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21 pages, 4077 KiB

Open AccessArticle

Accessing Promising Passerini Adducts in Anticancer Drug Design

by Ana Margarida Janeiro, Aday González-Bakker, José M. Padrón and Carolina S. Marques

Molecules 2024, 29(23), 5538; https://doi.org/10.3390/molecules29235538 - 23 Nov 2024

Viewed by 1091

Abstract

The 3-component Passerini reaction (3CPR), discovered little more than 100 years ago, has been demonstrated in the last few decades to be a valuable tool for accessing structural diversity and complexity, essential topics to consider in drug discovery programs. Focusing on accessing a [...] Read more.

The 3-component Passerini reaction (3CPR), discovered little more than 100 years ago, has been demonstrated in the last few decades to be a valuable tool for accessing structural diversity and complexity, essential topics to consider in drug discovery programs. Focusing on accessing a fine-tuned family of α-acyloxyamide–oxindole hybrids, we underline herein our latest insights regarding the use of this mild reaction approach to obtain promising anticancer agents. Cheap and commercially available isatin was used as starting material. The library of α-acyloxyamide–oxindole hybrids was tested against six human solid-tumor cell lines; among them, non-small cell lung carcinoma, cervical and colon adenocarcinoma, and breast and pancreas cancer. The most potent compound displayed GI₅₀ values in the range of 1.3–21 µM. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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13 pages, 1104 KiB

Open AccessArticle

Stereoselective Total Synthesis of Natural Decanolides Bellidisin C and Pinolidoxin

by Jingjing Bi, Minhao Chen, Pengpeng Nie, Yuanfang Liu, Jun Liu and Yuguo Du

Molecules 2024, 29(23), 5500; https://doi.org/10.3390/molecules29235500 - 21 Nov 2024

Viewed by 678

Abstract

A divergent total synthesis of bioactive, naturally occurring decanolides, pinolidoxin and bellidisin C, was accomplished by taking advantage of chiral templates L-ribose and L-malic acid. In particular, bellidisin C, which is the first total synthesis so far, was achieved through a [...] Read more.

A divergent total synthesis of bioactive, naturally occurring decanolides, pinolidoxin and bellidisin C, was accomplished by taking advantage of chiral templates L-ribose and L-malic acid. In particular, bellidisin C, which is the first total synthesis so far, was achieved through a cascade reaction of reductive elimination and nucleophilic addition in a one-pot process and a sodium–alkoxide-promoted intramolecular lactonization as the key steps. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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23 pages, 6688 KiB

Open AccessArticle

1,2,4-Oxadiazole Derivatives: Physicochemical Properties, Antileishmanial Potential, Docking and Molecular Dynamic Simulations of Leishmania infantum Target Proteins

by Deyzi C. S. Barbosa, Vanderlan N. Holanda, Elton M. A. Lima, Marton K. A. Cavalcante, Maria Carolina A. Brelaz-de-Castro, Elton J. F. Chaves, Gerd B. Rocha, Carla J. O. Silva, Ronaldo N. Oliveira and Regina C. B. Q. Figueiredo

Molecules 2024, 29(19), 4654; https://doi.org/10.3390/molecules29194654 - 30 Sep 2024

Cited by 1 | Viewed by 1845

Abstract

Visceral leishmaniasis (VL), caused by protozoa of the genus Leishmania, remains a significant public health concern due to its potentially lethal nature if untreated. Current chemotherapy options are limited by severe toxicity and drug resistance. Derivatives of 1,2,4-oxadiazole have emerged as promising [...] Read more.

Visceral leishmaniasis (VL), caused by protozoa of the genus Leishmania, remains a significant public health concern due to its potentially lethal nature if untreated. Current chemotherapy options are limited by severe toxicity and drug resistance. Derivatives of 1,2,4-oxadiazole have emerged as promising drug candidates due to their broad biological activity. This study investigated the effects of novel 1,2,4-oxadiazole derivatives (Ox1–Ox7) on Leishmania infantum, the etiological agent of VL. In silico predictions using SwissADME suggest that these compounds have high oral absorption and good bioavailability. Among them, Ox1 showed the most promise, with higher selectivity against promastigotes and lower cytotoxicity towards L929 fibroblasts and J774.G8 macrophages. Ox1 exhibited selectivity indices of 18.7 and 61.7 against L. infantum promastigotes and amastigotes, respectively, compared to peritoneal macrophages. Ultrastructural analyses revealed severe morphological damage in both parasite forms, leading to cell death. Additionally, Ox1 decreased the mitochondrial membrane potential in promastigotes, as shown by flow cytometry. Molecular docking and dynamic simulations indicated a strong affinity of Ox1 for the L. infantum CYP51 enzyme. Overall, Ox1 is a promising and effective compound against L. infantum. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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14 pages, 4387 KiB

Open AccessArticle

Pilose Antler Protein Relieves UVB-Induced HaCaT Cells and Skin Damage

by Kaiyue Liu, Chenxu Zhao, Ke Zhang, Xiaoyue Yang, Ruyi Feng, Ying Zong, Zhongmei He, Yan Zhao and Rui Du

Molecules 2024, 29(17), 4060; https://doi.org/10.3390/molecules29174060 - 27 Aug 2024

Cited by 3 | Viewed by 1846

Abstract

Extended exposure to UVB (280–315 nm) radiation results in oxidative damage and inflammation of the skin. Previous research has demonstrated that pilose antler extracts have strong anti-inflammatory properties and possess antioxidant effects. This study aimed to elucidate the mechanism of pilose antler protein in [...] Read more.

Extended exposure to UVB (280–315 nm) radiation results in oxidative damage and inflammation of the skin. Previous research has demonstrated that pilose antler extracts have strong anti-inflammatory properties and possess antioxidant effects. This study aimed to elucidate the mechanism of pilose antler protein in repairing photodamage caused by UVB radiation in HaCaT cells and ICR mice. Pilose antler protein (PAP) was found to increase the expression of type I collagen and hyaluronic acid in HaCaT cells under UVB irradiation while also inhibiting reactive oxygen species (ROS) production and oxidative stress in vitro. In vivo, the topical application of pilose antler protein effectively attenuated UVB-induced skin damage in ICR mice by reducing interleukin-1β (IL-β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and inhibiting skin inflammation while alleviating UVB-induced oxidative stress. It was shown that pilose antler protein repaired UVB-induced photodamage through the MAPK and TGF-β/Smad pathways. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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15 pages, 3785 KiB

Open AccessArticle

Molecular Docking-Based Virtual Screening of FDA-Approved Drugs Using Trypanothione Reductase Identified New Trypanocidal Agents

by Rogelio Gómez-Escobedo, Domingo Méndez-Álvarez, Citlali Vázquez, Emma Saavedra, Karina Vázquez, Verónica Alcántara-Farfán, Joaquín Cordero-Martínez, Alonzo Gonzalez-Gonzalez, Gildardo Rivera and Benjamín Nogueda-Torres

Molecules 2024, 29(16), 3796; https://doi.org/10.3390/molecules29163796 - 10 Aug 2024

Cited by 1 | Viewed by 1898

Abstract

American trypanosomiasis or Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects approximately 6–7 million people worldwide. However, its pharmacological treatment causes several uncomfortable side effects, causing patients’ treatment abandonment. Therefore, there is a need for new and better treatments. In [...] Read more.

American trypanosomiasis or Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects approximately 6–7 million people worldwide. However, its pharmacological treatment causes several uncomfortable side effects, causing patients’ treatment abandonment. Therefore, there is a need for new and better treatments. In this work, the molecular docking of nine hundred twenty-four FDA-approved drugs on three different sites of trypanothione reductase of T. cruzi (TcTR) was carried out to find potential trypanocidal agents. Finally, biological evaluations in vitro and in vivo were conducted with the selected FDA-approved drugs. Digoxin, alendronate, flucytosine, and dihydroergotamine showed better trypanocidal activity than the reference drugs benznidazole and nifurtimox in the in vitro evaluation against the trypomastigotes form. Further, these FDA-approved drugs were able to reduce 20–50% parasitemia in a short time in an in vivo model, although with less efficiency than benznidazole. Therefore, the results suggest a combined therapy of repurposed and canonical drugs against T. cruzi infection. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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13 pages, 7539 KiB

Open AccessArticle

N-(2-Hydroxyphenyl)-2-Propylpentanamide (HO-AAVPA) Induces Apoptosis and Cell Cycle Arrest in Breast Cancer Cells, Decreasing GPER Expression

by Berenice Prestegui Martel, Alma Delia Chávez-Blanco, Guadalupe Domínguez-Gómez, Alfonso Dueñas González, Patricia Gaona-Aguas, Raúl Flores-Mejía, Selma Alin Somilleda-Ventura, Octavio Rodríguez-Cortes, Rocío Morales-Bárcena, Alberto Martínez Muñoz, Cesar Miguel Mejia Barradas, Jessica Elena Mendieta Wejebe and José Correa Basurto

Molecules 2024, 29(15), 3509; https://doi.org/10.3390/molecules29153509 - 26 Jul 2024

Viewed by 1664

Abstract

In this work, we performed anti-proliferative assays for the compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) on breast cancer (BC) cells (MCF-7, SKBR3, and triple-negative BC (TNBC) MDA-MB-231 cells) to explore its pharmacological mechanism regarding the type of cell death associated with G protein-coupled estrogen receptor [...] Read more.

In this work, we performed anti-proliferative assays for the compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) on breast cancer (BC) cells (MCF-7, SKBR3, and triple-negative BC (TNBC) MDA-MB-231 cells) to explore its pharmacological mechanism regarding the type of cell death associated with G protein-coupled estrogen receptor (GPER) expression. The results show that HO-AAVPA induces cell apoptosis at 5 h or 48 h in either estrogen-dependent (MCF-7) or -independent BC cells (SKBR3 and MDA-MB-231). At 5 h, the apoptosis rate for MCF-7 cells was 68.4% and that for MDA-MB-231 cells was 56.1%; at 48 h, that for SKBR3 was 61.6%, that for MCF-7 cells was 54.9%, and that for MDA-MB-231 (TNBC) was 43.1%. HO-AAVPA increased the S phase in MCF-7 cells and reduced the G2/M phase in MCF-7 and MDA-MB-231 cells. GPER expression decreased more than VPA in the presence of HO-AAVPA. In conclusion, the effects of HO-AAVPA on cell apoptosis could be modulated by epigenetic effects through a decrease in GPER expression. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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17 pages, 2831 KiB

Open AccessArticle

Molecular Hybrid Design, Synthesis, In Vitro Cytotoxicity, In Silico ADME and Molecular Docking Studies of New Benzoate Ester-Linked Arylsulfonyl Hydrazones

by Erdem Ergan, Reşit Çakmak, Eyüp Başaran, Suraj N. Mali, Senem Akkoc and Sivakumar Annadurai

Molecules 2024, 29(15), 3478; https://doi.org/10.3390/molecules29153478 - 25 Jul 2024

Cited by 4 | Viewed by 1668

Abstract

In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9–20), as well as in vitro and in silico investigations of their cytotoxic properties [...] Read more.

In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9–20), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds (9–20) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, ¹H-, and ¹³C-NMR. The antiproliferative profiles of these compounds (1, 2, and 9–20) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2, other compounds (9–20) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds (9–20) demonstrated antiproliferative activities at a micromolar level, with IC₅₀ values in the range of 29.59–176.70 μM for the A549 cell line and 27.70–170.30 μM for the MCF-7 cell line. Among these compounds, compound 15 (IC₅₀ = 29.59 μM against A549 cell line and IC₅₀ = 27.70 μM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC₅₀ = 22.42 μM against A549 cell line and IC₅₀ = 18.01 μM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (−6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski’s rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood–brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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18 pages, 1838 KiB

Open AccessArticle

Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi

by Mauricio Moncada-Basualto, Jorge Saavedra-Olavarría, Paula S. Rivero-Jerez, Cristian Rojas, Juan D. Maya, Ana Liempi, Matías Zúñiga-Bustos, Claudio Olea-Azar, Michel Lapier, Edwin G. Pérez and Josué Pozo-Martínez

Molecules 2024, 29(12), 2762; https://doi.org/10.3390/molecules29122762 - 11 Jun 2024

Cited by 2 | Viewed by 1397

Abstract

The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds’ lipophilicity, [...] Read more.

The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds’ lipophilicity, affecting their ability to fight trypanosomes. The results indicate that these compounds are more effective against the epimastigote form of T. cruzi, with a 52 ± 4% trypanocidal effect for compound 9. However, they are less effective against the trypomastigote form, with a 15 ± 3% trypanocidal effect. Additionally, compound 11 interacts with a higher number of amino acid residues within the active site of the enzyme cruzipain. Furthermore, it was also found that the presence of a nitro group allows for the generation of free radicals; likewise, the large size of the compound enables increased interaction with aminoacidic residues in the active site of cruzipain, contributing to trypanocidal activity. This activity depends on the size and lipophilicity of the compounds. The study recommends exploring new compounds based on the nitroisoxazole skeleton, with larger substituents and lipophilicity to enhance their trypanocidal activity. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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18 pages, 5619 KiB

Open AccessArticle

Imidazole Carbamates as a Promising Alternative for Treating Trichomoniasis: In Vitro Effects on the Growth and Gene Expression of Trichomonas vaginalis

by Víctor Martínez-Rosas, Gabriel Navarrete-Vázquez, Daniel Ortega-Cuellar, Roberto Arreguin-Espinosa, Verónica Pérez de la Cruz, Ernesto Calderón-Jaimes, Sergio Enríquez-Flores, Carlos Wong-Baeza, Isabel Baeza-Ramírez, Laura Morales-Luna, Montserrat Vázquez-Bautista, Miriam Abigail Rojas-Alarcón, Beatriz Hernández-Ochoa and Saúl Gómez-Manzo

Molecules 2024, 29(11), 2585; https://doi.org/10.3390/molecules29112585 - 31 May 2024

Cited by 1 | Viewed by 1522

Abstract

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new [...] Read more.

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC₅₀ value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC₅₀ values in the nanomolar range and AGR-2 being the most potent (IC₅₀ 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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11 pages, 578 KiB

Open AccessArticle

Antimalarial Activity of Aqueous Extracts of Nasturtium (Tropaeolum majus L.) and Benzyl Isothiocyanate

by Ana Maria Pintão, Tiago Santos and Fátima Nogueira

Molecules 2024, 29(10), 2316; https://doi.org/10.3390/molecules29102316 - 15 May 2024

Viewed by 1419

Abstract

Malaria remains an important and challenging infectious disease, and novel antimalarials are required. Benzyl isothiocyanate (BITC), the main breakdown product of benzyl glucosinolate, is present in all parts of Tropaeolum majus L. (T. majus) and has antibacterial and antiparasitic activities. To [...] Read more.

Malaria remains an important and challenging infectious disease, and novel antimalarials are required. Benzyl isothiocyanate (BITC), the main breakdown product of benzyl glucosinolate, is present in all parts of Tropaeolum majus L. (T. majus) and has antibacterial and antiparasitic activities. To our knowledge, there is no information on the effects of BITC against malaria. The present study evaluates the antimalarial activity of aqueous extracts of BITC and T. majus seeds, leaves, and stems. We used flow cytometry to calculate the growth inhibition (GI) percentage of the extracts and BITC against unsynchronized cultures of the chloroquine-susceptible Plasmodium falciparum 3D7 − GFP strain. Extracts and/or compounds with at least 70% GI were validated by IC50 estimation against P. falciparum 3D7 − GFP and Dd2 (chloroquine-resistant strain) unsynchronized cultures by flow cytometry, and the resistance index (RI) was determined. T. majus aqueous extracts showed some antimalarial activity that was higher in seeds than in leaves or stems. BITC’s GI was comparable to chloroquine’s. BITC’s IC50 was similar in both strains; thus, a cross-resistance absence with aminoquinolines was found (RI < 1). BITC presented features that could open new avenues for malaria drug discovery. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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27 pages, 12535 KiB

Open AccessArticle

Anticancer Effects of Abietane Diterpene 7α-Acetoxy-6β-hydroxyroyleanone from Plectranthus grandidentatus and Its Semi-Synthetic Analogs: An In Silico Computational Approach

by Vera M. S. Isca, Przemysław Sitarek, Anna Merecz-Sadowska, Magdalena Małecka, Monika Owczarek, Joanna Wieczfińska, Radosław Zajdel, Paweł Nowak, Patricia Rijo and Tomasz Kowalczyk

Molecules 2024, 29(8), 1807; https://doi.org/10.3390/molecules29081807 - 16 Apr 2024

Cited by 2 | Viewed by 1845

Abstract

The abietane diterpenoid 7α-acetoxy-6β-hydroxyroyleanone (Roy) isolated from Plectranthus grandidentatus demonstrates cytotoxicity across numerous cancer cell lines. To potentiate anticancer attributes, a series of semi-synthetic Roy derivatives were generated and examined computationally. ADMET predictions were used to evaluate drug-likeness and toxicity risks. The antineoplastic [...] Read more.

The abietane diterpenoid 7α-acetoxy-6β-hydroxyroyleanone (Roy) isolated from Plectranthus grandidentatus demonstrates cytotoxicity across numerous cancer cell lines. To potentiate anticancer attributes, a series of semi-synthetic Roy derivatives were generated and examined computationally. ADMET predictions were used to evaluate drug-likeness and toxicity risks. The antineoplastic potential was quantified by PASS. The DFT models were used to assess their reactivity and stability. Molecular docking determined cancer-related protein binding. MS simulations examined ligand–protein stability. Additionally, network pharmacology was used to identify potential targets and signaling pathways. Favorable ADME attributes and acceptable toxicity profiles were determined for all compounds. Strong anticancer potential was shown across derivatives (Pa 0.819–0.879). Strategic modifications altered HOMO–LUMO gaps (3.39–3.79 eV) and global reactivity indices. Favorable binding was revealed against cyclin-dependent kinases, BCL-2, caspases, receptor tyrosine kinases, and p53. The ligand exhibited a stable binding pose in MD simulations. Network analysis revealed involvement in cancer-related pathways. In silico evaluations predicted Roy and derivatives as effective molecules with anticancer properties. Experimental progress is warranted to realize their chemotherapeutic potential. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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20 pages, 6399 KiB

Open AccessArticle

Discovery of a 4-Hydroxy-3′-Trifluoromethoxy-Substituted Resveratrol Derivative as an Anti-Aging Agent

by Yinhu Liang, Xi Chen, Zhifeng Teng, Xuekun Wang, Jie Yang and Guoyun Liu

Molecules 2024, 29(1), 86; https://doi.org/10.3390/molecules29010086 - 22 Dec 2023

Cited by 3 | Viewed by 1868

Abstract

With the intensification of population aging, aging-related diseases are attracting more and more attention, thus, the study of aging mechanisms and anti-aging drugs is becoming increasingly urgent. Resveratrol is a potential candidate as an anti-aging agent, but its low bioavailability limits its application [...] Read more.

With the intensification of population aging, aging-related diseases are attracting more and more attention, thus, the study of aging mechanisms and anti-aging drugs is becoming increasingly urgent. Resveratrol is a potential candidate as an anti-aging agent, but its low bioavailability limits its application in vivo. In this work, a 4-hydroxy-3′-trifluoromethoxy-substituted resveratrol derivative (4–6), owing to its superior cell accumulation, could inhibit NO production in an inflammatory cell model, inhibit oxidative cytotoxicity, and reduce ROS accumulation and the population of apoptotic cells in an oxidative stress cell model. In D-galactose (D-gal)-stimulated aging mice, 4–6 could reverse liver and kidney damage; protect the serum, brain, and liver against oxidative stress; and increase the body’s immunity in the spleen. Further D-gal-induced brain aging studies showed that 4–6 could improve the pathological changes in the hippocampus and the dysfunction of the cholinergic system. Moreover, protein expression related to aging, oxidative stress, and apoptosis in the brain tissue homogenate measured via Western blotting also showed that 4–6 could ameliorate brain aging by protecting against oxidative stress and reducing apoptosis. This work revealed that meta-trifluoromethoxy substituted 4–6 deserved to be further investigated as an effective anti-aging candidate drug. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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15 pages, 1222 KiB

Open AccessArticle

Total Synthesis of Nicrophorusamide A and Structural Disproof of the Proposed Noursamycin A

by Xiaoyun Liao, Shupeng Li, Yian Guo and Tao Ye

Molecules 2023, 28(21), 7442; https://doi.org/10.3390/molecules28217442 - 6 Nov 2023

Cited by 2 | Viewed by 2037

Abstract

Total synthesis of the proposed noursamycin A has been accomplished, which disproves the original structural assignments. The synthetic strategy described herein has also been employed in the first total synthesis of nicrophorusamide A, a cyclopeptide that is structurally related to noursamycin A. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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10 pages, 2298 KiB

Open AccessArticle

Design, Synthesis and Biological Evaluation of Novel PEG-Rakicidin B1 Hybrid as Clostridium difficile (CD) Targeted Anti-Bacterial Agent

by Lijun Xie, Li Chen, Yongbo Wei, Nannan Chen, Tong Wu, Jingming Zhou, Hong Jiang and Feng Lin

Molecules 2023, 28(16), 6152; https://doi.org/10.3390/molecules28166152 - 21 Aug 2023

Viewed by 1702

Abstract

Rakicidin B1 was isolated and purified from the culture broth of a marine Streptomyces sp. as a potent anti-cancer agent, and lately the compound and its derivatives have firstly been found to possess anti-Clostridium difficile (CD) activity but with high cytotoxicity. Herein, [...] Read more.

Rakicidin B1 was isolated and purified from the culture broth of a marine Streptomyces sp. as a potent anti-cancer agent, and lately the compound and its derivatives have firstly been found to possess anti-Clostridium difficile (CD) activity but with high cytotoxicity. Herein, following our previous discovery on anti-CD activity of Rakicidin B1, structure modification was performed at the OH position of Rakicidin B1 and a new Rakicidin B1-PEG hybrids FIMP2 was facilely designed and synthesized by conjugating the PEG2000 with the scaffolds of Rakicidin B1 via the linkage of carbamate. The cytotoxicity of the FIMP2 was first evaluated against three different cancer cell lines, including HCT-8 cells, PANC-1, and Caco-2, with IC₅₀ values at 0.519 μM, 0.815 μM, and 0.586 μM, respectively. Obviously, as compared with a positive control group treated with Rakicidin B1, the IC₅₀ value of FIMP2 increased by nearly 91-fold, 50-fold, and 67-fold, suggesting that the PEGylation strategy significantly reduced the cytotoxicity of FIMP2. Thus, this preliminary result may be beneficial to increase its safety index (SI) value due to the decreased cytotoxicity of FIMP2. In addition, this decreased cytotoxicity of FIMP2 was further confirmed based on a zebrafish screening model in vivo. Thereafter, the anti-CD activity of FIMP2 was evaluated in vivo, and its efficacy to treat CDI was found to be better than that of vancomycin. The mortality and recurrence rate of FIMP2 is not as low compared with that of vancomycin; these results demonstrated that compound FIMP2 is a new, promising anti-CD agent with significant efficacy against CD recurrence with low cytotoxicity towards bodies. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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Review

Jump to: Research

22 pages, 919 KiB

Open AccessReview

Vitamin K Properties in Stroke and Alzheimer’s Disease: A Janus Bifrons in Protection and Prevention

by Lorenzo Grimaldi, Rosaria A. Cavallaro, Domenico De Angelis, Andrea Fuso and Giulia Sancesario

Molecules 2025, 30(5), 1027; https://doi.org/10.3390/molecules30051027 - 24 Feb 2025

Viewed by 1628

Abstract

Vitamin K is essential for many physiological processes, including coagulation, bone metabolism, tissue calcification, and antioxidant activity. Vitamin K vitamers are represented by lipophilic compounds with similar chemical structure (i.e., phylloquinone (vitamin K1) and menaquinone (vitamin K2)). Vitamin K deficiency can affect coagulation [...] Read more.

Vitamin K is essential for many physiological processes, including coagulation, bone metabolism, tissue calcification, and antioxidant activity. Vitamin K vitamers are represented by lipophilic compounds with similar chemical structure (i.e., phylloquinone (vitamin K1) and menaquinone (vitamin K2)). Vitamin K deficiency can affect coagulation and vascular calcification, increasing the risk of hemorrhages, atherosclerosis, cerebrovascular diseases, and neurodegeneration. Recently, several studies have hypothesized a possible dual role of vitamin K vitamers in benefiting both vascular and cerebral health, e.g., by sphingolipids biosynthesis or ferroptosis inhibition. The aim of this narrative review is to deepen the understanding of biological activities of vitamin K and its possible dual protective/preventive actions in neurovascular and degenerative conditions, e.g., stroke and dementia. Given the difficulties related to hemorrhagic risk entailed in the prevention of strokes, the function of vitamin K antagonists is also investigated. Finally, we track the development of a clinical concept for a future preventive strategy and innovative use of vitamin K as a supplement to counteract neurovascular and pathological processes, focusing in particular on stroke and dementia. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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49 pages, 18308 KiB

Open AccessReview

Targeting Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2): Latest Insights on Synthetic Strategies

by Carolina S. Marques, Pedro Brandão and Anthony J. Burke

Molecules 2024, 29(22), 5341; https://doi.org/10.3390/molecules29225341 - 13 Nov 2024

Cited by 1 | Viewed by 2125

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a crucial mediator of angiogenesis, playing a pivotal role in both normal physiological processes and cancer progression. Tumors harness VEGFR-2 signaling to promote abnormal blood vessel growth, which is a key step in the metastasis [...] Read more.

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a crucial mediator of angiogenesis, playing a pivotal role in both normal physiological processes and cancer progression. Tumors harness VEGFR-2 signaling to promote abnormal blood vessel growth, which is a key step in the metastasis process, making it a valuable target for anticancer drug development. While there are VEGFR-2 inhibitors approved for therapeutic use, they face challenges like drug resistance, off-target effects, and adverse side effects, limiting their effectiveness. The quest for new drug candidates with VEGFR-2 inhibitory activity often starts with the selection of key structural motifs present in molecules currently used in clinical practice, expanding the chemical space by generating novel derivatives bearing one or more of these moieties. This review provides an overview of recent advances in the development of novel VEGFR-2 inhibitors, focusing on the synthesis of new drug candidates with promising antiproliferative and VEGFR-2 inhibition activities, organizing them by relevant structural features. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates)

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The Design, Synthesis, and Biological Activity of New Drug Candidates

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