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29 pages, 4432 KB

Open AccessArticle

When Does Machine Learning Add Value over Theory? Predicting API Solubility in Binary Mixtures with COSMO-RS and DOOIT2 Across Diverse and Homogeneous Systems

by Maciej Przybyłek, Tomasz Jeliński, Adrian Drużyński and Piotr Cysewski

Molecules 2026, 31(10), 1566; https://doi.org/10.3390/molecules31101566 - 8 May 2026

Viewed by 540

Abstract

Predicting the solubility of active pharmaceutical ingredients (APIs) in binary aqueous-organic mixtures is critical for formulation design, yet remains challenging. Physics-based models such as COSMO-RS provide a solid theoretical foundation but often struggle with non-ideal mixing behavior in complex systems. This study asks [...] Read more.

Predicting the solubility of active pharmaceutical ingredients (APIs) in binary aqueous-organic mixtures is critical for formulation design, yet remains challenging. Physics-based models such as COSMO-RS provide a solid theoretical foundation but often struggle with non-ideal mixing behavior in complex systems. This study asks a practical question: when does machine learning actually add value beyond established theory? We compared COSMO-RS with DOOIT2 (Dual-Objective Optimization with Iterative Feature Pruning), a hybrid COSMO-RS/machine-learning correction workflow, across two complementary datasets: 85 structurally diverse APIs and related formulation-relevant compounds (10,140 data points) and 37 acid-centered solutes (6030 data points). The datasets also incorporate newly measured solubilities of lidocaine, benzocaine, and vanillic acid in aqueous 4-formylmorpholine mixtures. DOOIT2 employs rigorous API-out Structured Group K-Fold validation with fold-specific ensemble models to ensure realistic assessment of generalization to unseen compounds. The obtained results are dataset-dependent. For the homogeneous acid series, COSMO-RS already delivers strong predictive performance (RMSD = 0.321, R² = 0.925), and DOOIT2 brings no meaningful improvement (RMSD = 0.310, R² = 0.923). In contrast, for the diverse API set, DOOIT2 reduces RMSD from 0.686 to 0.527 and increases R² from 0.829 to 0.849. Residual analysis indicates that prediction uncertainty is driven primarily by the low-solubility region rather than by a simple monotonic dependence on molecular weight alone. These findings delineate the practical boundaries of machine-learning assistance in solubility prediction and offer clear guidance for formulation scientists. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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19 pages, 3460 KB

Open AccessArticle

Comparative Antioxidant Profiling of Phenolic Acids and Flavonoids: Assay-Resolved Structure–Activity Relationships Under Harmonized In Vitro Conditions

by Zafer Ömer Özdemir, Merve Soy, Sibel Ataseven, Ayşenur Özer and Mahfuz Elmastaş

Molecules 2026, 31(9), 1478; https://doi.org/10.3390/molecules31091478 - 29 Apr 2026

Viewed by 477

Abstract

Phenolic acids and flavonoids remain attractive redox-active scaffolds in medicinal chemistry, where they are widely used for early-stage prioritization and intrinsic reactivity ranking. However, direct comparisons under harmonized conditions remain scarce, limiting structure-based assessment. Here, a structurally diverse panel of hydroxybenzoic acids, hydroxycinnamic [...] Read more.

Phenolic acids and flavonoids remain attractive redox-active scaffolds in medicinal chemistry, where they are widely used for early-stage prioritization and intrinsic reactivity ranking. However, direct comparisons under harmonized conditions remain scarce, limiting structure-based assessment. Here, a structurally diverse panel of hydroxybenzoic acids, hydroxycinnamic acids, flavonoids, a flavanone, and synthetic comparators was profiled using Folin–Ciocalteu response, ABTS radical cation scavenging, DPPH radical scavenging, and reducing power assays. The data reveal pronounced assay dependence alongside clear structure–activity trends. Gallic acid showed the strongest DPPH scavenging (half-maximal inhibitory concentration, IC₅₀ = 4.45 µmol/L) and reducing power (17.26 µmol TE/mg), while quercetin was consistently active across all four endpoints. Eriocitrin (IC₅₀ = 2.47 µmol/L) and rutin (IC₅₀ = 2.66 µmol/L) were particularly effective in the ABTS assay, showing that glycosylation does not abolish cation-radical scavenging. Lipinski’s Rule of Five and Veber oral-bioavailability criteria place these findings within a drug-likeness context. The results also highlight the limitations of the Folin–Ciocalteu assay as a standalone measure of total phenolic content, since its response depends strongly on hydroxylation density. Rather than asserting therapeutic efficacy, this work provides a harmonized comparative dataset identifying phenolic substructures with the strongest and most consistent redox activity, together with the structural drivers underlying these patterns. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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33 pages, 6742 KB

Open AccessArticle

Insights into the Design of MYC-Targeting Proteolysis Targeting Chimeras (PROTACs)

by Abdallah M. Alfayomy, Sven Hagemann, Matthias Schmidt, Ali Fouad, Mohamed Ayman El-Zahabi, Stefan Hüttelmaier and Wolfgang Sippl

Molecules 2026, 31(6), 1011; https://doi.org/10.3390/molecules31061011 - 17 Mar 2026

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Abstract

The oncogenic transcription factor MYC is a key driver of the development and progression of various types of cancer, but its intrinsically disordered structure and dependence on protein–protein interactions make it a difficult therapeutic target. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that can [...] Read more.

The oncogenic transcription factor MYC is a key driver of the development and progression of various types of cancer, but its intrinsically disordered structure and dependence on protein–protein interactions make it a difficult therapeutic target. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that can induce the selective degradation of disease-relevant proteins. In this study, we report the synthesis and biological testing of a series of novel MYC-targeted PROTACs derived from the MYC inhibitor EN4. These ligands were conjugated to cereblon (CRBN) or von Hippel–Lindau (VHL) E3 ligase recruiters using different linker architectures and connection sites. The resulting PROTACs were synthesized in high purity and characterized analytically. Cellular evaluation in HEK293T, Panc-1 and HCT-116 cancer cells revealed only moderate reductions in cell viability. Unfortunately, none of the synthesized PROTACs showed detectable MYC degradation at biologically relevant concentrations. Testing the stability of the PROTACs in microsomes showed rapid degradation, which may be a reason for the observed inactivity in cells. These results underscore the significant challenges associated with the targeted protein degradation of intrinsically disordered transcription factors such as MYC. Further studies are necessary to identify additional causes for the lack of MYC degradation and to optimize the chemical structures accordingly. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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22 pages, 2527 KB

Open AccessArticle

Synthesis and Study of Substituted Chalcones Combined with Fluoroazobenzenes—New Photoswitches for Application in Biological Systems

by Piotr Tobiasz, Damian Mielecki, Anna Stachurska-Skrodzka, Jakub Miętus, Filip Borys and Hanna Krawczyk

Molecules 2026, 31(2), 362; https://doi.org/10.3390/molecules31020362 - 20 Jan 2026

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Abstract

Chalcones have garnered significant research interest due to their various medical bioactivities. Several chalcone compounds have been approved for marketing and clinical use in the treatment of various diseases. A critical aspect of the action of chalcones is their effect on microtubules. They [...] Read more.

Chalcones have garnered significant research interest due to their various medical bioactivities. Several chalcone compounds have been approved for marketing and clinical use in the treatment of various diseases. A critical aspect of the action of chalcones is their effect on microtubules. They are considered an excellent target for chemotherapeutic agents for the treatment of cancer. Consequently, scientists are constantly developing novel chalcone drug agents and also innovative drug delivery strategies. In this manuscript, we report the first synthesis of 12 new visible-light-activated, photoswitchable chalcone-based microtubule inhibitors (17a–17l). Among the obtained compounds, one photoswitch demonstrated light-dependent cytotoxicity in the PC-3 cancer cell line. The IC₅₀ value of the Z conformer was determined to be 4.75 ± 1.00 μM after 48 h of treatment. The E conformer exhibited slightly lower activity compared to the Z conformer, with an IC₅₀ value of 5.80 ± 0.80 µM following 48 h of incubation. In this study, NMR and UV spectroscopy, along with computational methods, were employed. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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28 pages, 1572 KB

Open AccessArticle

Novel Halolactones Derived from Vanillin: Design, Synthesis, Structural Characterization, and Evaluation of Antiproliferative and Hemolytic Activities

by Anna Dunal, Witold Gładkowski, Ewa Dejnaka, Joanna Sulecka-Zadka, Aleksandra Pawlak, Aleksandra Włoch, Hanna Pruchnik and Gabriela Maciejewska

Molecules 2025, 30(21), 4180; https://doi.org/10.3390/molecules30214180 - 25 Oct 2025

Viewed by 1346

Abstract

A series of novel γ-halo-δ-lactones and δ-halo-γ-lactones bearing a phenolic ring at the β-position were synthesized from vanillin. The divergent seven-step synthetic route commenced with the benzyl protection of the hydroxy group of the starting material, followed by a four-step transformation that led [...] Read more.

A series of novel γ-halo-δ-lactones and δ-halo-γ-lactones bearing a phenolic ring at the β-position were synthesized from vanillin. The divergent seven-step synthetic route commenced with the benzyl protection of the hydroxy group of the starting material, followed by a four-step transformation that led to the corresponding β-aryl-γ,δ-unsaturated carboxylic acids. Subsequent halolactonization (iodo-, bromo-, and chlorolactonization), followed by selective benzyl deprotection, gave the target halolactones. The structures of all intermediates and final lactones were confirmed by comprehensive spectroscopic analyses, including NMR and HRMS. The resulting halolactones were evaluated for antiproliferative activity against two canine (CLBL-1, CLB70) and two human (T-24, CaCo-2) cancer cell lines, as well as non-cancerous mouse embryonic fibroblasts (NIH/3T3). Hemolytic assays were performed to assess toxicity against human red blood cells (RBCs). Among the tested lactones, the transδ-iodo-γ-lactone was the most active, particularly against CLBL-1 and T-24 cells. All compounds demonstrated no inhibitory effects on normal fibroblasts and no hemolytic toxicity. This favorable selectivity profile positions this group of lactones, particularly trans-δ-iodo-γ-lactone, as a promising candidate for further development as potential anticancer agents. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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31 pages, 7006 KB

Open AccessArticle

Balsalazide-Derived Heterotriaryls as Sirtuin 5 Inhibitors: A Case Study of a Reversible Covalent Inhibition Strategy

by Ricky Wirawan, Simon A. Huber, Thomas Wein and Franz Bracher

Molecules 2025, 30(18), 3821; https://doi.org/10.3390/molecules30183821 - 20 Sep 2025

Viewed by 1239

Abstract

Sirtuin 5 is an NAD⁺-dependent lysine deacylase that is involved in various biological processes and has emerged as a promising target for pharmaceutical therapies. The development of highly potent and subtype-selective sirtuin 5 inhibitors for their application as chemical tools and [...] Read more.

Sirtuin 5 is an NAD⁺-dependent lysine deacylase that is involved in various biological processes and has emerged as a promising target for pharmaceutical therapies. The development of highly potent and subtype-selective sirtuin 5 inhibitors for their application as chemical tools and drug candidates still poses a significant challenge. Based on our own optimized balsalazide-derived sirtuin 5 inhibitors, this work presents a systematic investigation of the inhibitory effects of derivatives with moieties that were guided by docking experiments to target the nicotinamide ribose vicinal hydroxy groups of the essential co-factor NAD⁺ via reversible covalent binding to potentially enhance their potency. Our results show that functionalizations with these moieties were tolerated to some extent and possessed a distinct stereo-selective preference. The (S)-configured cyanomethyl derivative 50 with an IC₅₀ of 27 µM emerged from our synthesized library of compounds as the most potent functionalized inhibitor and lies in a similar potency range to other established sirtuin 5 inhibitors. Our findings offer a deeper insight into the structure–activity relationships of our balsalazide-derived heterotriaryl-based sirtuin 5 inhibitors and thus could provide an avenue for further optimizations in the future. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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21 pages, 1902 KB

Open AccessArticle

Intramolecular Versus Intermolecular Bonding in Drug Gemcitabine and Nucleobases: A Computational Study

by Natarajan Sathiyamoorthy Venkataramanan, Ambigapathy Suvitha and Ryoji Sahara

Molecules 2025, 30(13), 2732; https://doi.org/10.3390/molecules30132732 - 25 Jun 2025

Cited by 1 | Viewed by 1309

Abstract

The adsorption of the drug gemcitabine on nucleobases was investigated using a dispersion-corrected density functional theory (DFT) study. The planar structure of complexes is more stable than those with stacked and buckle-angled configurations. The complexes were found to possess at least two intermolecular [...] Read more.

The adsorption of the drug gemcitabine on nucleobases was investigated using a dispersion-corrected density functional theory (DFT) study. The planar structure of complexes is more stable than those with stacked and buckle-angled configurations. The complexes were found to possess at least two intermolecular hydrogen bonds. The binding energy and interaction energy are both negative, with the highest values observed for the gemcitabine–guanine and the lowest in the gemcitabine–thymine complex. The complex formation was found to be an enthalpy-driven process. Pyrimidine nucleobases have a lower enthalpy of formation than purine nucleobases. The computed HOMA and NICS values on the gemcitabine–nucleobase complexes show a substantial increase compared to the pristine nucleobases. An MESP analysis of the complexes shows a directional interaction and electron density shift between the gemcitabine and the nucleobases. A QTAIM analysis indicates that the intermolecular hydrogen bonds have a partial covalent character. The computed bond energy demonstrates that intermolecular NH⋅⋅⋅N bonds are more potent than other bonds. An energy decomposition analysis using the DLPNO−CCSD(T) method indicates that the complexes exhibit a substantial electrostatic attraction, and dispersion contributes the least towards the system stability. The intermolecular bonds are stronger than the intramolecular bonds in the drug–nucleobase complexes. The strength of intramolecular bonds is determined by the deformation of the gemcitabine ring during the complex formation. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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15 pages, 779 KB

Open AccessArticle

Balancing Yields and Sustainability: An Eco-Friendly Approach to Losartan Synthesis Using Green Palladium Nanoparticles

by Edith M. Antunes, Yusuf A. Adegoke, Sinazo Mgwigwi, John J. Bolton, Sarel F. Malan and Denzil R. Beukes

Molecules 2025, 30(11), 2314; https://doi.org/10.3390/molecules30112314 - 25 May 2025

Viewed by 2395

Abstract

This study presents a sustainable, environmentally friendly synthetic route for the production of key intermediates in losartan using palladium nanoparticles (PdNPs) derived from a brown seaweed, Sargassum incisifolium, as a recyclable nanocatalyst. A key intermediate, biaryl, was synthesized with an excellent yield [...] Read more.

This study presents a sustainable, environmentally friendly synthetic route for the production of key intermediates in losartan using palladium nanoparticles (PdNPs) derived from a brown seaweed, Sargassum incisifolium, as a recyclable nanocatalyst. A key intermediate, biaryl, was synthesized with an excellent yield (98%) via Suzuki–Miyaura coupling between 2-bromobenzonitrile and 4-methylphenylboronic acid, catalyzed using bio-derived PdNPs under mild conditions. Subsequent bromination using N-bromosuccinimide (NBS) under LED light, followed by imidazole coupling and tetrazole ring formation, allowed for the production of losartan with an overall yield of 27%. The PdNP catalyst exhibited high stability and recyclability, as well as strong catalytic activity, even at lower loadings, and nitrosamine formation was not detected. While the overall yield was lower than that of traditional industrial methods, this was due to the deliberate avoidance of the use of toxic reagents, hazardous solvents, and protection/deprotection steps commonly used in conventional routes. This trade-off marks a shift in pharmaceutical process development, where environmental and safety considerations are increasingly prioritized in line with green chemistry and regulatory frameworks. This study provides a foundation for green scaling up strategies, incorporating sustainability principles into drug synthesis. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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25 pages, 2159 KB

Open AccessReview

Synthetic Flozins in Cancer Prevention and Combination Strategies: Structural Insights and Therapeutic Potential

by Michał Zieliński, Olga Michalak, Magdalena Ruszczak and Marcin Cybulski

Molecules 2025, 30(24), 4681; https://doi.org/10.3390/molecules30244681 - 6 Dec 2025

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Abstract

The growing number of cancer cases highlights the urgent need to develop new therapies based on effective molecules. Although anticancer activity remains a key element of oncological pharmacology, the importance of agents that support physiological functions and improve the quality of life of [...] Read more.

The growing number of cancer cases highlights the urgent need to develop new therapies based on effective molecules. Although anticancer activity remains a key element of oncological pharmacology, the importance of agents that support physiological functions and improve the quality of life of cancer patients is also recognised. Compounds that combine these two functions could represent a significant trend in oncology. Moreover, repurposing approved drugs for conditions beyond their original indications could be a promising strategy. An interesting example of this is synthetic flozins (SGLT2 inhibitors), which were originally designed and developed to treat type 2 diabetes mellitus. These compounds contain various aromatic and heteroaryl structures, and changes in these substituents affect the binding strength and therapeutic potency of SGLT2 inhibitors. Beyond their antidiabetic effects, SGLT2 inhibitors exert well-documented cardioprotective and nephroprotective actions, restoring metabolic homeostasis. Given these pleiotropic properties, they could benefit oncology by improving systemic functions and by directly influencing the invasion of cancer cells. This article provides an overview of the use of synthetic flozins in various contexts, with a particular focus on their potential impact on cancer biology and treatment, consolidating their position as multifunctional agents of growing systemic relevance. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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20 pages, 2027 KB

Open AccessReview

SGLT2 Inhibitors: From Molecular Mechanisms to Clinical Outcomes in Cardiology and Diabetology

by Marlena Stielow, Łukasz Fijałkowski, Aidas Alaburda, Grzegorz Grześk, Elżbieta Grześk, Jacek Nowaczyk and Alicja Nowaczyk

Molecules 2025, 30(15), 3112; https://doi.org/10.3390/molecules30153112 - 25 Jul 2025

Cited by 19 | Viewed by 10037

Abstract

Studies have shown that sodium-glucose cotransporter type 2 (SGLT2) inhibitors not only help lower blood glucose levels but also offer cardioprotective effects, reduce the progression of heart failure, and may even slow the progression of aortic stenosis. The mechanisms of these beneficial properties [...] Read more.

Studies have shown that sodium-glucose cotransporter type 2 (SGLT2) inhibitors not only help lower blood glucose levels but also offer cardioprotective effects, reduce the progression of heart failure, and may even slow the progression of aortic stenosis. The mechanisms of these beneficial properties are thought to involve multiple pathways, including reducing inflammation, oxidative stress, and improving cellular energy metabolism. Advancing knowledge about the mechanisms of action of these drugs and their effects on the course of the aforementioned diseases has become the subject of intensive clinical and scientific research. This publication aims to provide insight into the role of SGLT2 inhibitors in the context of diabetes mellitus, heart failure and acute coronary syndrome, through clinical analysis, mechanistic insights and comparison of the effects of these drugs. Full article

(This article belongs to the Special Issue Organic Molecules in Drug Discovery and Development)

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