Research

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19 pages, 10622 KiB

Open AccessArticle

One-Pot Synthesis of Novel Multisubstituted 1-Alkoxyindoles

by Ye Eun Kim, Hyunsung Cho, Yoo Jin Lim, Chorong Kim and Sang Hyup Lee

Molecules 2021, 26(5), 1466; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26051466 - 08 Mar 2021

Cited by 3 | Viewed by 1898

Studies on a one-pot synthesis of novel multisubstituted 1-alkoxyindoles 1 and their mechanistic investigations are presented. The synthesis of 1 was successfully achieved through consecutive four step reactions from substrates 2. The substrates 2, prepared through a two-step synthetic sequence, underwent [...] Read more.

Studies on a one-pot synthesis of novel multisubstituted 1-alkoxyindoles 1 and their mechanistic investigations are presented. The synthesis of 1 was successfully achieved through consecutive four step reactions from substrates 2. The substrates 2, prepared through a two-step synthetic sequence, underwent three consecutive reactions of nitro reduction, intramolecular condensation, and nucleophilic 1,5-addition to provide the intermediates, 1-hydroxyindoles 8, which then were alkylated in situ with alkyl halide to afford the novel target products 1. We optimized the reaction conditions for 1 focusing on the alkylation step, along with the consideration of formation of intermediates 8. The optimized condition was SnCl₂·2H₂O (3.3 eq) and alcohols (R¹OH, 2.0 eq) for 1–2 h at 40 °C and then, base (10 eq) and alkyl halides (R²Y, 2.0 eq) for 1–4 h at 25–50 °C. Notably, all four step reactions were performed in one-pot to give 1 in good to modest yields. Furthermore, the mechanistic aspects were also discussed regarding the reaction pathways and the formation of side products. The significance lies in development of efficient one-pot reactions and in generation of new 1-alkoxyindoles. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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16 pages, 8892 KiB

Open AccessArticle

Bioresearch of New 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones

by Dominika Szkatuła, Edward Krzyżak, Szczepan Mogilski, Jacek Sapa, Barbara Filipek and Piotr Świątek

Molecules 2020, 25(24), 5883; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25245883 - 12 Dec 2020

Cited by 3 | Viewed by 2078

Abstract

The subject of the work was the synthesis of new derivatives of1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione with potential analgesic and sedative activity. Eight compounds werereceived. The analgesic activity of the new compounds was confirmed in the “hot plate” test and in the “writhing” [...] Read more.

The subject of the work was the synthesis of new derivatives of1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione with potential analgesic and sedative activity. Eight compounds werereceived. The analgesic activity of the new compounds was confirmed in the “hot plate” test and in the “writhing” test. All tested imides 8–15 were more active in the “writhing” test than aspirin, and two of them, 9 and 11, were similar to morphine. In addition, all of the new imides inhibited the locomotor activity in mice to a statistically significant extent, and two of them also prolonged the duration of thiopental sleep.On the basis of the results obtained for the previously synthesized imides and the results presented in this paper, an attempt was madeto determine the relationship between thechemical structure of imides and their analgesic and sedativeproperties. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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26 pages, 12602 KiB

Open AccessArticle

Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer’s Disease

by Rosa Purgatorio, Nicola Gambacorta, Marco Catto, Modesto de Candia, Leonardo Pisani, Alba Espargaró, Raimon Sabaté, Saverio Cellamare, Orazio Nicolotti and Cosimo D. Altomare

Molecules 2020, 25(23), 5773; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25235773 - 07 Dec 2020

Cited by 10 | Viewed by 3538

Abstract

Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aβ) aggregation, a hallmark of pathophysiology of Alzheimer’s disease. The newly synthesized molecules spanned their IC₅₀ values from sub- [...] Read more.

Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aβ) aggregation, a hallmark of pathophysiology of Alzheimer’s disease. The newly synthesized molecules spanned their IC₅₀ values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the ‘active’ compounds from the ‘inactive’ (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of ‘active’ compounds, i.e., those achieving finite IC₅₀ values lower than 100 μM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set (n = 45, q² = 0.596) and in the external test set (n = 14, r²_ext = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the Aβ anti-aggregating potency of the indole and isatin derivatives studied herein. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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19 pages, 4111 KiB

Open AccessArticle

Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria

by Gian Marco Elisi, Annalida Bedini, Laura Scalvini, Caterina Carmi, Silvia Bartolucci, Valeria Lucini, Francesco Scaglione, Marco Mor, Silvia Rivara and Gilberto Spadoni

Molecules 2020, 25(18), 4057; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184057 - 04 Sep 2020

Cited by 8 | Viewed by 2824

Abstract

N-anilinoethylamides are a class of melatoninergic agents with the aniline portion mimicking the indole ring of the natural ligand and the ethylamide chain reproducing that of melatonin. The simplest compound in this class, N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (UCM793), has nanomolar binding affinity for MT [...] Read more.

N-anilinoethylamides are a class of melatoninergic agents with the aniline portion mimicking the indole ring of the natural ligand and the ethylamide chain reproducing that of melatonin. The simplest compound in this class, N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (UCM793), has nanomolar binding affinity for MT₁ and MT₂ membrane receptors. To explore the effect of chain conformation on receptor binding, a methyl group was inserted on the methylene alpha or beta to the amide nitrogen and conformational equilibria were investigated by NMR spectroscopy and molecular dynamics simulations. Receptor affinity was conserved only for the beta-methyl derivative, which also showed significant stereoselectivity, with the (S) enantiomer being the eutomer. Molecular dynamics simulations, validated by NMR spectroscopy, showed that the beta-methyl group affects the conformational preferences of the ethylamide chain. Docking into the receptor crystal structure provides a rationale for the observed chiral recognition, suggesting that the (S)-beta-methyl group favors the conformation that better fits the receptor binding site. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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19 pages, 4678 KiB

Open AccessFeature PaperArticle

5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)alkancarboxylic Acids as Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Studies

by Volodymyr Horishny, Victor Kartsev, Athina Geronikaki, Vasyl Matiychuk, Anthi Petrou, Jasmina Glamoclija, Ana Ciric and Marina Sokovic

Molecules 2020, 25(8), 1964; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25081964 - 23 Apr 2020

Cited by 21 | Viewed by 3308

Abstract

Background: Infectious diseases symbolize a global consequential strain on public health security and impact on the socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in crucial need for the discovery and development of novel entity [...] Read more.

Background: Infectious diseases symbolize a global consequential strain on public health security and impact on the socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in crucial need for the discovery and development of novel entity for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using classical methods of organic synthesis. Results: All 20 synthesized compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species. It should be mentioned that all compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Furthermore, 18 compounds appeared to be more potent than streptomycin against Staphylococcus aureus, Enterobacter cloacae, Pseudomonas aeruginosa, Listeria monocytogenes, and Escherichia coli. Three the most active compounds 4h, 5b, and 5g appeared to be more potent against MRSA than ampicillin, while streptomycin did not show any bactericidal activity. All three compounds displayed better activity also against resistant strains P. aeruginosa and E. coli than ampicillin. Furthermore, all compounds were able to inhibit biofilm formation 2- to 4-times more than both reference drugs. Compounds were evaluated also for their antifungal activity against eight species. The evaluation revealed that all compounds exhibited antifungal activity better than the reference drugs bifonazole and ketoconazole. Molecular docking studies on antibacterial and antifungal targets were performed in order to elucidate the mechanism of antibacterial activity of synthesized compounds. Conclusion: All tested compounds showed good antibacterial and antifungal activity better than that of reference drugs and three the most active compounds could consider as lead compounds for the development of new more potent agents. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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Review

Jump to: Research

21 pages, 11150 KiB

Open AccessFeature PaperReview

From Riluzole to Dexpramipexole via Substituted-Benzothiazole Derivatives for Amyotrophic Lateral Sclerosis Disease Treatment: Case Studies

by Serge Mignani, Jean-Pierre Majoral, Jean-François Desaphy and Giovanni Lentini

Molecules 2020, 25(15), 3320; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153320 - 22 Jul 2020

Cited by 20 | Viewed by 5223

Abstract

The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug [...] Read more.

The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of dexpramipexole, which was one of the most promising drugs against ALS. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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26 pages, 14731 KiB

Open AccessFeature PaperReview

Continuous Flow Synthesis of Heterocycles: A Recent Update on the Flow Synthesis of Indoles

by Marco Colella, Leonardo Degennaro and Renzo Luisi

Molecules 2020, 25(14), 3242; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25143242 - 16 Jul 2020

Cited by 27 | Viewed by 4816

Abstract

Indole derivatives are among the most useful and interesting heterocycles employed in drug discovery and medicinal chemistry. In addition, flow chemistry and flow technology are changing the synthetic paradigm in the field of modern synthesis. In this review, the role of flow technology [...] Read more.

Indole derivatives are among the most useful and interesting heterocycles employed in drug discovery and medicinal chemistry. In addition, flow chemistry and flow technology are changing the synthetic paradigm in the field of modern synthesis. In this review, the role of flow technology in the preparation of indole derivatives is showcased. Selected examples have been described with the aim to provide readers with an overview on the tactics and technologies used for targeting indole scaffolds. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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27 pages, 5348 KiB

Open AccessReview

Exploiting the Indole Scaffold to Design Compounds Binding to Different Pharmacological Targets

by Sabrina Taliani, Federico Da Settimo, Claudia Martini, Sonia Laneri, Ettore Novellino and Giovanni Greco

Molecules 2020, 25(10), 2331; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25102331 - 16 May 2020

Cited by 15 | Viewed by 3055

Abstract

Several indole derivatives have been disclosed by our research groups that have been collaborating for nearly 25 years. The results of our investigations led to a variety of molecules binding selectively to different pharmacological targets, specifically the type A γ-aminobutyric acid (GABA_A [...] Read more.

Several indole derivatives have been disclosed by our research groups that have been collaborating for nearly 25 years. The results of our investigations led to a variety of molecules binding selectively to different pharmacological targets, specifically the type A γ-aminobutyric acid (GABA_A) chloride channel, the translocator protein (TSPO), the murine double minute 2 (MDM2) protein, the A_2B adenosine receptor (A_2B AR) and the Kelch-like ECH-associated protein 1 (Keap1). Herein, we describe how these works were conceived and carried out thanks to the versatility of indole nucleus to be exploited in the design and synthesis of drug-like molecules. Full article

(This article belongs to the Special Issue Indole and Its Bioisosteric Replacements in Medicinal Chemistry)

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