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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

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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

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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

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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

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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

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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

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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

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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

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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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