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5 pages, 199 KiB

Open AccessEditorial

Indole Derivatives: Unveiling New Frontiers in Medicinal and Synthetic Organic Chemistry

by Faiza Saleem and Khalid Mohammed Khan

Molecules 2023, 28(14), 5477; https://doi.org/10.3390/molecules28145477 - 18 Jul 2023

Cited by 5 | Viewed by 1731

Abstract

In recent years, significant attention has been given to indoles, a diverse group of heterocyclic compounds widely found in nature that play a crucial role in various bioactive natural and synthetic substances [...] Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

Research

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15 pages, 2313 KiB

Open AccessArticle

Novel Approach to the Construction of Fused Indolizine Scaffolds: Synthesis of Rosettacin and the Aromathecin Family of Compounds

by Shohta Mizuno, Takashi Nishiyama, Mai Endo, Koharu Sakoguchi, Takaki Yoshiura, Hana Bessho, Toshio Motoyashiki, Noriyuki Hatae and Tominari Choshi

Molecules 2023, 28(10), 4059; https://doi.org/10.3390/molecules28104059 - 12 May 2023

Cited by 5 | Viewed by 1805

Abstract

Camptothecin-like compounds are actively employed as anticancer drugs in clinical treatments. The aromathecin family of compounds, which contains the same indazolidine core structure as the camptothecin family of compounds, is also expected to display promising anticancer activity. Therefore, the development of a suitable [...] Read more.

Camptothecin-like compounds are actively employed as anticancer drugs in clinical treatments. The aromathecin family of compounds, which contains the same indazolidine core structure as the camptothecin family of compounds, is also expected to display promising anticancer activity. Therefore, the development of a suitable and scalable synthetic method of aromathecin synthesis is of great research interest. In this study, we report the development of a new synthetic approach for constructing the pentacyclic scaffold of the aromathecin family by forming the indolizidine moiety after synthesizing the isoquinolone moiety. Thermal cyclization of 2-alkynylbenzaldehyde oxime to the isoquinoline N-oxide, followed by a Reissert–Henze-type reaction, forms the key strategy in this isoquinolone synthesis. Under the optimum reaction conditions for the Reissert–Henze-type reaction step, microwave irradiation-assisted heating of the purified N-oxide in acetic anhydride at 50 °C reduced the formation of the 4-acetoxyisoquinoline byproduct to deliver the desired isoquinolone at a 73% yield after just 3.5 h. The eight-step sequence employed afforded rosettacin (simplest member of the aromathecin family) at a 23.8% overall yield. The synthesis of rosettacin analogs was achieved by applying the developed strategy and may be generally applicable to the production of other fused indolizidine compounds. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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22 pages, 6020 KiB

Open AccessArticle

Indomethacin: Effect of Diffusionless Crystal Growth on Thermal Stability during Long-Term Storage

by Roman Svoboda, Nicola Koutná, Daniela Košťálová, Miloš Krbal and Alena Komersová

Molecules 2023, 28(4), 1568; https://doi.org/10.3390/molecules28041568 - 6 Feb 2023

Cited by 7 | Viewed by 1547

Abstract

Differential scanning calorimetry and Raman spectroscopy were used to study the nonisothermal and isothermal crystallization behavior of amorphous indomethacin powders (with particle sizes ranging from 50 to 1000 µm) and their dependence on long-term storage conditions, either 0–100 days stored freely at laboratory [...] Read more.

Differential scanning calorimetry and Raman spectroscopy were used to study the nonisothermal and isothermal crystallization behavior of amorphous indomethacin powders (with particle sizes ranging from 50 to 1000 µm) and their dependence on long-term storage conditions, either 0–100 days stored freely at laboratory ambient temperatures and humidity or placed in a desiccator at 10 °C. Whereas the γ-form polymorph always dominated, the accelerated formation of the α-form was observed in situations of heightened mobility (higher temperature and heating rate), increased amounts of mechanically induced defects, and prolonged free-surface nucleation. A complex crystallization behavior with two separated crystal growth modes (originating from either the mechanical defects or the free surface) was identified both isothermally and nonisothermally. The diffusionless glass–crystal (GC) crystal growth was found to proceed during the long-term storage at 10 °C and zero humidity, at the rate of ~100 µm of the γ-form surface crystalline layer being formed in 100 days. Storage at the laboratory temperature (still below the glass transition temperature) and humidity led only to a negligible/nondetectable GC growth for the fine indomethacin powders (particle size below ~150 µm), indicating a marked suppression of GC growth by the high density of mechanical defects under these conditions. The freely stored bulk material with no mechanical damage and a smooth surface exhibited zero traces of GC growth (as confirmed by microscopy) after >150 days of storage. The accuracy of the kinetic predictions of the indomethacin crystallization behavior was rather poor due to the combined influences of the mechanical defects, competing nucleation, and crystal growth processes of the two polymorphic phases as well as the GC growth complex dependence on the storage conditions within the vicinity of the glass transition temperature. Performing paired isothermal and nonisothermal kinetic measurements is thus highly recommended in macroscopic crystallization studies of drugs with similarly complicated crystal growth behaviors. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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16 pages, 4098 KiB

Open AccessArticle

Novel Indole-Containing Hybrids Derived from Millepachine: Synthesis, Biological Evaluation and Antitumor Mechanism Study

by Baoxia Liang, Qing Zou, Lintao Yu, Yali Wang, Jun Yan and Baiqi Huang

Molecules 2023, 28(3), 1481; https://doi.org/10.3390/molecules28031481 - 3 Feb 2023

Cited by 7 | Viewed by 2037

Abstract

Millepachine, a bioactive natural product isolated from the seeds of Millettia pachycarpa, is reported to display potential antitumor activity. In this study, novel indole-containing hybrids derived from millepachine were designed, synthesized and evaluated for their antitumor activities. Among all the compounds, compound 14b [...] Read more.

Millepachine, a bioactive natural product isolated from the seeds of Millettia pachycarpa, is reported to display potential antitumor activity. In this study, novel indole-containing hybrids derived from millepachine were designed, synthesized and evaluated for their antitumor activities. Among all the compounds, compound 14b exhibited the most potent cytotoxic activity against five kinds of human cancer cell lines, with IC₅₀ values ranging from 0.022 to 0.074 μM, making it almost 100 times more active than millepachine. Valuable structure–activity relationships (SARs) were obtained. Furthermore, the mechanism studies showed that compound 14b induced cell-cycle arrest at the G2/M phase by inhibiting tubulin polymerization and further induced cell apoptosis through reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) collapse. In addition, the low cytotoxicity toward normal human cells and equivalent sensitivity towards drug-resistant cells of compound 14b highlighted its potential for the development of antitumor drugs. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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20 pages, 2884 KiB

Open AccessFeature PaperArticle

Indole Derivatives Bearing Imidazole, Benzothiazole-2-Thione or Benzoxazole-2-Thione Moieties—Synthesis, Structure and Evaluation of Their Cytoprotective, Antioxidant, Antibacterial and Fungicidal Activities

by Beata Jasiewicz, Karolina Babijczuk, Beata Warżajtis, Urszula Rychlewska, Justyna Starzyk, Grzegorz Cofta and Lucyna Mrówczyńska

Molecules 2023, 28(2), 708; https://doi.org/10.3390/molecules28020708 - 10 Jan 2023

Cited by 13 | Viewed by 4160

Abstract

In the search for new bioactive compounds, a methodology based on combining two molecules with biological properties into a new hybrid molecule was used to design and synthesize of a series of ten indole derivatives bearing imidazole, benzothiazole-2-thione, or benzoxazole-2-thione moieties at the [...] Read more.

In the search for new bioactive compounds, a methodology based on combining two molecules with biological properties into a new hybrid molecule was used to design and synthesize of a series of ten indole derivatives bearing imidazole, benzothiazole-2-thione, or benzoxazole-2-thione moieties at the C-3 position. The compounds were spectroscopically characterized and tested for their antioxidant, antibacterial, and fungicidal activities. The crystal structures were determined for five of them. Comparison of the closely related structures containing either benzothiazole-2-thione or benzoxazole-2-thione clearly shows that the replacement of -S- and -O- ring atoms modify molecular conformation in the crystal, changes intermolecular interactions, and has a severe impact on biological activity. The results indicate that indole-imidazole derivatives with alkyl substituent exhibit an excellent cytoprotective effect against AAPH-induced oxidative hemolysis and act as effective ferrous ion chelating agents. The indole-imidazole compound with chlorine atoms inhibited the growth of fungal strains: Coriolus versicolor (Cv), Poria placenta (Pp), Coniophora puteana (Cp), and Gloeophyllum trabeum (Gt). The indole-imidazole derivatives showed the highest antibacterial activity, for which the largest growth-inhibition zones were noted in M. luteus and P. fluorescens cultures. The obtained results may be helpful in the development of selective indole derivatives as effective antioxidants and/or antimicrobial agents. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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24 pages, 9423 KiB

Open AccessArticle

Synthesis, Structural and Behavioral Studies of Indole Derivatives D2AAK5, D2AAK6 and D2AAK7 as Serotonin 5-HT_1A and 5-HT_2A Receptor Ligands

by Agnieszka A. Kaczor, Ewa Kędzierska, Tomasz M. Wróbel, Angelika Grudzińska, Angelika Pawlak, Tuomo Laitinen and Agata Bartyzel

Molecules 2023, 28(1), 383; https://doi.org/10.3390/molecules28010383 - 2 Jan 2023

Cited by 4 | Viewed by 2889

Abstract

Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Here we report synthesis and detailed structural and behavioral studies of three indole derivatives: D2AAK5, D2AAK6, and D2AAK7 as serotonin [...] Read more.

Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Here we report synthesis and detailed structural and behavioral studies of three indole derivatives: D2AAK5, D2AAK6, and D2AAK7 as serotonin 5-HT_1A and 5-HT_2A receptor ligands. X-ray studies revealed that the D2AAK5 compound crystallizes in centrosymmetric triclinic space group with one molecule in the asymmetric unit. The main interaction between the ligands and the receptors is the salt bridge between the protonatable nitrogen atom of the ligands and the conserved Asp (3.32) of the receptors. The complexes were stable in the molecular dynamic simulations. MD revealed that the studied ligands are relatively stable in their binding sites, with the exception of D2AAK7 in the serotonin 5-HT_1A receptor. D2AAK7 exerts anxiolytic activity in the EPM test, while D2AAK5 has a beneficial effect on the memory processes in the PA test. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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10 pages, 5066 KiB

Open AccessArticle

Chemoenzymatic Synthesis of Indole-Containing Acyloin Derivatives

by Saad Alrashdi, Federica Casolari, Aziz Alabed, Kwaku Kyeremeh and Hai Deng

Molecules 2023, 28(1), 354; https://doi.org/10.3390/molecules28010354 - 1 Jan 2023

Cited by 2 | Viewed by 2873

Abstract

Indole-containing acyloins are either key intermediates of many antimicrobial/antiviral natural products or building blocks in the synthesis of biologically active molecules. As such, access to structurally diverse indole-containing acyloins has attracted considerable attention. In this report, we present a pilot study of using [...] Read more.

Indole-containing acyloins are either key intermediates of many antimicrobial/antiviral natural products or building blocks in the synthesis of biologically active molecules. As such, access to structurally diverse indole-containing acyloins has attracted considerable attention. In this report, we present a pilot study of using biotransformation to provide acyloins that contain various indole substituents. The biotransformation system contains the tryptophan synthase standalone β-subunit variant, PfTrpB⁶, generated from directed evolution in the literature; a commercially available L-amino acid oxidase (LAAO); and the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of the first two enzymes, the PfTrpB variant and LAAO, is designed to provide structurally diverse indole 3-pyruvate derivatives as donor substrates for NzsH-catalysed biotransformation to provide acyloin derivatives. Our results demonstrate that NzsH displays a considerable substrate profile toward donor substrates for production of acyloins with different indole ring systems, suggesting that NzsH could be further explored as a potential biocatalyst via directed evolution to improve the catalytic efficiency in the future. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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15 pages, 1765 KiB

Open AccessArticle

Synthesis and Antiproliferative Activity against Cancer Cells of Indole-Aryl-Amide Derivatives

by Junwei Zhao, Jacopo Carbone, Giovanna Farruggia, Anna Janecka, Luca Gentilucci and Natalia Calonghi

Molecules 2023, 28(1), 265; https://doi.org/10.3390/molecules28010265 - 28 Dec 2022

Cited by 4 | Viewed by 2034

Abstract

Indoles constitute a large family of heterocyclic compounds widely occurring in nature which are present in a number of bioactive natural and synthetic compounds, including anticancer agents or atypical opioid agonists. As a result, exponential increases in the development of novel methods for [...] Read more.

Indoles constitute a large family of heterocyclic compounds widely occurring in nature which are present in a number of bioactive natural and synthetic compounds, including anticancer agents or atypical opioid agonists. As a result, exponential increases in the development of novel methods for the synthesis of indole-containing compounds have been reported in the literature. A series of indole-aryl amide derivatives 1–7 containing tryptamine or an indolylacetic acid nucleus were designed, synthesized, and evaluated as opioid ligands. These new indole derivatives showed negligible to very low affinity for μ- and δ-opioid receptor (OR). On the other hand, compounds 2, 5 and 7 showed Ki values in the low μM range for κ-OR. Since indoles are well known for their anticancer potential, their effect against a panel of tumor cell lines was tested. The target compounds were evaluated for their in vitro cytotoxicity in HT29, HeLa, IGROV-1, MCF7, PC-3, and Jurkat J6 cells. Some of the synthesized compounds showed good activity against the selected tumor cell lines, with the exception of IGROV1. In particular, compound 5 showed a noteworthy selectivity towards HT29 cells, a malignant colonic cell line, without affecting healthy human intestinal cells. Further studies revealed that 5 caused the cell cycle arrest in the G1 phase and promoted apoptosis in HT29 cells. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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19 pages, 4099 KiB

Open AccessArticle

Design, Synthesis and Antiproliferative Evaluation of Bis-Indole Derivatives with a Phenyl Linker: Focus on Autophagy

by Marianna Budovska, Radka Michalkova, Martin Kello, Janka Vaskova and Jan Mojzis

Molecules 2023, 28(1), 251; https://doi.org/10.3390/molecules28010251 - 28 Dec 2022

Cited by 6 | Viewed by 2166

Abstract

This work deals with the study of the synthesis of new bis-indole analogues with a phenyl linker derived from indole phytoalexins. Synthesis of target bis-indole thiourea linked by a phenyl linker was achieved by the reaction of [1-(tert-butoxycarbonyl)indol-3-yl]methyl isothiocyanate with p-phenylenediamine. By replacing [...] Read more.

This work deals with the study of the synthesis of new bis-indole analogues with a phenyl linker derived from indole phytoalexins. Synthesis of target bis-indole thiourea linked by a phenyl linker was achieved by the reaction of [1-(tert-butoxycarbonyl)indol-3-yl]methyl isothiocyanate with p-phenylenediamine. By replacing the sulfur of the thiocarbonyl group in bis-indole thiourea with oxygen using mesityl nitrile oxide, a bis-indole homodimer with a urea group was obtained. A cyclization protocol utilizing bis-indole thiourea and methyl bromoacetate was applied to synthesize a bis-indole homodimer with a thiazolidin-4-one moiety. Bis-indole homodimers derived from 1-methoxyspirobrassinol methyl ether were prepared by bromospirocyclization methodology. Among the synthesized analogues, compound 49 was selected for further study. To evaluate the mode of the mechanism of action, we used flow cytometry, Western blot, and spectroscopic analyses. Compound 49 significantly inhibited the proliferation of lung cancer cell line A549 with minimal effects on the non-cancer cells. We also demonstrated that compound 49 induced autophagy through the upregulation of Beclin-1, LC3A/B, Atg7 and AMPK and ULK1. Furthermore, chloroquine (CQ; an autophagy inhibitor) in combination with compound 49 decreased cell proliferation and induced G1 cell cycle arrest and apoptosis. Compound 49 also caused GSH depletion and significantly potentiated the antiproliferative effect of cis-platin. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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18 pages, 1169 KiB

Open AccessArticle

Hypsizygus marmoreus as a Source of Indole Compounds and Other Bioactive Substances with Health-Promoting Activities

by Katarzyna Kała, Wojciech Pająk, Katarzyna Sułkowska-Ziaja, Agata Krakowska, Jan Lazur, Maciej Fidurski, Krystian Marzec, Piotr Zięba, Agata Fijałkowska, Agnieszka Szewczyk and Bożena Muszyńska

Molecules 2022, 27(24), 8917; https://doi.org/10.3390/molecules27248917 - 15 Dec 2022

Cited by 9 | Viewed by 2646

Abstract

Hypsizygus marmoreus is an edible medicinal mushroom species with a high dietary value. In this study, the fruiting bodies of commercial and self-cultivated crops and mycelium from in vitro H. marmoreus cultures (both white and brown varieties) were evaluated. This study aimed to [...] Read more.

Hypsizygus marmoreus is an edible medicinal mushroom species with a high dietary value. In this study, the fruiting bodies of commercial and self-cultivated crops and mycelium from in vitro H. marmoreus cultures (both white and brown varieties) were evaluated. This study aimed to analyze the presence of indole compounds and other biologically active substances and determine the effect that the addition of zinc and magnesium ions to the culture medium has on the content of the tested compounds in mycelial cultures. The content of indole compounds and other organic compounds was determined using high-performance liquid chromatography, the content of bioelements was determined using flame atomic absorption spectrometry, the glucan content was determined spectrophotometrically, and the antioxidant activity of extracts was estimated using DPPH, FRAP, and ABTS methods. The results showed that H. marmoreus mycelium from in vitro cultures is a good source of indole compounds, bioelements, glucans, and lovastatin. Mycelia from in vitro cultures showed the most diverse composition of indole compounds (L-tryptophan, 5-hydroxy-L-tryptophan, tryptamine, 5-methyltryptamine, and melatonin). Additionally, in vitro cultures of H. marmoreus enriched with Zn and Mg salts increased the contents of Na, Ca, Zn, 5-methyltryptamine, melatonin, protocatechuic acid, sterols, and total glucans. Only in the case of the white variety of mycelial enriched cultures, ergothioneine and Mg levels also increased. To summarize, the content of the active compounds differed depending on the H. marmoreus variety and the tested material. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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17 pages, 5783 KiB

Open AccessArticle

Syntheses of New Multisubstituted 1-Acyloxyindole Compounds

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

Molecules 2022, 27(19), 6769; https://doi.org/10.3390/molecules27196769 - 10 Oct 2022

Cited by 2 | Viewed by 1758

Abstract

The syntheses of novel 1-acyloxyindole compounds 1 and the investigations on reaction pathways are presented. Nitro ketoester substrate 2, obtained in a two-step synthetic process, underwent reduction, intramolecular addition, nucleophilic 1,5-addition, and acylation to afford 1-acyloxyindoles 1 in one pot. Based on [...] Read more.

The syntheses of novel 1-acyloxyindole compounds 1 and the investigations on reaction pathways are presented. Nitro ketoester substrate 2, obtained in a two-step synthetic process, underwent reduction, intramolecular addition, nucleophilic 1,5-addition, and acylation to afford 1-acyloxyindoles 1 in one pot. Based on the systematic studies, we established the optimized reaction conditions for 1 focusing on the final acylation step of the intermediate 1-hydroxyindole 8. With the optimized conditions, we succeeded in synthesizing 21 examples of new 1-acyloxyindole derivatives 1 in modest yields (Y = 24 − 35%). Among the 1-acyloxyindole compounds, 1-acetoxyindole compounds 1x were generally unstable, and their yields were relatively lower than the other 1-acyloxyindoles. We expect that a bulkier alkyl or aromatic group on R² could stabilize the 1-acyloxyindole compounds. Significantly, one-pot reactions of a four-step sequence successfully generated compounds 1 that are all new and might be difficult to be synthesized otherwise. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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Review

Jump to: Editorial, Research

19 pages, 2797 KiB

Open AccessReview

Target-Based Anticancer Indole Derivatives for the Development of Anti-Glioblastoma Agents

by Silvia Salerno, Elisabetta Barresi, Emma Baglini, Valeria Poggetti, Federico Da Settimo and Sabrina Taliani

Molecules 2023, 28(6), 2587; https://doi.org/10.3390/molecules28062587 - 13 Mar 2023

Cited by 13 | Viewed by 2738

Abstract

Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor, with a poor prognosis and the highest mortality rate. Currently, GBM therapy consists of surgical resection of the tumor, radiotherapy, and adjuvant chemotherapy with temozolomide. Consistently, there are poor treatment options and [...] Read more.

Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor, with a poor prognosis and the highest mortality rate. Currently, GBM therapy consists of surgical resection of the tumor, radiotherapy, and adjuvant chemotherapy with temozolomide. Consistently, there are poor treatment options and only modest anticancer efficacy is achieved; therefore, there is still a need for the development of new effective therapies for GBM. Indole is considered one of the most privileged scaffolds in heterocyclic chemistry, so it may serve as an effective probe for the development of new drug candidates against challenging diseases, including GBM. This review analyzes the therapeutic benefit and clinical development of novel indole-based derivatives investigated as promising anti-GBM agents. The existing indole-based compounds which are in the pre-clinical and clinical stages of development against GBM are reported, with particular reference to the most recent advances between 2013 and 2022. The main mechanisms of action underlying their anti-GBM efficacy, such as protein kinase, tubulin and p53 pathway inhibition, are also discussed. The final goal is to pave the way for medicinal chemists in the future design and development of novel effective indole-based anti-GBM agents. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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34 pages, 7932 KiB

Open AccessReview

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

by Haofan Zhang, Fengming He, Guiping Gao, Sheng Lu, Qiaochu Wei, Hongyu Hu, Zhen Wu, Meijuan Fang and Xiumin Wang

Molecules 2023, 28(3), 943; https://doi.org/10.3390/molecules28030943 - 17 Jan 2023

Cited by 7 | Viewed by 3513

Abstract

Kinases are among the most important families of biomolecules and play an essential role in the regulation of cell proliferation, apoptosis, metabolism, and other critical physiological processes. The dysregulation and gene mutation of kinases are linked to the occurrence and development of various [...] Read more.

Kinases are among the most important families of biomolecules and play an essential role in the regulation of cell proliferation, apoptosis, metabolism, and other critical physiological processes. The dysregulation and gene mutation of kinases are linked to the occurrence and development of various human diseases, especially cancer. As a result, a growing number of small-molecule drugs based on kinase targets are being successfully developed and approved for the treatment of many diseases. The indole/azaindole/oxindole moieties are important key pharmacophores of many bioactive compounds and are generally used as excellent scaffolds for drug discovery in medicinal chemistry. To date, 30 ATP-competitive kinase inhibitors bearing the indole/azaindole/oxindole scaffold have been approved for the treatment of diseases. Herein, we summarize their research and development (R&D) process and describe their binding models to the ATP-binding sites of the target kinases. Moreover, we discuss the significant role of the indole/azaindole/oxindole skeletons in the interaction of their parent drug and target kinases, providing new medicinal chemistry inspiration and ideas for the subsequent development and optimization of kinase inhibitors. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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32 pages, 10464 KiB

Open AccessReview

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

by Siva S. Panda, Adel S. Girgis, Marian N. Aziz and Mohamed S. Bekheit

Molecules 2023, 28(2), 618; https://doi.org/10.3390/molecules28020618 - 7 Jan 2023

Cited by 54 | Viewed by 3200

Abstract

Spirooxindoles occupy an important place in heterocyclic chemistry. Many natural spirooxindole-containing compounds have been identified as bio-promising agents. Synthetic analogs have also been synthesized utilizing different pathways. The present article summarizes the recent development of both natural and synthetic spirooxindole-containing compounds prepared from [...] Read more.

Spirooxindoles occupy an important place in heterocyclic chemistry. Many natural spirooxindole-containing compounds have been identified as bio-promising agents. Synthetic analogs have also been synthesized utilizing different pathways. The present article summarizes the recent development of both natural and synthetic spirooxindole-containing compounds prepared from isatin or its derivatives reported in the last five years. The spirooxindoles are categorized based on their mentioned biological properties. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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45 pages, 5322 KiB

Open AccessFeature PaperReview

Indole-Containing Natural Products 2019–2022: Isolations, Reappraisals, Syntheses, and Biological Activities

by Syed Muhammad Umer, Mehwish Solangi, Khalid Mohammed Khan and Rahman Shah Zaib Saleem

Molecules 2022, 27(21), 7586; https://doi.org/10.3390/molecules27217586 - 5 Nov 2022

Cited by 48 | Viewed by 9163

Abstract

Indole alkaloids represent a large subset of natural products, with more than 4100 known compounds. The majority of these alkaloids are biologically active, with some exhibiting excellent antitumor, antibacterial, antiviral, antifungal, and antiplasmodial activities. Consequently, the natural products of this class have attracted [...] Read more.

Indole alkaloids represent a large subset of natural products, with more than 4100 known compounds. The majority of these alkaloids are biologically active, with some exhibiting excellent antitumor, antibacterial, antiviral, antifungal, and antiplasmodial activities. Consequently, the natural products of this class have attracted considerable attention as potential leads for novel therapeutics and are routinely isolated, characterized, and profiled to gauge their biological potential. However, data on indole alkaloids, their various structures, and bioactivities are complex due to their diverse sources, such as plants, fungi, bacteria, sponges, tunicates, and bryozoans; thus, isolation methods produce an incredible trove of information. The situation is exacerbated when synthetic derivatives, as well as their structures, bioactivities, and synthetic schemes, are considered. Thus, to make such data comprehensive and inform researchers about the current field’s state, this review summarizes recent reports on novel indole alkaloids. It deals with the isolation and characterization of 250 novel indole alkaloids, a reappraisal of previously reported compounds, and total syntheses of indole alkaloids. In addition, several syntheses and semi-syntheses of indole-containing derivatives and their bioactivities are reported between January 2019 and July 2022. Full article

(This article belongs to the Special Issue Recent Advances in Indole Derivatives in Medicinal and Synthetic Organic Chemistry)

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