The current work examined the pharmacological potential of a selected flavanone derivative 2-hydroxyflavanone as a promising remedy for the treatment and management of pain. The selected flavanone derivative (2-HF) was evaluated for its analgesic and anti-inflammatory potentials following standard pharmacological protocols including hot [...] Read more.

The current work examined the pharmacological potential of a selected flavanone derivative 2-hydroxyflavanone as a promising remedy for the treatment and management of pain. The selected flavanone derivative (2-HF) was evaluated for its analgesic and anti-inflammatory potentials following standard pharmacological protocols including hot plate, acetic acid-induced writhing and tail immersion tests. Naloxone and pentylenetetrazol were used to evaluate the potential implication of GABAergic and opioidergic mechanisms. The anti-inflammatory potential of 2-HF was confirmed using carrageenan-, serotonin- and histamine-induced paw edema models as well as a xylene-induced ear edema model. Furthermore, the anti-neuropathic potential of 2-HF was tested using a cisplatin-induced neuropathic pain model. Our sample, at the tested concentrations of 15, 30 and 45 mg kg⁻¹, showed considerable analgesic, anti-inflammatory effects, as well as efficacy against neuropathic pain. Naloxone and pentylenetetrazol at 1 and 15 mg kg⁻¹ antagonized the anti-nociceptive activities of 2-hydroxyflavanone indicating the involvement of opioidergic and GABAergic mechanisms. In the static allodynia model, combination of gabapentin 75 mg kg⁻¹ with 2-HF at 15, 30, 45 mg kg⁻¹ doses exhibited considerable efficacy. In cold allodynia, 2-hydroxyflavanone, at doses of 15, 30 and 45 mg kg⁻¹ and in combination with gabapentin (75 mg kg⁻¹), demonstrated prominent anti-allodynic effects. The paw withdrawal latency was considerably increased in gabapentin + cisplatin treated groups. Moreover, cisplatin + 2-hydroxyflavanone 15, 30, 45 mg kg⁻¹ showed increases in paw withdrawal latency. Likewise, considerable efficacy was observed for 2-hydroxyflavanone in thermal hyperalgesia and dynamic allodynia models. Our findings suggest that 2-hydroxyflavanone is a potential remedy for pain syndrome, possibly mediated through opioidergic and GABAergic mechanisms. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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22 pages, 1237 KiB

Open AccessArticle

Synthesis of Bio-Inspired 1,3-Diarylpropene Derivatives via Heck Cross-Coupling and Cytotoxic Evaluation on Breast Cancer Cells

by Aik Sian Tan, Jaymeer Singh, Nurul Syafiqah Rezali, Musthahimah Muhamad, Nik Nur Syazni Nik Mohamed Kamal, Yvan Six and Mohamad Nurul Azmi

Molecules 2022, 27(17), 5373; https://doi.org/10.3390/molecules27175373 - 23 Aug 2022

Viewed by 2262

Abstract

The Heck cross-coupling reaction is a well-established chemical tool for the synthesis of unsaturated compounds by formation of a new C-C bond. In this study, 1,3-diarylpropene derivatives, designed as structural analogues of stilbenoids and dihydrostilbenoids, were synthesised by the palladium-catalysed reactions of 2-amidoiodobenzene [...] Read more.

The Heck cross-coupling reaction is a well-established chemical tool for the synthesis of unsaturated compounds by formation of a new C-C bond. In this study, 1,3-diarylpropene derivatives, designed as structural analogues of stilbenoids and dihydrostilbenoids, were synthesised by the palladium-catalysed reactions of 2-amidoiodobenzene derivatives with either estragole or eugenol. The products were obtained with high (E) stereoselectivity but as two regioisomers. The ratios of isomers were found to be dependent on the nature of the allylbenzene partner and were rationalised by electronic effects exercising a determining influence in the β-hydride elimination step. In addition, the cytotoxic effects of all the Heck reaction products were evaluated against MCF-7 and MDA-MB-231 human breast cancer cells, with unpromising results. Among all, compound 7d exhibited weak cytotoxic activity towards MCF-7 cell lines with IC₅₀ values of 47.92 µM in comparison with tamoxifen and was considered to have general toxicity (SI value < 2). Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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18 pages, 2520 KiB

Open AccessArticle

Novel Isoxazole Derivative Attenuates Ethanol-Induced Gastric Mucosal Injury through Inhibition of H⁺/K⁺-ATPase Pump, Oxidative Stress and Inflammatory Pathways

by Sidra Razzaq, Amber Mahmood Minhas, Neelum Gul Qazi, Humaira Nadeem, Arif-ullah Khan, Fawad Ali, Syed Shams ul Hassan and Simona Bungau

Molecules 2022, 27(16), 5065; https://doi.org/10.3390/molecules27165065 - 09 Aug 2022

Cited by 16 | Viewed by 1957

Abstract

Isoxazole derivatives are significant enough due to their wide range of pharmacological and therapeutic activities. The purpose of the current study is to use computational, in vitro, in vivo, and extensive molecular approaches to examine the possible anti-ulcer activity of 4-benzylidene-3 methyl-1,2-isoxazol-5(4H)-one (MBO). [...] Read more.

Isoxazole derivatives are significant enough due to their wide range of pharmacological and therapeutic activities. The purpose of the current study is to use computational, in vitro, in vivo, and extensive molecular approaches to examine the possible anti-ulcer activity of 4-benzylidene-3 methyl-1,2-isoxazol-5(4H)-one (MBO). Biovia Discovery Studio visualizer (DSV) was utilized for virtual screening. A tissue antioxidant investigation, H⁺/K⁺-ATPase test, and anti-H. pylori activities were carried out. ELISA, immunohistochemistry, and PCR methods were employed for the proteome analysis. An ethanol-induced stomach ulcer model was used to examine the anti-ulcer potential in rats. The binding affinities for MBO ranged from −5.4 to −8.2 Kcal/mol. In vitro findings revealed inhibitory activity against H. pylori and the H⁺/K⁺-ATPase pump. It also enhanced levels of glutathione, catalase, and glutathione-S-transferase and reduced lipid peroxidation levels in gastric tissues of rats. In vivo results showed the gastro-protective effect of MBO (30 mg/kg) in ulcerative rat stomachs. The proteomic study revealed decreased expression of inflammatory markers (cyclooxygenase-2, p-NFkB, and TNF-α). In RT-PCR analysis, the expression levels of H⁺/K⁺-ATPase were reduced. Furthermore, ADMET (absorption, distribution, metabolism, excretion and toxicity) studies revealed that MBO has high GIT solubility and has a safer profile for cardiac toxicity. This study suggests that MBO displayed anti-ulcer potential, which may have been mediated through the inhibition of the H⁺/K⁺-ATPase pump, as well as antioxidant and anti-inflammatory pathways. It has the potential to be a lead molecule in the treatment of peptic ulcers with fewer adverse effects. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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26 pages, 3518 KiB

Open AccessArticle

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

by Manar G. Salem, Dina M. Abu El-Maaty, Yassmina I. Mohey El-Deen, Basem H. Elesawy, Ahmad El Askary, Asmaa Saleh, Essa M. Saied and Mohammed El Behery

Molecules 2022, 27(15), 4898; https://doi.org/10.3390/molecules27154898 - 31 Jul 2022

Cited by 17 | Viewed by 2431

Abstract

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic [...] Read more.

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC₅₀ of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC₅₀ = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC₅₀ = 0.093 µM) compared to Sorafenib (IC₅₀ = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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28 pages, 4465 KiB

Open AccessArticle

Methylenedioxy Piperamide-Derived Compound D5 Regulates Inflammatory Cytokine Secretion in a Culture of Human Glial Cells

by Sajad Shahbazi and Tara Zakerali

Molecules 2022, 27(11), 3527; https://doi.org/10.3390/molecules27113527 - 30 May 2022

Cited by 1 | Viewed by 1879

Abstract

Neuroinflammation is the cornerstone of most neuronal disorders, particularly neurodegenerative diseases. During the inflammatory process, various pro-inflammatory cytokines, chemokines, and enzymes—such as interleukin 1-β (IL1-β), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthases (iNOS), inhibitory kappa kinase (IKK), and inducible [...] Read more.

Neuroinflammation is the cornerstone of most neuronal disorders, particularly neurodegenerative diseases. During the inflammatory process, various pro-inflammatory cytokines, chemokines, and enzymes—such as interleukin 1-β (IL1-β), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthases (iNOS), inhibitory kappa kinase (IKK), and inducible nitric oxide (NO)—are over-expressed in response to every stimulus. Methods: In the present study, we focused on the anti-neuroinflammatory efficacy of (2E,4E)-N,5-bis(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamide, encoded D5. We investigated the efficacy of D5 on the upstream and downstream products of inflammatory pathways in CHME3 and SVG cell lines corresponding to human microglia and astrocytes, respectively, using various in silico, in vitro, and in situ techniques. Results: The results showed that D5 significantly reduced the level of pro-inflammatory cytokines by up-regulating PPAR-γ expression and suppressing IKK-β, iNOS, NO production, and NF-κB activation in inflamed astrocytes (SVG) and microglia (CHME3) after 24 h of incubation. The data demonstrated remarkably higher efficacy of D5 compared to ASA (Aspirin) in reducing NF-κB-dependent neuroinflammation. Conclusions: We observed that the functional-group alteration had an extreme influence on the levels of druggability and the immunomodulatory properties of two analogs of piperamide, D5, and D4 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(4-(hydroxymethyl)phenyl)penta-2,4-dienamide)). The present study suggested D5 as a potential anti-neuroinflammatory agent for further in vitro, in vivo, and clinical investigations. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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12 pages, 2649 KiB

Open AccessArticle

Gamma-Irradiation-Induced Degradation of the Water-Soluble Polysaccharide from Auricularia polytricha and Its Anti-Hypercholesterolemic Activity

by Ping Li, Chuan Xiong and Wenli Huang

Molecules 2022, 27(3), 1110; https://doi.org/10.3390/molecules27031110 - 07 Feb 2022

Cited by 10 | Viewed by 1714

Abstract

The water-soluble polysaccharides (APPs) isolated from the edible mushroom Auricularia polytricha were irradiated by γ-ray at doses of 10, 100, and 1000 kGy. The effect of gamma irradiation on the degradation of the polysaccharide was investigated. After irradiation treatment, the viscosity and molecular [...] Read more.

The water-soluble polysaccharides (APPs) isolated from the edible mushroom Auricularia polytricha were irradiated by γ-ray at doses of 10, 100, and 1000 kGy. The effect of gamma irradiation on the degradation of the polysaccharide was investigated. After irradiation treatment, the viscosity and molecular weight of APPs decreased with the increase in the irradiation dose. The changes in the enthalpy of APPs after irradiation treatment were observed. Meanwhile, SEM showed that R-APPs were crushed into fragments and the surfaces became smooth and wrinkled after irradiation. In further spectrum analysis, it was found that the glycoside bonds of the polysaccharides were broken and accompanied by the formation of double bonds. This suggested that gamma irradiation could cause the depolymerization and oxidation of polysaccharides. In addition, irradiated APPs could reduce the body weight of hyperlipidemia mice. The levels of serum and liver TC, TG, and serum LDH-c significantly decreased in hyperlipidemia mice after treatment by irradiated APPs. It indicated that gamma irradiation significantly improved the anti-hypolipidemic activity of APPs. The relationship between the physicochemical properties and hypolipidemic activity of polysaccharides was interpreted, which provides a theoretical basis for the further development of APP products. Gamma irradiation is a viable technology for macromolecular modification for degradation. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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16 pages, 7183 KiB

Open AccessArticle

GIF-2209, an Oxindole Derivative, Accelerates Melanogenesis and Melanosome Secretion via the Modification of Lysosomes in B16F10 Mouse Melanoma Cells

by Miyu Watanabe, Kyoka Kawaguchi, Yusuke Nakamura, Kyoji Furuta and Hiroshi Takemori

Molecules 2022, 27(1), 177; https://doi.org/10.3390/molecules27010177 - 28 Dec 2021

Cited by 3 | Viewed by 1829

Abstract

Melanogenesis and melanosome secretion are regulated by several mechanisms. In this study, we found that the oxindole derivative GIF-2209 accelerated melanogenesis associated with the discrimination in the expression and intracellular distributions of two melanogenic enzymes, tyrosinase (TYR) and tyrosinase-related protein-1 (TYRP-1). GIF-2209 upregulated [...] Read more.

Melanogenesis and melanosome secretion are regulated by several mechanisms. In this study, we found that the oxindole derivative GIF-2209 accelerated melanogenesis associated with the discrimination in the expression and intracellular distributions of two melanogenic enzymes, tyrosinase (TYR) and tyrosinase-related protein-1 (TYRP-1). GIF-2209 upregulated the expression of TYR via a microphthalmia transcription factor (MITF)-independent mechanism, leading to high expression of protein. In contrast, GIF-2209 did not alter the mRNA levels of TYRP-1 and suppressed its protein levels. GIF-2209 induced the dissociation of TYR from TYRP-1 but did not alter the association between TYR and CD63, a melanosome and lysosome marker. The protein levels of CD63 were also upregulated by GIF-2209. GIF-2209 induced lysosome expansion and redistribution in all areas of the cytosol, accompanied by autophagy acceleration (upregulation of LC3BII protein levels and downregulation of p62 protein levels). In addition, GIF-2209 stimulated the secretion of melanosomes containing high levels of TYR, TYRP-1, and CD63 proteins. The GIF-2209 mediated melanosome secretion was sensitive to the lysosome inhibitor chloroquine. These results suggest that GIF-2209 may activate lysosomal functions with TYR gene expression, while it accelerates melanosome secretion, which finally leads to the depletion of intracellular melanogenic enzyme, especially TYRP-1 protein. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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30 pages, 6892 KiB

Open AccessReview

Review of Phytochemical Potency as a Natural Anti-Helicobacter pylori and Neuroprotective Agent

by Yohanes Tandoro, Bo-Kai Chen, Asif Ali and Chin-Kun Wang

Molecules 2023, 28(20), 7150; https://doi.org/10.3390/molecules28207150 - 18 Oct 2023

Viewed by 1367

Abstract

Phytochemicals are plant secondary metabolites that show health benefits for humans due to their bioactivity. There is a huge variety of phytochemicals that have already been identified, and these compounds can act as antimicrobial and neuroprotection agents. Due to their anti-microbial activity and [...] Read more.

Phytochemicals are plant secondary metabolites that show health benefits for humans due to their bioactivity. There is a huge variety of phytochemicals that have already been identified, and these compounds can act as antimicrobial and neuroprotection agents. Due to their anti-microbial activity and neuroprotection, several phytochemicals might have the potency to be used as natural therapeutic agents, especially for Helicobacter pylori infection and neurodegenerative disease, which have become a global health concern nowadays. According to previous research, there are some connections between H. pylori infection and neurodegenerative diseases, especially Alzheimer’s disease. Hence, this comprehensive review examines different kinds of phytochemicals from natural sources as potential therapeutic agents to reduce H. pylori infection and improve neurodegenerative disease. An additional large-scale study is needed to establish the connection between H. pylori infection and neurodegenerative disease and how phytochemicals could improve this condition. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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45 pages, 4078 KiB

Open AccessReview

Emerging Biopharmaceuticals from Pimpinella Genus

by Jiajia Wu, Zhen Cao, Syed Shams ul Hassan, Haozhen Zhang, Muhammad Ishaq, Xu Yu, Shikai Yan, Xue Xiao and Hui-Zi Jin

Molecules 2023, 28(4), 1571; https://doi.org/10.3390/molecules28041571 - 06 Feb 2023

Viewed by 2318

Abstract

Evolved over eons to encode biological assays, plants-derived natural products are still the first dawn of drugs. Most researchers have focused on natural compounds derived from commonly used Pimpinella species, such as P. anisum, P. thellungiana, P. saxifrage, and P. [...] Read more.

Evolved over eons to encode biological assays, plants-derived natural products are still the first dawn of drugs. Most researchers have focused on natural compounds derived from commonly used Pimpinella species, such as P. anisum, P. thellungiana, P. saxifrage, and P. brachycarpa, to investigate their antioxidant, antibacterial, and anti-inflammatory properties. Ethnopharmacological studies demonstrated that the genus Pimpinella has the homology characteristics of medicine and food and mainly in the therapy of gastrointestinal dysfunction, respiratory diseases, deworming, and diuresis. The natural product investigation of Pimpinella spp. revealed numerous natural products containing phenylpropanoids, terpenoids, flavonoids, coumarins, sterols, and organic acids. These natural products have the potential to provide future drugs against crucial diseases, such as cancer, hypertension, microbial and insectile infections, and severe inflammations. It is an upcoming field of research to probe a novel and pharmaceutically clinical value on compounds from the genus Pimpinella. In this review, we attempt to summarize the present knowledge on the traditional applications, phytochemistry, and pharmacology of more than twenty-five species of the genus Pimpinella. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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15 pages, 499 KiB

Open AccessReview

Electrolyzed Water and Its Pharmacological Activities: A Mini-Review

by Bo-Kai Chen and Chin-Kun Wang

Molecules 2022, 27(4), 1222; https://doi.org/10.3390/molecules27041222 - 11 Feb 2022

Cited by 15 | Viewed by 5225

Abstract

Electrolyzed water (EW) is a new type of cleaning and disinfecting agent obtained by means of electrolysis with a dilute sodium chloride solution. It has low cost and harm to the human body and is also friendly to the environment. The anode produces [...] Read more.

Electrolyzed water (EW) is a new type of cleaning and disinfecting agent obtained by means of electrolysis with a dilute sodium chloride solution. It has low cost and harm to the human body and is also friendly to the environment. The anode produces acidic electrolyzed water (AEW), which is mainly used to inhibit bacterial growth and disinfect. The cathode provides basic electrolyzed water (BEW), which is implemented to promote human health. EW is a powerful multifunctional antibacterial agent with a wide range of applications in the medicine, agriculture, and food industry. Studies in vitro and in vivo show that it has an inhibitory effect on pathogenic bacteria and viruses. Therefore, EW is used to prevent chronic diseases, while it has been found to be effective against various kinds of infectious viruses. Animal experiments and clinical trials clearly showed that it accelerates wound healing, and has positive effects in oral health care, anti-obesity, lowering blood sugar, anti-cancer and anti-infectious viral diseases. This review article summarizes the application of EW in treating bacteria and viruses, the prevention of chronic diseases, and health promotion. Full article

(This article belongs to the Special Issue Probing Pharmacological and Biological Performance of Synthetic and Natural Compounds)

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