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17 pages, 4980 KiB

Open AccessArticle

Synthesis, Evaluation of Biological Activity, and Structure–Activity Relationships of New Amidrazone Derivatives Containing Cyclohex-1-ene-1-Carboxylic Acid

by Renata Paprocka, Jolanta Kutkowska, Ewelina Paczkowska, Godwin Munroe Mwaura, Andrzej Eljaszewicz and Anna Helmin-Basa

Molecules 2025, 30(8), 1853; https://doi.org/10.3390/molecules30081853 - 21 Apr 2025

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Abstract

In recent years, the incidence of acute and chronic inflammatory diseases has increased significantly worldwide, intensifying the search for new therapeutic agents, especially anti-inflammatory drugs. Therefore, the aim of this work was to synthesize, biologically assess, and explore the structure–activity relationships of new [...] Read more.

In recent years, the incidence of acute and chronic inflammatory diseases has increased significantly worldwide, intensifying the search for new therapeutic agents, especially anti-inflammatory drugs. Therefore, the aim of this work was to synthesize, biologically assess, and explore the structure–activity relationships of new compounds containing the cyclohex-1-ene-1-carboxylic acid moiety. Six new derivatives, 2a–2f, were synthesized through the reaction of amidrazones 1a–1f with 3,4,5,6-tetrahydrophthalic anhydride. Their toxicity was evaluated in cultures of human peripheral blood mononuclear cells (PBMCs). Additionally, their antiproliferative properties and effects on the synthesis of TNF-α, IL-6, IL-10, and IL-1β were assessed in mitogen-stimulated PBMCs. The antimicrobial activity of derivatives 2a–2f was determined by measuring the minimal inhibitory concentration (MIC) values against five bacterial strains—Staphylococcus aureus, Mycobacterium smegmatis, Escherichia coli, Yersinia enterocolitica, and Klebsiella pneumoniae—and the fungal strain Candida albicans. All compounds demonstrated antiproliferative activity, with derivatives 2a, 2d, and 2f at a concentration of 100 µg/mL being more effective than ibuprofen. Compound 2f strongly inhibited the secretion of TNF-α by approximately 66–81% at all studied doses (10, 50, and 100 µg/mL). Derivative 2b significantly reduced the release of cytokines, including TNF-α, IL-6, and IL-10, at a high dose (by approximately 92–99%). Compound 2c exhibited bacteriostatic activity against S. aureus and M. smegmatis, while derivative 2b selectively inhibited the growth of Y. enterocolitica (MIC = 64 µg/mL). Some structure–activity relationships were established for the studied compounds. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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26 pages, 5048 KiB

Open AccessArticle

Anticancer Activity and Safety Profile of Novel 1-(4-Fluorophenoxyacetyl)-4-substituted Thio/Semicarbazide Derivatives

by Paweł Kozyra, Ewelina Humeniuk, Zbigniew Karczmarzyk, Adrian Borzęcki, Grzegorz Adamczuk, Agnieszka Korga-Plewko, Waldemar Wysocki and Monika Pitucha

Molecules 2025, 30(7), 1576; https://doi.org/10.3390/molecules30071576 - 31 Mar 2025

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Abstract

Compounds with thiosemicarbazide and semicarbazide scaffolds are among the most promising structures in medicinal chemistry due to the possibility of forming multiple hydrogen bonds. Therefore, six new derivatives of 4-fluorophenoxyacetylthiosemicarbazide and 4-fluorophenoxyacetylthiosemicarbazide were designed to compare their physicochemical properties, biological activity, and in [...] Read more.

Compounds with thiosemicarbazide and semicarbazide scaffolds are among the most promising structures in medicinal chemistry due to the possibility of forming multiple hydrogen bonds. Therefore, six new derivatives of 4-fluorophenoxyacetylthiosemicarbazide and 4-fluorophenoxyacetylthiosemicarbazide were designed to compare their physicochemical properties, biological activity, and in silico pharmacokinetic parameters. All compounds were characterized by ¹H, ¹³C NMR, ¹⁹F, IR spectra. For selected derivatives (AB2 and AB5), X-ray studies were performed to confirm their synthetic route and identify the tautomeric forms and intra- and intermolecular interactions occurring in the crystalline state. In the in silico pharmacokinetic study, a clear difference in lipophilicity was observed between thiosemicarbazide and semicarbazide derivatives. In vitro biological studies have shown the promising activity of thiosemicarbazides against prostate cancer cell line LNCaP, with a higher safety profile than semicarbazides. The most active compound AB2 showed IC₅₀ = 108.14 μM against LNCaP. Based on biological studies, topoisomerase IIα was proposed as a potential molecular target, which was confirmed by molecular docking studies. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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19 pages, 3367 KiB

Open AccessArticle

Differentiation of Isomeric TAT1-CARNOSINE Peptides by Energy-Resolved Mass Spectrometry and Principal Component Analysis

by Alicia Maroto, Olivier Briand, Alessia Distefano, Filiz Arioz, Olivier Monasson, Elisa Peroni, Giuseppe Grasso, Christine Enjalbal and Antony Memboeuf

Molecules 2025, 30(4), 853; https://doi.org/10.3390/molecules30040853 - 12 Feb 2025

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Abstract

L-carnosine (Car) is an endogenous dipeptide with significant potential in drug discovery for neurodegenerative diseases, while TAT1, a small arginine-rich peptide derived from the HIV-1 trans-activator protein (TAT), is known to stimulate proteasome activity. In this study, three isomeric peptides were synthesised by [...] Read more.

L-carnosine (Car) is an endogenous dipeptide with significant potential in drug discovery for neurodegenerative diseases, while TAT1, a small arginine-rich peptide derived from the HIV-1 trans-activator protein (TAT), is known to stimulate proteasome activity. In this study, three isomeric peptides were synthesised by incorporating the Car moiety at the N-terminus, C-terminus, or central position of the TAT1 sequence. To differentiate these isomers, high-resolution and energy-resolved CID MS/MS experiments were conducted. The resulting MS/MS spectra showed a high degree of similarity among the peptides, predominantly characterised by fragment ion peaks arising from arginine-specific neutral losses. Energetic analysis was similarly inconclusive in resolving the isomers. However, Principal Component Analysis (PCA) enabled clear differentiation of the three peptides by considering the entire MS/MS spectra rather than focusing solely on precursor ion intensities or major fragment peaks. PCA loadings revealed distinct fragment ions for each peptide, albeit with lower intensities, providing insights into consecutive fragmentation patterns. Some of these specific peaks could also be attributed to scrambling during fragmentation. These results demonstrate the potential of PCA as a simple chemometric tool for semi-automated peak identification in complex MS/MS spectra. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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18 pages, 2627 KiB

Open AccessArticle

Development and Evaluation of a Cost-Effective, Carbon-Based, Extended-Release Febuxostat Tablet

by Israa Hamid Al-Ani, Mohammad Hailat, Dina J. Mohammed, Sina Mahmoud Matalqah, Alaa Azeez Abu Dayah, Bashar J. M. Majeed, Riad Awad, Lorena Filip and Wael Abu Dayyih

Molecules 2024, 29(19), 4629; https://doi.org/10.3390/molecules29194629 - 29 Sep 2024

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Abstract

This study outlines the development of a cost-effective, extended-release febuxostat (FEB) tablet using activated charcoal as an adsorbent to enhance drug release. FEB, a BCS Class II drug, presents formulation challenges due to low solubility and high lipophilicity. We evaluated eight formulations with [...] Read more.

This study outlines the development of a cost-effective, extended-release febuxostat (FEB) tablet using activated charcoal as an adsorbent to enhance drug release. FEB, a BCS Class II drug, presents formulation challenges due to low solubility and high lipophilicity. We evaluated eight formulations with varying FEB-to-charcoal ratios using FTIR and DSC for physical interactions and followed USP standards for overall assessment. The optimal 1:0.25 FEB-to-charcoal ratio demonstrated a consistent 12 h zero-order release pattern. In vivo studies indicated a significantly extended plasma profile compared to immediate-release tablets. The optimal tablets demonstrated acceptable hardness and disintegration times. This innovative approach enhances patient compliance, improves bioavailability, and reduces production costs, offering a promising solution for controlled FEB delivery. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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14 pages, 5777 KiB

Open AccessArticle

Design and Synthesis of Dimethylaminomethyl-Substituted Curcumin Derivatives: Potent Anti-Inflammatory, Anti-Oxidant, and Radioprotection Activity, Improved Aqueous Solubility Compared with Curcumin

by Huiling Gu, Sifan Liu, Kai Liang, Ziming Xia, Guangjie Zhang, Bin Li and Shuchen Liu

Molecules 2024, 29(9), 1985; https://doi.org/10.3390/molecules29091985 - 26 Apr 2024

Cited by 1 | Viewed by 1301

Abstract

Although the wide variety of bioactivities of curcumin has been reported by researchers, the clinical application of curcumin is still limited due to its poor aqueous solubility. In view of this, a series of dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized (compounds 1 [...] Read more.

Although the wide variety of bioactivities of curcumin has been reported by researchers, the clinical application of curcumin is still limited due to its poor aqueous solubility. In view of this, a series of dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized (compounds 1–15). Acetate of these derivatives were prepared (compounds 1a–15a). The Mannich reaction and aldol condensation reaction are the main reactions involved in this study. Compounds 6, 10, 12, 3a, 5a, 6a, 7a, 8a, 10a, 11a, 12a, 13a, 14a, and 15a exhibited better in vitro anti-inflammatory activity compared to curcumin in the RAW264.7 cell line. Compounds 5, 1a, 5a, 8a, and 12a exhibited better in vitro antioxidant activity compared to curcumin in the PC 12 cell line. Compounds 11, 13, 5a, 7a, and 13a exhibited better in vitro radiation protection compared to curcumin in the PC 12 cell line. The aqueous solubilities of all the curcumin derivative acetates were greatly improved compared to curcumin. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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12 pages, 1290 KiB

Open AccessArticle

Synthesis and Structural Characterization of Novel Dimers of Dipyridothiazine as Promising Antiproliferative Agents

by Emilia Martula, Beata Morak-Młodawska, Małgorzata Jeleń, Patrick N. Okechukwu, Abbirami Balachandran, Prethika Tehirunavukarasu, Kirthani Anamalay and Vaidehi Ulaganathan

Molecules 2023, 28(22), 7662; https://doi.org/10.3390/molecules28227662 - 19 Nov 2023

Cited by 2 | Viewed by 1585

Abstract

Many new isomeric dipyridothiazine dimers have been presented as molecules with anticancer potential. These compounds were obtained in efficient syntheses of 1,6-, 1,8-, 2,7- and 3,6-diazaphenothiazines with selected alkylaromatic linkers. The structures of these compounds has been proven with two-dimensional spectroscopic techniques (COSY, [...] Read more.

Many new isomeric dipyridothiazine dimers have been presented as molecules with anticancer potential. These compounds were obtained in efficient syntheses of 1,6-, 1,8-, 2,7- and 3,6-diazaphenothiazines with selected alkylaromatic linkers. The structures of these compounds has been proven with two-dimensional spectroscopic techniques (COSY, NOESY, HSQC and HMBC) and high-resolution mass spectrometry (HRMS). In silico analyses of probable molecular targets were performed using the Way2Drug server. All new dimers were tested for anticancer activity against breast cancer line MCF7 and colon cancer line SW480. Cytotoxicity was assessed on normal L6 muscle cells. The tested dimers had high anticancer potential expressed as IC₅₀ and the selectivity index SI. The most active derivative, 4c, showed an IC₅₀ activity of less than 1 µM and an SI selectivity index higher than 100. Moreover, the compounds were characterized by low toxicity towards normal cells, simultaneously indicating a high cytostatic potential. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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31 pages, 12346 KiB

Open AccessFeature PaperReview

Phosphorylated Nitrones—Synthesis and Applications

by Iwona Rozpara, José Marco-Contelles, Dorota G. Piotrowska and Iwona E. Głowacka

Molecules 2025, 30(6), 1333; https://doi.org/10.3390/molecules30061333 - 16 Mar 2025

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Abstract

Phosphorylated nitrones belong to an important class of compounds with several applications, such as their therapeutic potency to reduce oxidative stress or as spin-trapping agents. This review covers available synthetic methods for the preparation of both non-cyclic and cyclic phosphorylated nitrones, including the [...] Read more.

Phosphorylated nitrones belong to an important class of compounds with several applications, such as their therapeutic potency to reduce oxidative stress or as spin-trapping agents. This review covers available synthetic methods for the preparation of both non-cyclic and cyclic phosphorylated nitrones, including the possibilities of the modification of structures with selected functional groups, as well as examples of their application. As reported, the incorporation of diethoxyphosphoryl function into the structure of PBN and DMPO resulted in obtaining their phosphorylated analogs, i.e., N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) and 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide (DEPMPO), respectively, both forming spin adducts of improved stability in comparison to the reference non-phosphorus nitrones. Moreover, antioxidant and neuroprotective activity observed in the group of phosphorylated nitrones makes them promising candidates for therapeutics. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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24 pages, 6571 KiB

Open AccessReview

Oxazolo[5,4-d]pyrimidines as Anticancer Agents: A Comprehensive Review of the Literature Focusing on SAR Analysis

by Aleksandra Sochacka-Ćwikła and Marcin Mączyński

Molecules 2025, 30(3), 666; https://doi.org/10.3390/molecules30030666 - 3 Feb 2025

Viewed by 753

Abstract

Oxazolo[5,4-d]pyrimidines have been found to exhibit a wide range of biological activities, including the inhibition of various enzymes and signaling pathways associated with carcinogenesis. The objective of this review is to demonstrate that the oxazolo[5,4-d]pyrimidine scaffold represents a valuable [...] Read more.

Oxazolo[5,4-d]pyrimidines have been found to exhibit a wide range of biological activities, including the inhibition of various enzymes and signaling pathways associated with carcinogenesis. The objective of this review is to demonstrate that the oxazolo[5,4-d]pyrimidine scaffold represents a valuable structure for the design of novel anticancer therapies. The article provides a comprehensive overview of the chemical structure and pharmacological properties of oxazolo[5,4-d]pyrimidine derivatives, drawing upon the literature and international patents from 1974 until the present. Notably, the review explores structure–activity relationships (SAR) with a view to enhancing the therapeutic efficacy of oxazolo[5,4-d]pyrimidines. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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