International Journal of Molecular Sciences

2023

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20 pages, 1736 KiB

Open AccessReview

Ferulic Acid: A Review of Pharmacology, Toxicology, and Therapeutic Effects on Pulmonary Diseases

by Yiman Zhai, Tingyu Wang, Yunmei Fu, Tong Yu, Yan Ding and Hongguang Nie

Int. J. Mol. Sci. 2023, 24(9), 8011; https://doi.org/10.3390/ijms24098011 - 28 Apr 2023

Cited by 18 | Viewed by 4164

Abstract

Ferulic acid (FA), a prevalent dietary phytochemical, has many pharmacological effects, including anti-oxidation and anti-inflammation effects, and has been widely used in the pharmaceutical, food, and cosmetics industries. Many studies have shown that FA can significantly downregulate the expression of reactive oxygen species [...] Read more.

Ferulic acid (FA), a prevalent dietary phytochemical, has many pharmacological effects, including anti-oxidation and anti-inflammation effects, and has been widely used in the pharmaceutical, food, and cosmetics industries. Many studies have shown that FA can significantly downregulate the expression of reactive oxygen species and activate nuclear factor erythroid-2-related factor-2/heme oxygenase-1 signaling, exerting anti-oxidative effects. The anti-inflammatory effect of FA is mainly related to the p38 mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways. FA has demonstrated potential clinical applications in the treatment of pulmonary diseases. The transforming growth factor-β1/small mothers against decapentaplegic 3 signaling pathway can be blocked by FA, thereby alleviating pulmonary fibrosis. Moreover, in the context of asthma, the T helper cell 1/2 imbalance is restored by FA. Furthermore, FA ameliorates acute lung injury by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase pathways via toll-like receptor 4, consequently decreasing the expression of downstream inflammatory mediators. Additionally, there is a moderate neuraminidase inhibitory activity showing a tendency to reduce the interleukin-8 level in response to influenza virus infections. Although the application of FA has broad prospects, more preclinical mechanism-based research should be carried out to test these applications in clinical settings. This review not only covers the literature on the pharmacological effects and mechanisms of FA, but also discusses the therapeutic role and toxicology of FA in several pulmonary diseases. Full article

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27 pages, 3886 KiB

Open AccessReview

Nature-Inspired Surface Structures Design for Antimicrobial Applications

by Meng-Shiue Lee, Hussein Reda Hussein, Sheng-Wen Chang, Chia-Yu Chang, Yi-Ying Lin, Yueh Chien, Yi-Ping Yang, Lik-Voon Kiew, Ching-Yun Chen, Shih-Hwa Chiou and Chia-Ching Chang

Int. J. Mol. Sci. 2023, 24(2), 1348; https://doi.org/10.3390/ijms24021348 - 10 Jan 2023

Cited by 7 | Viewed by 3207

Abstract

Surface contamination by microorganisms such as viruses and bacteria may simultaneously aggravate the biofouling of surfaces and infection of wounds and promote cross-species transmission and the rapid evolution of microbes in emerging diseases. In addition, natural surface structures with unique anti-biofouling properties may [...] Read more.

Surface contamination by microorganisms such as viruses and bacteria may simultaneously aggravate the biofouling of surfaces and infection of wounds and promote cross-species transmission and the rapid evolution of microbes in emerging diseases. In addition, natural surface structures with unique anti-biofouling properties may be used as guide templates for the development of functional antimicrobial surfaces. Further, these structure-related antimicrobial surfaces can be categorized into microbicidal and anti-biofouling surfaces. This review introduces the recent advances in the development of microbicidal and anti-biofouling surfaces inspired by natural structures and discusses the related antimicrobial mechanisms, surface topography design, material application, manufacturing techniques, and antimicrobial efficiencies. Full article

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2022

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13 pages, 5067 KiB

Open AccessArticle

Asymmetric Synthesis of Trifluoroethyl-Based, Chiral 3-Benzyloxy-1- and -2-Phenyl-quinazolinones of Biomedicinal Interest by Radical Type Cross-Coupling to Olefins

by Chien-Tien Chen, Yu-Chang Chang, Pin-Xuan Tseng, Chien-I Lein, Shiang-Fu Hung and Hsyueh-Liang Wu

Int. J. Mol. Sci. 2023, 24(1), 513; https://doi.org/10.3390/ijms24010513 - 28 Dec 2022

Cited by 5 | Viewed by 1746

Abstract

Several 2-substituted (H, Ph, and S-Me) and 1-substituted (H, Ph, and Bn), 3-hydroxy-1,3-quinazolin(di)ones were utilized for the first time as radical trapping agents in asymmetric 1,2-oxytrifluoromethylation of styrenes catalyzed by chiral vanadyl methoxide complexes bearing 3,5-disubstituted-N-salicylidene-t-leucinate templates. The effects [...] Read more.

Several 2-substituted (H, Ph, and S-Me) and 1-substituted (H, Ph, and Bn), 3-hydroxy-1,3-quinazolin(di)ones were utilized for the first time as radical trapping agents in asymmetric 1,2-oxytrifluoromethylation of styrenes catalyzed by chiral vanadyl methoxide complexes bearing 3,5-disubstituted-N-salicylidene-t-leucinate templates. The effects of catalysts and solvents on the asymmetric induction were systematically examined. The best and complementary scenarios involved the use of vanadyl complexes V(O)-1 and V(O)-2, which bear 3-(2,5-dimethyl)phenyl-5-bromophenyl and 3-t-butyl-5-bromophenyl groups in an i-propanol solvent at ambient temperature. The corresponding (R)-cross-coupling products by V(O)-1 were obtained in 45–71% (for 2-substituted series) and 59–93% yields (for 1-substituted series) for p-/m-methylstyrenes and m-halo/CF₃/CO₂Me-styrenes in 38–63% ees (the best in 2-H case) and 60–84% ees (the best in 1-benzyl cases), respectively. The corresponding (S)-cross-coupling products by V(O)-2 were obtained in 28–55% (for 2-substituted series) and 45–72% yields (for 1-substituted series) for the same substrate class in 50–91% ees (85–91% ees in 2-phenyl cases) and 64–75% ees (up to 74–75% ees for each 1-H, Ph, and Bn cases), respectively. Theoretical calculations were carried out to explain the origin and extent of enantiocontrols. They both may serve as potential inhibitors of acetohydroxyacid synthase and epidermal growth factor receptor (EGFR) kinases. Full article

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26 pages, 2497 KiB

Open AccessArticle

Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease

by Sergey O. Bachurin, Elena F. Shevtsova, Galina F. Makhaeva, Alexey Yu. Aksinenko, Vladimir V. Grigoriev, Tatiana V. Goreva, Tatiana A. Epishina, Nadezhda V. Kovaleva, Natalia P. Boltneva, Sofya V. Lushchekina, Elena V. Rudakova, Darya V. Vinogradova, Pavel N. Shevtsov, Elena A. Pushkareva, Ludmila G. Dubova, Tatiana P. Serkova, Ivan M. Veselov, Vladimir P. Fisenko and Rudy J. Richardson

Int. J. Mol. Sci. 2022, 23(22), 13925; https://doi.org/10.3390/ijms232213925 - 11 Nov 2022

Cited by 7 | Viewed by 2044

Abstract

The development of multi-target-directed ligands (MTDLs) would provide effective therapy of neurodegenerative diseases (ND) with complex and nonclear pathogenesis. A promising method to create such potential drugs is combining neuroactive pharmacophoric groups acting on different biotargets involved in the pathogenesis of ND. We [...] Read more.

The development of multi-target-directed ligands (MTDLs) would provide effective therapy of neurodegenerative diseases (ND) with complex and nonclear pathogenesis. A promising method to create such potential drugs is combining neuroactive pharmacophoric groups acting on different biotargets involved in the pathogenesis of ND. We developed a synthetic algorithm for the conjugation of indole derivatives and methylene blue (MB), which are pharmacophoric ligands that act on the key stages of pathogenesis. We synthesized hybrid structures and performed a comprehensive screening for a specific set of biotargets participating in the pathogenesis of ND (i.e., cholinesterases, NMDA receptor, mitochondria, and microtubules assembly). The results of the screening study enabled us to find two lead compounds (4h and 4i) which effectively inhibited cholinesterases and bound to the AChE PAS, possessed antioxidant activity, and stimulated the assembly of microtubules. One of them (4i) exhibited activity as a ligand for the ifenprodil-specific site of the NMDA receptor. In addition, this lead compound was able to bypass the inhibition of complex I and prevent calcium-induced mitochondrial depolarization, suggesting a neuroprotective property that was confirmed using a cellular calcium overload model of neurodegeneration. Thus, these new MB-cycloalkaneindole conjugates constitute a promising class of compounds for the development of multitarget neuroprotective drugs which simultaneously act on several targets, thereby providing cognitive stimulating, neuroprotective, and disease-modifying effects. Full article

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14 pages, 1691 KiB

Open AccessArticle

Carborane-Containing Folic Acid bis-Amides: Synthesis and In Vitro Evaluation of Novel Promising Agents for Boron Delivery to Tumour Cells

by Dmitry A. Gruzdev, Angelina A. Telegina, Galina L. Levit, Olga I. Solovieva, Tatiana Ya. Gusel’nikova, Ivan A. Razumov, Victor P. Krasnov and Valery N. Charushin

Int. J. Mol. Sci. 2022, 23(22), 13726; https://doi.org/10.3390/ijms232213726 - 8 Nov 2022

Cited by 9 | Viewed by 2275

Abstract

The design of highly selective low-toxic, low-molecular weight agents for boron delivery to tumour cells is of decisive importance for the development of boron neutron capture therapy (BNCT), a modern efficient combined method for cancer treatment. In this work, we developed a simple [...] Read more.

The design of highly selective low-toxic, low-molecular weight agents for boron delivery to tumour cells is of decisive importance for the development of boron neutron capture therapy (BNCT), a modern efficient combined method for cancer treatment. In this work, we developed a simple method for the preparation of new closo- and nido-carborane-containing folic acid bis-amides containing 18–20 boron atoms per molecule. Folic acid derivatives containing nido-carborane residues were characterised by high water solubility, low cytotoxicity, and demonstrated a good ability to deliver boron to tumour cells in in vitro experiments (up to 7.0 µg B/10⁶ cells in the case of U87 MG human glioblastoma cells). The results obtained demonstrate the high potential of folic acid–nido-carborane conjugates as boron delivery agents to tumour cells for application in BNCT. Full article

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20 pages, 4234 KiB

Open AccessArticle

Diversity-Oriented Synthesis of a Molecular Library of Immunomodulatory α-Galactosylceramides with Fluorous-Tag-Assisted Purification and Evaluation of Their Bioactivities in Regard to IL-2 Secretion

by Yeng-Nan Chen, Jung-Tung Hung, Fan-Dan Jan, Yung-Yu Su, Jih-Ru Hwu, Alice L. Yu, Avijit K. Adak and Chun-Cheng Lin

Int. J. Mol. Sci. 2022, 23(21), 13403; https://doi.org/10.3390/ijms232113403 - 2 Nov 2022

Cited by 1 | Viewed by 1948

Abstract

Structural variants of α-galactosylceramide (α-GalCer) that stimulate invariant natural killer T (iNKT) cells constitute an emerging class of immunomodulatory agents in development for numerous biological applications. Variations in lipid chain length and/or fatty acids in these glycoceramides selectively trigger specific pro-inflammatory responses. Studies [...] Read more.

Structural variants of α-galactosylceramide (α-GalCer) that stimulate invariant natural killer T (iNKT) cells constitute an emerging class of immunomodulatory agents in development for numerous biological applications. Variations in lipid chain length and/or fatty acids in these glycoceramides selectively trigger specific pro-inflammatory responses. Studies that would link a specific function to a structurally distinct α-GalCer rely heavily on the availability of homogeneous and pure materials. To address this need, we report herein a general route to the diversification of the ceramide portion of α-GalCer glycolipids. Our convergent synthesis commences from common building blocks and relies on the Julia–Kocienski olefination as a key step. A cleavable fluorous tag is introduced at the non-reducing end of the sugar that facilitates quick purification of products by standard fluorous solid-phase extraction. The strategy enabled the rapid generation of a focused library of 61 α-GalCer analogs by efficiently assembling various lipids and fatty acids. Furthermore, when compared against parent α-GalCer in murine cells, many of these glycolipid variants were found to have iNKT cell stimulating activity similar to or greater than KRN7000. ELISA assaying indicated that glycolipids carrying short fatty N-acyl chains (1fc and 1ga), an unsubstituted (1fh and 1fi) or CF₃-substituted phenyl ring at the lipid tail, and a flexible, shorter fatty acyl chain with an aromatic ring (1ge, 1gf, and 1gg) strongly affected the activation of iNKT cells by the glycolipid-loaded antigen-presenting molecule, CD1d. This indicates that the method may benefit the design of structural modifications to potent iNKT cell-binding glycolipids. Full article

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19 pages, 1301 KiB

Open AccessArticle

Bis(Benzofuran–1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus

by Nitesh K. Gupta, Srinivasan Jayakumar, Wen-Chieh Huang, Pieter Leyssen, Johan Neyts, Sergey O. Bachurin, Jih Ru Hwu and Shwu-Chen Tsay

Int. J. Mol. Sci. 2022, 23(20), 12675; https://doi.org/10.3390/ijms232012675 - 21 Oct 2022

Cited by 3 | Viewed by 2721

Abstract

The yellow fever virus (YFV) is an emerging RNA virus and has caused large outbreaks in Africa and Central and South America. The virus is often transmitted through infected mosquitoes and spreads from area to area because of international travel. Being an acute [...] Read more.

The yellow fever virus (YFV) is an emerging RNA virus and has caused large outbreaks in Africa and Central and South America. The virus is often transmitted through infected mosquitoes and spreads from area to area because of international travel. Being an acute viral hemorrhagic disease, yellow fever can be prevented by an effective, safe, and reliable vaccine, but not be eliminated. Currently, there is no antiviral drug available for its cure. Thus, two series of novel bis(benzofuran–1,3-imidazolidin-4-one)s and bis(benzofuran–1,3-benzimidazole)s were designed and synthesized for the development of anti-YFV lead candidates. Among 23 new bis-conjugated compounds, 4 of them inhibited YFV strain 17D (Stamaril) on Huh-7 cells in the cytopathic effect reduction assays. These conjugates exhibited the most compelling efficacy and selectivity with an EC₅₀ of <3.54 μM and SI of >15.3. The results are valuable for the development of novel antiviral drug leads against emerging diseases. Full article

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17 pages, 5121 KiB

Open AccessArticle

Two Synthetic Peptides Corresponding to the Human Follicle-Stimulating Hormone β-Subunit Promoted Reproductive Functions in Mice

by Xingfa Han, Xinyu Bai, Huan Yao, Weihao Chen, Fengyan Meng, Xiaohan Cao, Yong Zhuo, Lun Hua, Guixian Bu, Xiaogang Du, Qiuxia Liang and Xianyin Zeng

Int. J. Mol. Sci. 2022, 23(19), 11735; https://doi.org/10.3390/ijms231911735 - 3 Oct 2022

Viewed by 2041

Abstract

A follicle stimulating hormone (FSH) is widely used in the assisted reproduction and a synthetic peptide corresponding to a receptor binding region of the human (h) FSH-β-(34–37) (TRDL) modulated reproduction. Furthermore, a 13-amino acid sequence corresponding to hFSH-β-(37–49) (LVYKDPARPKIQK) was recently identified as [...] Read more.

A follicle stimulating hormone (FSH) is widely used in the assisted reproduction and a synthetic peptide corresponding to a receptor binding region of the human (h) FSH-β-(34–37) (TRDL) modulated reproduction. Furthermore, a 13-amino acid sequence corresponding to hFSH-β-(37–49) (LVYKDPARPKIQK) was recently identified as the receptor binding site. We hypothesized that the synthetic peptides corresponding to hFSH-β-(37–49) and hFSH-β-(34–49), created by merging hFSH-β-(34–37) and hFSH-β-(37–49), modulate the reproductive functions, with the longer peptide being more biologically active. In male or female prepubertal mice, a single injection of 200 μg/g BW ip of hFSH-β-(37–49) or hFSH-β-(34–49) hastened (p < 0.05) puberty, whereas the same treatments given daily for 4 d promoted (p < 0.05) the gonadal steroidogenesis and gamete formation. In addition of either peptide to the in vitro cell cultures, promoted (p < 0.05) the proliferation of primary murine granulosa cells and the estradiol production by upregulating the expression of Ccnd2 and Cyp19a1, respectively. In adult female mice, 200 μg/g BW ip of either peptide during diestrus antagonized the FSH-stimulated estradiol increase and uterine weight gain during proestrus. Furthermore, hFSH-β-(34–49) was a more potent (p < 0.05) reproductive modulator than hFSH-β-(37–49), both in vivo and in vitro. We concluded that hFSH-β-(37–49) and especially hFSH-β-(34–49), have the potential for reproductive modulation. Full article

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14 pages, 2711 KiB

Open AccessArticle

Magnetic-Responsive Doxorubicin-Containing Materials Based on Fe₃O₄ Nanoparticles with a SiO₂/PEG Shell and Study of Their Effects on Cancer Cell Lines

by Alexander M. Demin, Alexander V. Vakhrushev, Alexandra G. Pershina, Marina S. Valova, Lina V. Efimova, Alexandra A. Syomchina, Mikhail A. Uimin, Artem S. Minin, Galina L. Levit, Victor P. Krasnov and Valery N. Charushin

Int. J. Mol. Sci. 2022, 23(16), 9093; https://doi.org/10.3390/ijms23169093 - 13 Aug 2022

Cited by 16 | Viewed by 2863

Abstract

Novel nanocomposite materials based on Fe₃O₄ magnetic nanoparticles (MNPs) coated with silica and covalently modified by [(3-triethoxysilyl)propyl]succinic acid–polyethylene glycol (PEG 3000) conjugate, which provides a high level of doxorubicin (Dox) loading, were obtained. The efficiency of Dox desorption from the [...] Read more.

Novel nanocomposite materials based on Fe₃O₄ magnetic nanoparticles (MNPs) coated with silica and covalently modified by [(3-triethoxysilyl)propyl]succinic acid–polyethylene glycol (PEG 3000) conjugate, which provides a high level of doxorubicin (Dox) loading, were obtained. The efficiency of Dox desorption from the surface of nanomaterials under the action of an alternating magnetic field (AMF) in acidic and neutral media was evaluated. Their high cytotoxicity against tumor cells, as well as the drug release upon application of AMF, which leads to an increase in the cytotoxic effect, was demonstrated. Full article

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42 pages, 16320 KiB

Open AccessReview

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

by Oluwakemi Ebenezer, Maryam Amra. Jordaan, Gea Carena, Tommaso Bono, Michael Shapi and Jack A. Tuszynski

Int. J. Mol. Sci. 2022, 23(15), 8117; https://doi.org/10.3390/ijms23158117 - 23 Jul 2022

Cited by 49 | Viewed by 5066

Abstract

Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This [...] Read more.

Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This has made them an indispensable motif in the drug discovery field. Heterocyclic compounds are usually classified according to the ring size, type, and the number of heteroatoms present in the ring. Among different heterocyclic ring systems, nitrogen heterocyclic compounds are more abundant in nature. They also have considerable pharmacological significance. This review highlights recent pioneering studies in the biological assessment of nitrogen-containing compounds, namely: triazoles, tetrazoles, imidazole/benzimidazoles, pyrimidines, and quinolines. It explores publications between April 2020 and February 2022 and will benefit researchers in medicinal chemistry and pharmacology. The present work is organized based on the size of the heterocyclic ring. Full article

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20 pages, 3103 KiB

Open AccessArticle

Computer-Aided Design and Synthesis of (Functionalized quinazoline)–(α-substituted coumarin)–arylsulfonate Conjugates against Chikungunya Virus

by Jih Ru Hwu, Animesh Roy, Shwu-Chen Tsay, Wen-Chieh Huang, Chun-Cheng Lin, Kuo Chu Hwang, Yu-Chen Hu, Fa-Kuen Shieh, Pieter Leyssen and Johan Neyts

Int. J. Mol. Sci. 2022, 23(14), 7646; https://doi.org/10.3390/ijms23147646 - 11 Jul 2022

Cited by 1 | Viewed by 1964

Abstract

Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could [...] Read more.

Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the β carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazolinone moiety exhibited potency with EC₅₀ = 6.46 μM, low toxicity with CC₅₀ = 59.7 μM, and the selective index (SI) = 9.24. Furthermore, the corresponding 4-anilinoquinazoline derivative improved the anti-CHIKV potency to EC₅₀ = 3.84 μM, CC₅₀ = 72.3 μM, and SI = 18.8. The conjugate with 4-anilinoquinazoline exhibited stronger binding affinity towards the macro domain than that with quinazolinone via hydrophobic and hydrogen bond interactions. Full article

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