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Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 October 2026 | Viewed by 7219

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Dr. Renato Emanuel Felix Boto

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RISE-Health, Faculty of Sciences, University of Beira Interior, Rua Marquês d'Ávila e Bolama, 6201-001 Covilhã, Portugal
Interests: organic synthesis; synthesis of new organic compounds with medicinal and pharmaceutical interests
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Prof. Dr. Samuel Martins Silvestre

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RISE-Health, Faculty of Sciences, University of Beira Interior, Rua Marquês d'Ávila e Bolama, 6201-001 Covilhã, Portugal
Interests: design of bioactive compounds; chemical synthesis; biological evaluation; compounds with medicinal and pharmaceutical interests
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The design, synthesis, and biological evaluation of new compounds present a promising strategy in modern drug discovery. The discovery and development of new, modern drugs require a deep understanding of the biological pathways involved in the disease, as well as the structure of molecules that can act as bioactive compounds.

Bioactive compounds are molecules that exert pharmacological and/or toxicological effects on a living organism, tissue, or cell, and can be extracted from natural compounds—mainly secondary metabolites—from plants or other types of living organisms. These compounds can also be obtained using different strategies, such as the organic synthesis of new molecules or via the modification of existing ones, followed by biological screening. In silico-based methods are being increasingly used to support the different steps of this process.

This Special Issue aims to collect the most recent developments regarding the design, synthesis, and biological evaluation of bioactive compounds that can lead to an increase in natural or synthetic small active molecules in the search for promising new drugs to prevent and/or treat human diseases.

Therefore, we invite researchers to contribute manuscripts that not only focus on the design and synthesis of bioactive compounds and relevant synthetic intermediates but also on their in vitro or in vivo biological evaluation.

Dr. Renato Emanuel Felix Boto
Prof. Dr. Samuel Martins Silvestre
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

bioactive compounds
design
synthesis
biological evaluation
in silico evaluation
in vitro evaluation
in vivo evaluation

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Related Special Issue

Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds in Molecules (11 articles)

Published Papers (8 papers)

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Research

13 pages, 1572 KB

Open AccessArticle

In Vitro Antiproliferative Effects of Benzothiazole-Based Aminosquaraine Dyes Against Cancer Cell Lines

by Elisabete Alves, João L. Serrano, Ahmed Al-Najada, Sara Cegonho, Vânia Graça, Eurico Lima, Alexandra Varges, Adriana O. Santos, Paulo Almeida, Paulo F. Santos and Samuel M. Silvestre

Molecules 2026, 31(9), 1537; https://doi.org/10.3390/molecules31091537 - 6 May 2026

Viewed by 506

Abstract

The introduction of amine groups into the four-membered central ring of squaraine dyes is expected to enhance the intrinsic cytotoxicity of this scaffold. In this study, the biological effects of eight benzothiazole-based aminosquaraine dyes were investigated by varying the length of the N-alkyl chains and the nature of the introduced amine. Biological activity was evaluated through different assays in several cell lines, including apoptosis and cell cycle analysis, as well as confocal microscopy studies. Overall, the incorporation of amino, methylamino, and ethanolamino groups significantly increased cytotoxicity, with the corresponding dyes displaying low half-maximal inhibitory concentration values, in some cases even lower than that of the positive control, 5-fluorouracil. In contrast, derivatives bearing diethanolamino or ethylenediamino groups exhibited lower cytotoxicity, particularly the dye containing N-decyl chain. For the dyes selected for further investigation, bearing a methylamino group and N-butyl or -hexyl chains, the induction of apoptosis was evident, especially for methylaminosquaraine dye 3. These dyes also exhibited antiproliferative effects, as evidenced by their ability to induce cell cycle arrest. Confocal microscopy revealed a predominantly cytoplasmic distribution, likely associated with cytoplasmic organelles, with limited penetration into the nucleus. Overall, although squaraines are widely recognized as promising photodynamic agents, the present results suggest that they may also be explored in chemotherapeutic approaches, particularly when exhibiting high intrinsic cytotoxicity. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition)

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18 pages, 3193 KB

Open AccessArticle

Synthesis, Antifungal Activity, 3D-QSAR, and Molecular Docking Study of Anethole-Based Thiazolinone-Hydrazone Compounds

by Yao Chen, Yu-Cheng Cui, You-Qiong Bi, Zhang-Li Guo, Xian-Li Ma, Wen-Gui Duan and Gui-Shan Lin

Molecules 2026, 31(7), 1078; https://doi.org/10.3390/molecules31071078 - 25 Mar 2026

Viewed by 522

Abstract

In order to find green fungicides derived from natural products, 22 unreported anethole-based thiazolinone-hydrazone compounds were designed and synthesized, and their structures were characterized by FT-IR, ¹H NMR, ¹³C NMR, and HRMS. At a concentration of 50 mg/L, the preliminary antifungal activity of the target compounds against eight plant pathogens was evaluated. The results showed that 5q (R = m-OH C₆H₄) exhibited the best inhibitory activity against most of the tested plant pathogenic fungi, demonstrating that this compound had certain broad-spectrum antifungal activity. In addition, a reasonable and effective 3D-QSAR model (r² = 0.994, q² = 0.529) was established using the comparative molecular field analysis (CoMFA) method to study the relationship between the structures of the target compounds and their antifungal activity against Physalospora piricola. Meanwhile, the results of electrostatic potential calculation of the compounds indicated that the electronic effect caused by different substituents on the benzene ring might be one of the factors affecting antifungal activity. In addition, frontier molecular orbital calculations implied that the anethole moiety and the thiazolinone-hydrazone-benzene structure in the target compounds might play an important role in antifungal activity. The potential binding mode between the target compound 5q (R = m-OH C₆H₄) and the homology-modeled succinic dehydrogenase was explored by molecular docking. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition)

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25 pages, 4264 KB

Open AccessArticle

Probing Combined Experimental and Computational Profiling to Identify N-(benzo[d]thiazol-2-yl) Carboxamide Derivatives: A Path to Potent α-Amylase and α-Glucosidase Inhibitors for Treating Diabetes Mellitus

by Fakhria A. Al-Joufi, Mariam Mojally, Maher S. Alwethaynani, Nawal Al-Hoshani and Ghulam Nabi

Molecules 2026, 31(4), 751; https://doi.org/10.3390/molecules31040751 - 23 Feb 2026

Cited by 1 | Viewed by 979

Abstract

A novel series of benzothiazole scaffolds were presented to test their in vitro α-amylase and α-glucosidase activities for combating diabetes mellitus, which is one of the most rapidly growing diseases. The tested compounds were elucidated structurally by various spectroscopic techniques like ¹H NMR, ¹³C NMR and HRMS. All compounds exhibited a varied range of inhibitory activities against targeted α-amylase and α-glucosidase enzymes, with IC₅₀ values of 1.58 ± 1.20 to 7.54 ± 3.60 µM (α-amylase) and 2.10 ± 1.10 to 8.90 ± 4.10 (α-glucosidase), respectively. The obtained results were compared with the standard acarbose drug, with IC₅₀ values of 0.91 ± 0.20 µM (α-amylase) and 1.80 ± 1.10 µM (α-glucosidase). Specifically, methyl 2-amino-4-((6-methoxypyridin-3-yl)methoxy)benzo[d]thiazole-6-carboxylate (5c) and methyl 4-((6-methoxypyridin-3-yl)methoxy)-2-(thiazole-2-carboxamido)benzo[d]thiazole-6-carboxylate (6b) emerged as potent inhibitors of α-amylase and α-glucosidase enzymes. These potent compounds were further screened for in silico molecular docking studies to investigate possible binding interactions with active sites of targeted enzymes, and results obtained demonstrated that potent compounds exhibited stronger binding affinities toward anti-diabetic enzymes compared to the positive control acarbose. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition)

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30 pages, 3219 KB

Open AccessArticle

Indocyanine Green as a Theragnostic Agent in MCF-7 Breast Cancer Cells

by Wiktoria Mytych, Dorota Bartusik-Aebisher, Piotr Oleś, Aleksandra Kawczyk-Krupka, David Aebisher and Gabriela Henrykowska

Molecules 2026, 31(3), 520; https://doi.org/10.3390/molecules31030520 - 2 Feb 2026

Cited by 1 | Viewed by 871

Abstract

Background/Objectives: Indocyanine green (ICG) is an FDA-approved, near-infrared fluorescent dye widely used for tumor imaging. This study aimed to evaluate the photodynamic efficacy and selectivity of ICG as a photosensitizer in photodynamic therapy (PDT) against MCF-7 breast cancer cells in 2D monolayers and 3D collagen-embedded cell cultures that simulate ECM diffusion, and to confirm direct generation of singlet oxygen (¹O₂) as the primary cytotoxic species. Methods: MCF-7 breast adenocarcinoma cells and HMEC normal mammary epithelial cells were cultured in 2D monolayers, with MCF-7 cells additionally grown in 3D collagen type I matrices to mimic tumor environments. Cells were incubated with 50 µM ICG for 30 min, washed, and irradiated with a 780 nm diode laser at 39.8 mW/cm². Cell viability was quantified using the Muse^® Count & Viability assay at multiple time points, while ICG uptake and penetration were assessed via flow cytometry, fluorescence microscopy, and confocal imaging. Direct ¹O₂ production was measured through its characteristic 1270 nm phosphorescence using time-resolved near-infrared spectrometry. Results: ICG-PDT reduced MCF-7 viability to 58.3 ± 7.4% in 2D cultures (41.7% cell kill, p < 0.0001) and 70.2 ± 10.7% in 3D cultures (29.8% cell kill, p = 0.0002). In contrast, normal HMECs maintained 91.0 ± 1.3% viability (only 9% reduction, p = 0.08), resulting in a therapeutic index of approximately 4.6. IC₅₀ values in 2D MCF-7 cultures decreased over time from 51.4 ± 3.0 µM at 24 h to 27.3 ± 3.0 µM at 72 h. ICG uptake was higher in 2D (78%) than in 3D (65%) MCF-7 cultures, with diffusion in 3D collagen exhibiting linear depth-dependent penetration. Notably, the singlet-oxygen phosphorescence signal, though weak and requiring highly sensitive detectors, provided direct evidence of efficient ¹O₂ generation. Conclusions: ICG as a photosensitizer in photodynamic therapy using clinically compatible parameters is highly cytotoxic to MCF-7 breast cancer cells while largely sparing HMECs in 2D cell culture. Direct spectroscopic evidence confirms efficient ¹O₂ generation, which contributes significantly to the cytotoxicity. The reduced efficacy in 3D versus 2D models highlights the importance of penetration barriers also present in solid tumors. These results support further preclinical and clinical investigation of ICG as a dual imaging-and-therapy (theragnostic) agent for selective photodynamic treatment of breast cancer. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition)

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13 pages, 1063 KB

Open AccessArticle

Radiation-Induced Synthesis of a Minocycline-Derived Polycyclic Scaffold with Anti-Inflammatory and Antibacterial Effects

by Gyeong Han Jeong, Hanui Lee, Tae Hoon Kim, Byung Yeoup Chung, Seung Sik Lee and Hyoung-Woo Bai

Molecules 2026, 31(3), 435; https://doi.org/10.3390/molecules31030435 - 27 Jan 2026

Viewed by 541

Abstract

Radiation is widely used as a powerful tool for inducing molecular transformation and expanding chemical diversity; however, its application in clinically relevant antibiotics remains limited. Minocycline (1), a clinically used tetracycline antibiotic, was subjected to gamma irradiation at doses of up to 30 kGy, resulting in the formation of a previously unreported radiation-induced derivative, minocyclinosin A (2). The structure of the newly generated compound was elucidated by comprehensive spectroscopic analyses, including one- and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution electrospray ionization mass spectrometry, which revealed extensive A-ring cleavage, degradation, and recyclization to form a unique cyclopenta[b]anthracene-type tetracycline scaffold. Biological evaluation revealed that minocyclinosin A exhibited enhanced anti-inflammatory activity by suppressing lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages, while maintaining antibacterial activity against skin inflammation-associated Staphylococcus species. High-performance liquid chromatography further demonstrated a clear dose-dependent molecular conversion, with irradiation at 30 kGy affording minocyclinosin A as the major product with a conversion efficiency of approximately 78.3%. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition)

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28 pages, 7110 KB

Open AccessArticle

New Dimethylpyridine-3-Carboxamide Derivatives as MMP-13 Inhibitors with Anticancer Activity

by Remigiusz Płaczek, Tomasz Janek, Małgorzata Strzelecka, Aleksandra Kotynia, Piotr Świątek and Żaneta Czyżnikowska

Molecules 2025, 30(24), 4662; https://doi.org/10.3390/molecules30244662 - 5 Dec 2025

Viewed by 950

Abstract

A series of dimethylpyridine-3-carboxamide derivatives was designed as potential, selective, non-zinc chelating inhibitors of matrix metalloproteinase 13 (MMP-13), and subsequently synthesized. The identity of the obtained compounds was confirmed by FT-IR, ¹H/¹³C NMR, and HR-MS methods. Fluorescence spectroscopy was applied to study the interaction of synthesized compounds with human serum albumin, providing insight into their potential transport properties in plasma. In parallel, the electronic properties and reactivity parameters relevant to enzyme binding of the designed molecules were analyzed using density functional theory. Molecular docking and molecular dynamics simulations revealed the compounds to interact preferentially and stably within the S₁ pocket of MMP-13 via hydrogen bonds and π-stacking interactions. The calculated binding free energy confirmed the stability and persistence of the complexes during simulation, indicating a strong and specific recognition pattern. On the other hand, their affinity towards MMP-8 was considerably weaker, which is consistent with the predicted selectivity profile. In addition, the biological evaluation confirmed MMP-13 inhibition. Finally, in vitro tests revealed their cytotoxic activity against cancer cell lines. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition)

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14 pages, 1930 KB

Open AccessArticle

Design, Synthesis, Molecular Docking, and Anticancer Activity of Chalcone Derivatives as VEGFR-2 Inhibitors

by Mingjun Yu, Xin Zhang, Hui Zhu and Xiaoqian Zhang

Molecules 2025, 30(23), 4526; https://doi.org/10.3390/molecules30234526 - 24 Nov 2025

Cited by 1 | Viewed by 1063

Abstract

A series of 4-phenylurea chalcones (2a–2s) as VEGFR-2 inhibitors has been designed, synthesized, and evaluated for in vitro cytotoxic activity against K562, SiHa, and B16 cancer cells. Compared to sorafenib, the compounds exhibited strong cytotoxicity against K562, SiHa and B16 cells. Compounds 2r, 2o, and 2l exhibited remarkable cytotoxicity against K562, SiHa, and B16 cells, with IC₅₀ values of 0.97 μM, 1.22 μM, and 1.39 μM, respectively. Moreover, compound 2l exhibited potent cytotoxicity against K562, SiHa, and B16, with IC₅₀ values ranging from 1.25 μM to 1.39 μM. Compounds 2l and 2o also exhibited excellent inhibitory activity on VEGFR-2 kinase, with IC₅₀ values of 0.42 ± 0.03 and 0.31 ± 0.02 μM, respectively. Molecular docking proved that the target compounds had strong binding interactions with VEGFR-2 proteins. Flow cytometry analysis showed that compound 2l induced apoptosis and arrested the cell cycle at the G1 and S phases. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition)

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21 pages, 4709 KB

Open AccessArticle

Comparative Analysis of Gold Nanoparticle Synthesis Using PAMAM G2 Dendrimers via Microwave and Sonication Methods for Potential Cancer Theranostic Applications

by Magdalena Grala, Bolesław Karwowski and Agnieszka Maria Kołodziejczyk

Molecules 2025, 30(23), 4509; https://doi.org/10.3390/molecules30234509 - 22 Nov 2025

Cited by 2 | Viewed by 1047

Abstract

The rapid development of nanomedicine is driving extensive research and the synthesis of new nanomaterials. Biocompatible nanoparticles have the potential to serve as both imaging agents for medical diagnostics and carriers for targeted therapy. Among the various nanocomplexes investigated for cancer theranostics, gold nanoparticles stabilized by polyamidoamine (PAMAM) dendrimers have proven to be a promising platform. The unique physicochemical properties of gold nanoparticles, when combined with the branched architecture of PAMAM dendrimers, enhance stability, biocompatibility, and functionalization capability, enabling precise tumour targeting, improved imaging contrast, and controlled drug release. In this paper, we demonstrate the synthesis of gold nanoparticles stabilized by 2nd generation PAMAM dendrimers using three different methods: sonication, microwave, and unassisted techniques. The described synthesis approaches provide a rapid and straightforward method to achieve monodisperse particle size distribution and high colloidal stability up to 3 months. Physicochemical characterization of the nanocomplexes was carried out using ultraviolet-visible light spectroscopy, dynamic light scattering with zeta potential analysis, infrared spectroscopy, and atomic force microscopy. Furthermore, the effects of selected concentrations of PAMAM:HAuCl₄ nanoparticles for all types of synthesis on human breast adenocarcinoma and human osteosarcoma cell lines were investigated using cytotoxicity assays. The results of the conducted tests show cytotoxicity values at a similar level. However, the sample synthesized using the sonication technique exhibited the lowest toxicity. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds—2nd Edition)

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