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12 pages, 2770 KiB

Open AccessArticle

Synthesis of 2-Amino-4, 5-Diarylthiazole Derivatives and Evaluation of Their Anti-Candida Albicans Activity

by Dongmei Gao, Lele Shi, Yuhang Huang, Yingmei Lv, Xuan Yang and Zhenting Du

Molecules 2025, 30(7), 1643; https://doi.org/10.3390/molecules30071643 - 7 Apr 2025

Viewed by 263

Abstract

The thiazole heterocycle is one of the most common moieties found in various drugs. Using 2-aminothiazole as the core structure, the amino group was functionalized with an amide. As a result, 30 trisubstituted 2-amino-4, 5-diarylthiazole derivatives were synthesized, with different substitutions introduced at [...] Read more.

The thiazole heterocycle is one of the most common moieties found in various drugs. Using 2-aminothiazole as the core structure, the amino group was functionalized with an amide. As a result, 30 trisubstituted 2-amino-4, 5-diarylthiazole derivatives were synthesized, with different substitutions introduced at the C2, C4, and C5 positions. The anti-Candida albicans biological activities of these synthetic compounds on five kinds of Candida albicans at different concentrations were detected by the microdilution method. In the first round, four derivatives of 2-amino-4, 5-diarylthiazole exhibited moderate anti-Candida albicans activity. Among them, 4a8 was chosen to be subjected to a demethylation process. Thus, 5a8 was synthesized successfully, giving anti-Candida albicans activity (MIC₈₀ = 9 μM) similar to that of a typical antifungal drug, fluconazole. To understand the mechanism of anti-Candida albicans, molecular docking of the most active 5a8 against four target proteins of anti-Candida albicans, such as glutamine-fructose-6-phosphoamidamitransferase (GFAT), protein kinase (Yck2), heat-shock protein 90 (Hsp90), and lanosterol 14a-demethylase (CYP51) was carried out. Our research will provide an experimental basis and theoretical guidance for the further design of a new aminothiazole-leading pharmaceutical molecule. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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21 pages, 5316 KiB

Open AccessArticle

Total Synthesis and Stereochemical Assignment of Alternapyrone

by Hui Zhang, Jiaxuan Feng, Di Wang, Bencan Tang, Chao Xu and Tao Ye

Molecules 2025, 30(7), 1597; https://doi.org/10.3390/molecules30071597 - 3 Apr 2025

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Abstract

Alternapyrone, a bioactive polyketide produced by the fungal host Aspergillus oryzae, is biosynthesized by a polyketide synthase encoded by the alt1-5 gene cluster. Despite its known bioactivity, the stereochemical configuration of the three stereogenic centers in its polyketide backbone has remained unresolved. [...] Read more.

Alternapyrone, a bioactive polyketide produced by the fungal host Aspergillus oryzae, is biosynthesized by a polyketide synthase encoded by the alt1-5 gene cluster. Despite its known bioactivity, the stereochemical configuration of the three stereogenic centers in its polyketide backbone has remained unresolved. In this study, we determined the complete stereostructure of alternapyrone using an integrative approach that combines predictive, rule-based stereochemical analysis with experimental validation through total synthesis. The efficient total synthesis enabled the precise assignment of the hypothesized stereochemistry by matching the synthetic product to the natural compound. This comprehensive study conclusively established the absolute configuration of alternapyrone. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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17 pages, 9983 KiB

Open AccessArticle

Diastereodivergent Construction of Octahydrophenanthridinone and Octahydrophenanthridine Cores

by Chunzhao Sun, Hiromichi Nishikawa, Tsubasa Inokuma and Ken-ichi Yamada

Molecules 2025, 30(2), 371; https://doi.org/10.3390/molecules30020371 - 17 Jan 2025

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Abstract

Diastereodivergent synthesis of octahydrophenanthridinone and octahydrophenanthridine skeletons, structural motifs often found in biologically active natural products, is described. We previously reported a total synthesis of a pancratistatin analog using novel octahydrophenanthridinone construction. In this study, we examined the generality of our method and [...] Read more.

Diastereodivergent synthesis of octahydrophenanthridinone and octahydrophenanthridine skeletons, structural motifs often found in biologically active natural products, is described. We previously reported a total synthesis of a pancratistatin analog using novel octahydrophenanthridinone construction. In this study, we examined the generality of our method and its extension to octahydrophenanthridine formation. Conjugate addition of diarylcuprates to nitrosocyclohexenes, which were generated in situ from 2-chlorocyclohexanone oximes, provided 2-arylcyclohexanone oximes. Subsequent reduction of the oxime moiety gave cis- and trans-configured amines. Both amines were separately converted into the corresponding octahydrophenanthridinones and octahydrophenanthridines via hexahydrophenanthridine intermediates. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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23 pages, 7871 KiB

Open AccessArticle

Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability

by Maja Sviben, Ilijana Odak, Danijela Barić, Milena Mlakić, Ottó Horváth, Lajos Fodor, Sunčica Roca, Ivana Šagud and Irena Škorić

Molecules 2025, 30(2), 316; https://doi.org/10.3390/molecules30020316 - 15 Jan 2025

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Abstract

Considering our previous experience in the design of new cholinesterase inhibitors, especially resveratrol analogs, in this research, the basic stilbene skeleton was used as a structural unit for new carbamates designed as potentially highly selective butyrylcholinesterase (BChE) inhibitors with excellent absorption, distribution, metabolism, [...] Read more.

Considering our previous experience in the design of new cholinesterase inhibitors, especially resveratrol analogs, in this research, the basic stilbene skeleton was used as a structural unit for new carbamates designed as potentially highly selective butyrylcholinesterase (BChE) inhibitors with excellent absorption, distribution, metabolism, excretion and toxicity ADMET properties. The inhibitory activity of newly prepared carbamates 1–13 was tested toward the enzymes acetylcholinesterase (AChE) and BChE. In the tested group of compounds, the leading inhibitors were 1 and 7, which achieved excellent selective inhibitory activity for BChE with IC₅₀ values of 0.12 ± 0.09 μM and 0.38 ± 0.01 μM, respectively. Both were much more active than the standard inhibitor galantamine against BChE. Molecular docking of the most promising inhibitor candidates, compounds 1 and 7, revealed that stabilizing interactions between the active site residues of BChE and the ligands involve π-stacking, alkyl-π interactions, and, when the carbamate orientation allows, H-bond formation. MD analysis confirmed the stability of the obtained complexes. Some bioactive resveratrol-based carbamates displayed complex-forming capabilities with Fe³⁺ ions as metal centers. Spectrophotometric investigation indicated that they coordinate one or two metal ions, which is in accordance with their chemical structure, offering two binding sites: an amine and a carboxylic group in the carbamate moiety. Based on the obtained in silico, experimental and computational results on biological activity in the present work, new carbamates 1 and 7 represent potential selective BChE inhibitors as new therapeutics for neurological disorders. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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15 pages, 1372 KiB

Open AccessArticle

Synthesis, Structure and Biological Activity of 2-Methyl-5-nitro-6-phenylnicotinohydrazide-Based Hydrazones

by Oralgazy A. Nurkenov, Anel Z. Mendibayeva, Serik D. Fazylov, Tulegen M. Seilkhanov, Saule K. Kabieva, Ardak K. Syzdykov, Ilya I. Kulakov, Aleksandr V. Iashnikov, Alexey S. Vasilchenko, Larisa E. Alkhimova and Ivan V. Kulakov

Molecules 2025, 30(1), 169; https://doi.org/10.3390/molecules30010169 - 4 Jan 2025

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Abstract

The synthetic availability and wide range of biological activity of hydrazides and hydrazones make them attractive subjects for investigation. In this study, we focused on synthesis of 2-methyl-5-nitro-6-phenylnicotinohydrazide-based hydrazones derived from the corresponding substituted aldehydes. The structure of the obtained compounds was studied [...] Read more.

The synthetic availability and wide range of biological activity of hydrazides and hydrazones make them attractive subjects for investigation. In this study, we focused on synthesis of 2-methyl-5-nitro-6-phenylnicotinohydrazide-based hydrazones derived from the corresponding substituted aldehydes. The structure of the obtained compounds was studied using NMR spectroscopy and DFT calculations. After repeated recrystallization, all the synthesized compounds remained as mixtures of isomers. As a result of a detailed analysis, we found that the duplication and bifurcation of signals in the ¹H NMR spectra for some atoms is a consequence of the existence of four isomers, namely Z-I, Z-II, E-I and E-II. Duplicate proton signals with a chemical shift difference of 0.1–0.2 ppm and in a ratio of about 2:1 were noticed in the experimental data. By modeling the structures of individual configurations and conformations, Gibbs free energy values were obtained, which allowed us to estimate the approximate content of rotamers for the E-isomer equal to 3:2, which coincided with experimental data. We also tested the antibacterial and antifungal activity of the synthesized compounds. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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20 pages, 1737 KiB

Open AccessArticle

Licochalcone A-Inspired Chalcones: Synthesis and Their Antiproliferative Potential in Prostate Cancer Cells

by Roxana Gonzalez Dorado, Esveidy Isabel Oceguera Nava, Guanglin Chen, Qiang Zhang, Guangdi Wang and Qiao-Hong Chen

Molecules 2024, 29(24), 6023; https://doi.org/10.3390/molecules29246023 - 20 Dec 2024

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Abstract

Prostate cancer remains a significant global health concern, prompting ongoing exploration of novel therapeutic agents. Licochalcone A, a natural product in the chalcone family isolated from licorice root, is characterized by its enone structure and demonstrates antiproliferative activity in the micromolar range across [...] Read more.

Prostate cancer remains a significant global health concern, prompting ongoing exploration of novel therapeutic agents. Licochalcone A, a natural product in the chalcone family isolated from licorice root, is characterized by its enone structure and demonstrates antiproliferative activity in the micromolar range across various cell lines, including prostate cancer. Building on our prior success in enhancing curcumin’s antiproliferative potency by replacing the substituted phenol with a 1-alkyl-1H-imizadol-2-yl moiety, we applied a similar approach to design a new class of licochalcone A-inspired chalcones. The synthesis of these target chalcones involved key [3,3]-sigmatropic rearrangement of aryl prenyl ethers and Claisen–Schmidt condensations, yielding three derivative series. These compounds were evaluated for antiproliferative activity in both androgen receptor (AR)-positive and AR-null prostate cancer cell models using WST-1 cell proliferation assay. Systematic evaluation of licochalcone A across four prostate cancer cell lines indicated a modest advantage over enzalutamide, an FDA-approved AR antagonist, in suppressing 22Rv1 cell proliferation. Interestingly, three ester derivatives by replacing the phenol next to the carbonyl with an alkoxide demonstrated similar antiproliferative potency to licochalcone A in both AR-positive and AR-negative prostate cancer cell lines. This suggests that the phenol moiety on licochalcone A may be a promising site for chemical manipulations to enhance anti-prostate cancer activity. Among the synthesized chalcones, nine derivatives showed improved selectivity for AR-positive LNCaP and 22RV1 cells relative to AR-negative PC-3 and DU145 cells, surpassing licochalcone A in selectivity. Additionally, the antiproliferative potency was highly dependent on the R group attached to the imidazole. Most of the derivatives showed antiproliferative potency against androgen receptor-positive LNCaP and 22Rv1 cells, comparable to that of enzalutamide and licochalcone A. These findings suggest that optimization of licochalcone A-inspired chalcones as potential anti-prostate cancer agents warrants further investigation. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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18 pages, 9854 KiB

Open AccessArticle

Synthesis and Antimicrobial Activity of (E)-1-Aryl-2-(1H-tetrazol-5-yl)acrylonitrile Derivatives via [3+2] Cycloaddition Reaction Using Reusable Heterogeneous Nanocatalyst under Microwave Irradiation

by Ayashkanta Nanda, Navneet Kaur, Manvinder Kaur, Fohad Mabood Husain, Haesook Han, Pradip K. Bhowmik and Harvinder Singh Sohal

Molecules 2024, 29(18), 4339; https://doi.org/10.3390/molecules29184339 - 12 Sep 2024

Cited by 1 | Viewed by 1203

Abstract

The magnetically recoverable heterogeneous Fe₂O₃@cellulose@Mn nanocomposite was synthesized by a stepwise fabrication of Mn nanoparticles on cellulose-modified magnetic Fe₂O₃ nanocomposites, and the morphology of the nanocomposite was characterized through advanced spectroscopic techniques. This nanocomposite was investigated [...] Read more.

The magnetically recoverable heterogeneous Fe₂O₃@cellulose@Mn nanocomposite was synthesized by a stepwise fabrication of Mn nanoparticles on cellulose-modified magnetic Fe₂O₃ nanocomposites, and the morphology of the nanocomposite was characterized through advanced spectroscopic techniques. This nanocomposite was investigated as a heterogeneous catalyst for the synthesis of medicinally important tetrazole derivatives through Knoevenagel condensation between aromatic/heteroaromatic aldehyde and malononitrile followed by [3+2] cycloaddition reaction with sodium azide. Thirteen potent (E)-1-aryl-2-(1H-tetrazol-5-yl)acrylonitrile derivatives are reported in this paper with very high yields (up to 98%) and with excellent purity (as crystals) in a very short period (3 min @ 120 W) using microwave irradiation. The present procedure offers several advantages over recent protocols, including minimal catalyst loading, quick reaction time, and the utilization of an eco-friendly solvent. Furthermore, the synthesized (E)-1-aryl-2-(1H-tetrazol-5-yl)acrylonitrile derivatives (4b, 4c, and 4m) are shown to have excellent resistance against various fungal strains over bacterial strains as compared to the standard drugs Cefixime (4 μg/mL) and Fluconazole (2 μg/mL). Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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10 pages, 1599 KiB

Open AccessArticle

Amphetamine-like Deferiprone and Clioquinol Derivatives as Iron Chelating Agents

by Mahmoud El Safadi, Katie A. Wilson, Indigo J. Strudwicke, Megan L. O’Mara, Mohan Bhadbhade, Tristan Rawling and Andrew M. McDonagh

Molecules 2024, 29(17), 4213; https://doi.org/10.3390/molecules29174213 - 5 Sep 2024

Viewed by 1098

Abstract

The accumulation of iron in dopaminergic neurons can cause oxidative stress and dopaminergic neuron degeneration. Iron chelation therapy may reduce dopaminergic neurodegeneration, but chelators should be targeted towards dopaminergic cells. In this work, two series of compounds based on 8-hydroxyquinoline and deferiprone, iron [...] Read more.

The accumulation of iron in dopaminergic neurons can cause oxidative stress and dopaminergic neuron degeneration. Iron chelation therapy may reduce dopaminergic neurodegeneration, but chelators should be targeted towards dopaminergic cells. In this work, two series of compounds based on 8-hydroxyquinoline and deferiprone, iron chelators that have amphetamine-like structures, have been designed, synthesized and characterized. Each of these compounds chelated iron ions in aqueous solution. The hydroxyquinoline-based compounds exhibited stronger iron-binding constants than those of the deferiprone derivatives. The hydroxyquinoline-based compounds also exhibited greater free radical scavenging activities compared to the deferiprone derivatives. Molecular dynamics simulations showed that the hydroxyquinoline-based compounds generally bound well within human dopamine transporter cavities. Thus, these compounds are excellent candidates for future exploration as drugs against diseases that are affected by iron-induced dopaminergic neuron damage, such as Parkinson’s disease. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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15 pages, 881 KiB

Open AccessArticle

Halogenated Analogs to Natural A-Type Proanthocyanidins: Evaluation of Their Antioxidant and Antimicrobial Properties and Possible Application in Food Industries

by Antonio Cobo, Alfonso Alejo-Armijo, Daniel Cruz, Joaquín Altarejos, Sofía Salido and Elena Ortega-Morente

Molecules 2024, 29(15), 3622; https://doi.org/10.3390/molecules29153622 - 31 Jul 2024

Cited by 1 | Viewed by 1101

Abstract

A description of new antimicrobial agents suitable for food industries has become necessary, and natural compounds are being considered as promising sources of new active derivatives to be used with the aim of improving food safety. We have previously described desirable antimicrobial and [...] Read more.

A description of new antimicrobial agents suitable for food industries has become necessary, and natural compounds are being considered as promising sources of new active derivatives to be used with the aim of improving food safety. We have previously described desirable antimicrobial and antibiofilm activities against foodborne bacteria by analogs to A-type proanthocyanidins (PACs) with a nitro (NO₂) group at carbon 6 of the A-ring. We report herein the synthesis of eight additional analogs with chloro and bromo atoms at the A-ring and the systematic study of their antimicrobial and antioxidant activities in order to evaluate their possible application as biocides or food preservatives, as well as to elucidate new structure–activity relationships. The results from this study show that halogenated analogs to natural A-type proanthocyanidins rise above the nitro derivatives previously reported in their antimicrobial activities. Gram-positive bacteria are the most sensitive to all the analogs and combinations assayed, showing MICs from 10 to 50 μg/mL in most cases, as well as reductions in biofilm formation and the disruption of preformed biofilms of at least 75%. Some structure–activity relationships previously described have also been corroborated. Analogs with just one OH group at the B-ring show better antimicrobial activities than those with two OH groups, and those analogs with two or three OH groups in the whole structure are more active than those with four OH groups. In addition, the analogs with two OH groups at the B-ring and chloro at the A-ring are the most effective when antibiofilm activities are studied, especially at low concentrations. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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14 pages, 2892 KiB

Open AccessArticle

Bioactive Naphthoquinone and Phenazine Analogs from the Endophytic Streptomyces sp. PH9030 as α-Glucosidase Inhibitors

by Qingxian Ma, Yani Zhong, Pingzhi Huang, Aijie Li, Ting Jiang, Lin Jiang, Hao Yang, Zhong Wang, Guangling Wu, Xueshuang Huang, Hong Pu and Jianxin Liu

Molecules 2024, 29(15), 3450; https://doi.org/10.3390/molecules29153450 - 23 Jul 2024

Cited by 1 | Viewed by 1196

Abstract

A talented endophytic Streptomyces sp. PH9030 is derived from the medicinal plant Kadsura coccinea (Lem.) A.C. Smith. The undescribed naphthoquinone naphthgeranine G (5) and seven previously identified compounds, 6–12, were obtained from Streptomyces sp. PH9030. The structure of [...] Read more.

A talented endophytic Streptomyces sp. PH9030 is derived from the medicinal plant Kadsura coccinea (Lem.) A.C. Smith. The undescribed naphthoquinone naphthgeranine G (5) and seven previously identified compounds, 6–12, were obtained from Streptomyces sp. PH9030. The structure of 5 was identified by comprehensive examination of its HRESIMS, 1D NMR, 2D NMR and ECD data. The inhibitory activities of all the compounds toward α-glucosidase and their antibacterial properties were investigated. The α-glucosidase inhibitory activities of 5, 6, 7 and 9 were reported for the first time, with IC₅₀ values ranging from 66.4 ± 6.7 to 185.9 ± 0.2 μM, as compared with acarbose (IC₅₀ = 671.5 ± 0.2 μM). The molecular docking and molecular dynamics analysis of 5 with α-glucosidase further indicated that it may have a good binding ability with α-glucosidase. Both 9 and 12 exhibited moderate antibacterial activity against methicillin-resistant Staphylococcus aureus, with minimum inhibitory concentration (MIC) values of 16 μg/mL. These results indicate that 5, together with the naphthoquinone scaffold, has the potential to be further developed as a possible inhibitor of α-glucosidase. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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14 pages, 2047 KiB

Open AccessArticle

Assessing the Effects of Thiazole-Carboxamide Derivatives on the Biophysical Properties of AMPA Receptor Complexes as a Potential Neuroprotective Agent

by Mohammad Qneibi, Mohammed Hawash, Sosana Bdir, Mohammad Bdair and Samia Ammar Aldwaik

Molecules 2024, 29(13), 3232; https://doi.org/10.3390/molecules29133232 - 8 Jul 2024

Viewed by 1741

Abstract

An optimal balance between excitatory and inhibitory transmission in the central nervous system provides essential neurotransmission for good functioning of the neurons. In the neurology field, a disturbed balance can lead to neurological diseases like epilepsy, Alzheimer’s, and Autism. One of the critical [...] Read more.

An optimal balance between excitatory and inhibitory transmission in the central nervous system provides essential neurotransmission for good functioning of the neurons. In the neurology field, a disturbed balance can lead to neurological diseases like epilepsy, Alzheimer’s, and Autism. One of the critical agents mediating excitatory neurotransmission is α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, which are concerned with synaptic plasticity, memory, and learning. An imbalance in neurotransmission finally results in excitotoxicity and neurological pathologies that should be corrected through specific compounds. Hence, the current study will prove to be an evaluation of new thiazole-carboxamide derivatives concerning AMPAR-modulating activity and extended medicinal potential. In the current project, five previously synthesized thiazole-carboxamide derivatives, i.e., TC-1 to TC-5, were used to interact with the AMPARs expressed in HEK293T cells, which overexpress different subunits of the AMPAR. Patch-clamp analysis was carried out while the effect of the drugs on AMPAR-mediated currents was followed with a particular emphasis on the kinetics of inhibition, desensitization, and deactivation. All tested TC compounds, at all subunits, showed potent inhibition of AMPAR-mediated currents, with TC-2 being the most powerful for all subunits. These compounds shifted the receptor kinetics efficiently, mainly enhancing the deactivation rates, and hence acted as a surrogate for their neuroprotective potentials. Additionally, recently published structure–activity relationship studies identified particular substituent groups as necessary for improving the pharmacologic profiles of these compounds. In this regard, thiazole-carboxamide derivatives, particularly those classified as TC-2, have become essential negative allosteric modulators of AMPAR function and potential therapeutics in neurological disturbances underlain by the dysregulation of excitatory neurotransmission. Given their therapeutic effectiveness and safety profiles, these in vivo studies need to be further validated, although computational modeling can be further developed for drug design and selectivity. This will open possibilities for new drug-like AMPAR negative allosteric modulators with applications at the clinical level toward neurology. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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20 pages, 3281 KiB

Open AccessArticle

Identification of Benzothiazoles Bearing 1,3,4-Thiadiazole as Antiproliferative Hybrids Targeting VEGFR-2 and BRAF Kinase: Design, Synthesis, BIO Evaluation and In Silico Study

by Wafaa A. Ewes, Samar S. Tawfik, Aya M. Almatary, Mashooq Ahmad Bhat, Hamed W. El-Shafey, Ahmed A. B. Mohamed, Abdullah Haikal, Mohammed A. El-Magd, Abdullah A. Elgazar, Marwa Balaha and Abdelrahman Hamdi

Molecules 2024, 29(13), 3186; https://doi.org/10.3390/molecules29133186 - 4 Jul 2024

Cited by 9 | Viewed by 1800

Abstract

Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop [...] Read more.

Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds—4a, 4f, 4l, and 4r—demonstrated remarkable cytotoxicity, with IC₅₀ values ranging from 3.58 to 15.36 μM, against three cancer cell lines. Furthermore, these compounds showed IC₅₀ values of 38.77–66.22 μM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC₅₀ values similar to sorafenib (0.071 and 0.194 μM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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14 pages, 1511 KiB

Open AccessFeature PaperArticle

Enantioselective Synthesis of the Active Sex Pheromone Components of the Female Lichen Moth, Lyclene dharma dharma, and Their Enantiomers

by Yun Zhou, Jianan Wang, Yueru Zhang, Xiaochen Fu, Hongqing Xie, Jinlong Han, Jianhua Zhang, Jiangchun Zhong and Chenggang Shan

Molecules 2024, 29(12), 2918; https://doi.org/10.3390/molecules29122918 - 19 Jun 2024

Viewed by 1153

Abstract

The Lichen moth, Lyclene dharma dharma (Arctiidae, Lithosiinae), plays a significant role in forest ecosystem dynamics. A concise and novel method to synthesize the active sex pheromone components, (S)-14-methyloctadecan-2-one ((S)-1), (S)-6-methyloctadecan-2-one (( [...] Read more.

The Lichen moth, Lyclene dharma dharma (Arctiidae, Lithosiinae), plays a significant role in forest ecosystem dynamics. A concise and novel method to synthesize the active sex pheromone components, (S)-14-methyloctadecan-2-one ((S)-1), (S)-6-methyloctadecan-2-one ((S)-2), and their enantiomers has been developed. Key steps in the synthesis include the use of Evans’ chiral auxiliaries, Grignard cross-coupling reactions, hydroboration–oxidation, and Wacker oxidation. The synthesized sex pheromone components hold potential value for studies on communication mechanisms, species identification, and ecological management. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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14 pages, 2040 KiB

Open AccessArticle

Synthesis and Photophysical Characterization of Fluorescent Naphtho[2,3-d]thiazole-4,9-Diones and Their Antimicrobial Activity against Staphylococcus Strains

by Masayori Hagimori, Fumiko Hara, Naoko Mizuyama, Shinya Takada, Saki Hayashi, Tamami Haraguchi, Yoshiro Hatanaka, Toshihiro Nagao, Shigemitsu Tanaka, Miki Yoshii and Miyako Yoshida

Molecules 2024, 29(12), 2777; https://doi.org/10.3390/molecules29122777 - 11 Jun 2024

Viewed by 1140

Abstract

The chemical reaction of 2-(methylsulfinyl)naphtho[2,3-d]thiazole-4,9-dione (3) using different amines, including benzylamine (4a), morpholine (4b), thiomorpholine (4c), piperidine (4d), and 4-methylpiperazine (4e), produced corresponding new tricyclic naphtho[2,3-d]thiazole–4,9–dione compounds [...] Read more.

The chemical reaction of 2-(methylsulfinyl)naphtho[2,3-d]thiazole-4,9-dione (3) using different amines, including benzylamine (4a), morpholine (4b), thiomorpholine (4c), piperidine (4d), and 4-methylpiperazine (4e), produced corresponding new tricyclic naphtho[2,3-d]thiazole–4,9–dione compounds (5a–e) in moderate-to-good yields. The photophysical properties and antimicrobial activities of these compounds (5a–e) were then characterized. Owing to the extended π-conjugated system of naphtho[2,3-d]thiazole–4,9–dione skeleton and substituent effect, 5a–e showed fluorescence both in solution and in the solid state. The introduction of nitrogen-containing heterocycles at position 2 of the thiazole ring on naphtho[2,3-d]thiazole-4,9-dione led to large bathochromic shifts in solution, and 5b–e exhibited orange-red fluorescence with emission maxima of over 600 nm in highly polar solvents. Staphylococcus aureus (S. aureus) is a highly pathogenic bacterium, and infection with its antimicrobial-resistant pathogen methicillin-resistant S. aureus (MRSA) results in serious clinical problems. In this study, we also investigated the antimicrobial activities of 5a–e against S. aureus, MRSA, and S. epidermidis. Compounds 5c with thiomorpholine group and 5e with 4-methylpiperazine group showed potent antimicrobial activity against these bacteria. These results will lead to the development of new fluorescent dyes with antimicrobial activity in the future. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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19 pages, 6703 KiB

Open AccessArticle

Design, Synthesis, and Antitumor Activity of Isoliquiritigenin Amino Acid Ester Derivatives

by Chi Liu, Xinyue Liu, Qing Ma, Fengyan Su and Enbo Cai

Molecules 2024, 29(11), 2641; https://doi.org/10.3390/molecules29112641 - 3 Jun 2024

Cited by 1 | Viewed by 1093

Abstract

Isoliquiritigenin (ISL) is a chalcone that has shown great potential in the treatment of cancer. However, its relatively weak activity and low water solubility limit its clinical application. In this study, we designed and synthesized 21 amino acid ester derivatives of ISL and [...] Read more.

Isoliquiritigenin (ISL) is a chalcone that has shown great potential in the treatment of cancer. However, its relatively weak activity and low water solubility limit its clinical application. In this study, we designed and synthesized 21 amino acid ester derivatives of ISL and characterized the compounds using ¹H NMR and ¹³C NMR. Among them, compound 9 (IC₅₀ = 14.36 μM) had a better inhibitory effect on human cervical cancer (Hela) than ISL (IC₅₀ = 126.5 μM), and it was superior to the positive drug 5-FU (IC₅₀ = 33.59 μM). The mechanism of the action experiment showed that compound 9 could induce Hela cell apoptosis and autophagy through the PI3K/Akt/mTOR pathway. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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28 pages, 7372 KiB

Open AccessArticle

Are Terminal Alkynes Necessary for MAO-A/MAO-B Inhibition? A New Scaffold Is Revealed

by Panagiou Mavroeidi, Leandros P. Zorba, Nikolaos V. Tzouras, Stavros P. Neofotistos, Nikitas Georgiou, Kader Sahin, Murat Şentürk, Serdar Durdagi, Georgios C. Vougioukalakis and Thomas Mavromoustakos

Molecules 2024, 29(11), 2486; https://doi.org/10.3390/molecules29112486 - 24 May 2024

Cited by 1 | Viewed by 1390

Abstract

A versatile family of quaternary propargylamines was synthesized employing the KA² multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of [...] Read more.

A versatile family of quaternary propargylamines was synthesized employing the KA² multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC₅₀ values for hMAO-B range from 152.1 to 164.7 nM while the IC₅₀ values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski’s rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson’s disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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25 pages, 5588 KiB

Open AccessArticle

Synthesis, In Vivo Anticonvulsant Activity Evaluation and In Silico Studies of Some Quinazolin-4(3H)-One Derivatives

by Raluca Pele, Gabriel Marc, Cristina Mogoșan, Anamaria Apan, Ioana Ionuț, Brîndușa Tiperciuc, Cristina Moldovan, Cătălin Araniciu, Ilioara Oniga, Adrian Pîrnău, Laurian Vlase and Ovidiu Oniga

Molecules 2024, 29(9), 1951; https://doi.org/10.3390/molecules29091951 - 24 Apr 2024

Cited by 3 | Viewed by 1898

Abstract

Two series, “a” and “b”, each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABA_A receptor at the [...] Read more.

Two series, “a” and “b”, each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABA_A receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D_1–3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABA_A receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABA_A receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a–9a and 1b–9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the “b” series, particularly for compound 8b. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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Review

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61 pages, 53143 KiB

Open AccessReview

Biological Activities of Novel Oleanolic Acid Derivatives from Bioconversion and Semi-Synthesis

by Nahla Triaa, Mansour Znati, Hichem Ben Jannet and Jalloul Bouajila

Molecules 2024, 29(13), 3091; https://doi.org/10.3390/molecules29133091 - 28 Jun 2024

Cited by 4 | Viewed by 1780

Abstract

Oleanolic acid (OA) is a vegetable chemical that is present naturally in a number of edible and medicinal botanicals. It has been extensively studied by medicinal chemists and scientific researchers due to its biological activity against a wide range of diseases. A significant [...] Read more.

Oleanolic acid (OA) is a vegetable chemical that is present naturally in a number of edible and medicinal botanicals. It has been extensively studied by medicinal chemists and scientific researchers due to its biological activity against a wide range of diseases. A significant number of researchers have synthesized a variety of analogues of OA by modifying its structure with the intention of creating more potent biological agents and improving its pharmaceutical properties. In recent years, chemical and enzymatic techniques have been employed extensively to investigate and modify the chemical structure of OA. This review presents recent advancements in medical chemistry for the structural modification of OA, with a special focus on the biotransformation, semi-synthesis and relationship between the modified structures and their biopharmaceutical properties. Full article

(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)

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