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Design, Synthesis and Biological Evaluation of N-Heterocyclic Derivatives and Related Compounds

A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Chemical and Molecular Sciences".

Deadline for manuscript submissions: closed (10 April 2022) | Viewed by 16963

Special Issue Editors

Dr. Samuel Martins Silvestre

E-Mail Website
Guest Editor
CICS—Health Sciences Research Center, Faculty of Health Sciences, University of Beira Interior, 6201-001 Covilhã, Portugal
Interests: design of bioactive compounds; chemical synthesis; biological evaluation; compounds with medicinal and pharmaceutical interests
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Paulo S. Almeida

E-Mail Website
Guest Editor
CICS - Health Sciences Research Center, Faculty of Sciences, University of Beira Interior, Covilhã, Portugal
Interests: chemical synthesis; development of new synthetic processes; heterocyclic compounds; compounds with medicinal and pharmaceutical interests
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Heterocyclic structures, mainly aza-heterocycles, can be found in a large group of natural compounds, especially in the plant and animal kingdoms. In addition, different nitrogenated cyclic systems are fundamental for human and animal physiology and pathology. Therefore, it is not surprising that a large number of commercially available drugs are N-heterocycles. Relevant examples include antibacterial β-lactamics, antimalaric quinolines, anticancer purines, and pyrimidines, among others.

Due to lifespan increase and population aging, lifestyle, and pollution, a significant increase in oncologic, cardiovascular, and neurodegenerative diseases has been observed in recent decades, as well as of multi-resistant infections, among other relevant pathological conditions. Therefore, the discovery of new drugs for these needs is of significant interest for society, to improve the efficacy and safety of the treatments as well as to develop new therapeutic approaches.

This Special Issue intends to collect original research as well as review articles addressing the discovery and development of N-heterocycles with medicinal and pharmaceutical interests. Therefore, we kindly invite researchers to contribute manuscripts focusing not only on the design and total or semi-synthesis of bioactive aza-heterocycles and relevant synthetic intermediates but also on their in vitro and in vivo biological evaluation, namely, as potential anti-cancer, anti-infectious, anti-neurodegenerative, or cardiovascular agents.

Dr. Samuel Martins Silvestre
Prof. Dr. Paulo S. Almeida
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • N-Heterocycles
  • Molecular modelling
  • Organic synthesis
  • Biological evaluation
  • Structure–activity relationships

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Published Papers (6 papers)

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Research

12 pages, 2757 KiB  
Article
Ability of 2-Chloro-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylacetamide to Stimulate Endogenous Nitric Oxide Synthesis
by Vera Gledacheva, Mina Pencheva, Stoyanka Nikolova and Iliyana Stefanova
Appl. Sci. 2022, 12(9), 4473; https://doi.org/10.3390/app12094473 - 28 Apr 2022
Cited by 3 | Viewed by 1700
Abstract
Papaverine is one of the isoquinoline alkaloids derived from opium which is a vasodilator and smooth muscle relaxant. Using its chemical structure as a basic model, we synthesized 2-chloro-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylacetamide as an isoquinoline precursor (IQP). Aim: Clarifying the nature of the relationship between IQP [...] Read more.
Papaverine is one of the isoquinoline alkaloids derived from opium which is a vasodilator and smooth muscle relaxant. Using its chemical structure as a basic model, we synthesized 2-chloro-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylacetamide as an isoquinoline precursor (IQP). Aim: Clarifying the nature of the relationship between IQP as a new biologically active molecule and the neurotransmitters acetylcholine (ACh) and serotonin (5-hydroxytryptamine, 5-HT), as well as with the nitric oxide (NO). Materials and methods: The IQP compound was tested on the isolated gastric smooth muscle preparations (SMPs) from rats to determine its effects on spontaneous contractile activity. NO concentration in tissue homogenates was determined, and immunohistochemistry was used to visualize the expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) in smooth muscle (SM) cells. Results: The data from the isometric measurements suggest that IQP has an additional specific action affecting the intracellular signaling pathways of 5-HT. Using immunohistochemistry, we found that the combination of 5-HT and IQP affected the density and intensity of nNOS-positive cells, which increase significantly in the myenteric plexus and SM cells. Conclusions: In conclusion, IQP is involved in the regulation of intestinal neurons expressing nNOS, affects the function of nNOS/NO, and, by this mechanism, probably regulates the spontaneous contractile activity of gastric SM. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of N-Heterocyclic Derivatives and Related Compounds)
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11 pages, 719 KiB  
Article
Screening of Scaffolds for the Design of G-Quadruplex Ligands
by Joana Figueiredo, David Peitinho, Maria Paula Cabral Campello, Maria Cristina Oliveira, António Paulo, Jean-Louis Mergny and Carla Cruz
Appl. Sci. 2022, 12(4), 2170; https://doi.org/10.3390/app12042170 - 18 Feb 2022
Cited by 2 | Viewed by 2477
Abstract
In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small [...] Read more.
In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) heterocycle compounds, containing different aromatic scaffolds, such as phenyl, quinoline, naphthalene, phenanthroline and acridine moieties, in order to explore their stabilization effect towards different DNA G4s, such as those found in c-MYC, KRAS21 and VEGF promoters, 21G human telomeric motif and pre-MIR150. The fluorescence resonance energy transfer (FRET) melting assay indicates that the acridine moiety is the most active scaffold, followed by phenanthroline. The different scaffolds are promising in terms of drug-like properties and, in general, the IC50 values of the respective heterocycle compounds are lower in a cancer cell line, when compared with a normal cell line. The acridine derivative C5NH2 has the most favorable cytotoxic profile in terms of cell selectivity. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of N-Heterocyclic Derivatives and Related Compounds)
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13 pages, 1558 KiB  
Article
Synthesis and Biological Evaluation of Thiazolyl-Ethylidene Hydrazino-Thiazole Derivatives: A Novel Heterocyclic System
by Laila A. Al-Mutabagani, Fathy M. Abdelrazek, Sobhi M. Gomha, Ali S. Hebishy, Mohamed S. Abdelfattah, Safaa M. Hassan, Abdelwahed R. Sayed and Mahmoud M. Elaasser
Appl. Sci. 2021, 11(19), 8908; https://doi.org/10.3390/app11198908 - 24 Sep 2021
Cited by 23 | Viewed by 2398
Abstract
The reaction of 2-(1-(2-(2-(4-methoxybenzylidene)hydrazinyl)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbothioamide with a range of hydrazonoyl chlorides and α-halo-compounds yielded three new series of thiazole derivatives. Chemical and physical techniques were used to analyze all newly prepared derivatives (1H-NMR, 13C-NMR, FT-IR and mass spectrometry). The potential antimicrobial [...] Read more.
The reaction of 2-(1-(2-(2-(4-methoxybenzylidene)hydrazinyl)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbothioamide with a range of hydrazonoyl chlorides and α-halo-compounds yielded three new series of thiazole derivatives. Chemical and physical techniques were used to analyze all newly prepared derivatives (1H-NMR, 13C-NMR, FT-IR and mass spectrometry). The potential antimicrobial and anticancer properties of the synthesized derivatives were investigated using various in vitro biological experiments. Most of the thiazole compounds tested were effective against Gram-positive and Gram-negative bacteria. In addition, a minimum inhibition concentration was determined for the antibiotic properties of the most active produced substances. The cytotoxic activities were tested on HepG-2 (liver carcinoma), HCT-116 (colorectal carcinoma) and MDA-MB-231 (breast carcinoma) cell lines in comparison with cisplatin reference drug and using colorimetric MTT assay. The results detected that compound 10c was the most potent against the three tested cell lines. Interestingly, when the tested compounds were evaluated for their toxicity against normal (MRC-5) cells, they exhibited low toxic effects indicating the safe use of most of them that may require further in vivo and pharmacological studies. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of N-Heterocyclic Derivatives and Related Compounds)
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9 pages, 2184 KiB  
Article
Synthesis of Aromatic and Aliphatic N-Heterocyclic Salts and Their Application as Organic Electrolyte Supporters in Electrochemical Capacitor
by Young-Ji Kim, Jae-Yeong Choi, Soo-Yeoun Kim and Seong-Ho Choi
Appl. Sci. 2021, 11(19), 8824; https://doi.org/10.3390/app11198824 - 23 Sep 2021
Viewed by 1749
Abstract
Aromatic and aliphatic N-heterocyclic chemical salts were synthesized by counter-anion-exchange reactions after substitution reactions in order to apply them as organic electrolyte supporters in an electrochemical capacitor (super capacitor). The aromatic N-heterocyclic salts were N-methylpyridinium tetrafluoroborate ([MPy]+[BF4]−), [...] Read more.
Aromatic and aliphatic N-heterocyclic chemical salts were synthesized by counter-anion-exchange reactions after substitution reactions in order to apply them as organic electrolyte supporters in an electrochemical capacitor (super capacitor). The aromatic N-heterocyclic salts were N-methylpyridinium tetrafluoroborate ([MPy]+[BF4]−), N-methylpyridinium hexafluorophosphate ([MPy]+[PF6]−), 1,3-dibuthylimidazolium tetrafluoroborate ([DI]+[BF4]−), 1,3-dibuthylimidazolium hexafluorophosphate ([DI]+[PF6]−), 1-buthyl-4-methyl-1,2,4-triazolium tetrafluoroborate ([BMTA]+[BF4]−), and 1-buthyl-4-methyl-1,2,4-triazolium hexafluorophosphate ([BMTA]+[PF6]−). The aliphatic N-heterocyclic salts were N,N-dimethylpiperilidium tetrafluoroborate ([DMP]+[BF4]−), N,N-dimethylpiperilidium hexafluorophosphate ([DMPy]+[PF6]−), N,N-dimethylpyrrolidium tetrafluoroborate ([DMPy]+[BF4]−) and N,N-dimethylpyrrolidium hexafluorophosphate ([DMPy]+[PF6]−), 1-ethyltriethamine tetrafluoroborate ([E-TEDA]+[BF4]−), and 1-ethyltriethamine hexafluorophosphate ([E-TEDA]+[PF6]−), respectively. We confirmed the successful synthesis of the aromatic and aliphatic N-heterocyclic chemical salts by 1H-NMR, FT-IR, and GC/MS analysis before conducting the counter-anion-exchange reactions. Then, we determined the electrochemical potential of vanadium acetylacetonate (V(acac)3) under acetonitrile in the presence of the N-heterocyclic chemical salts as energy-storage chemicals. By cyclic voltammetry, the maximum voltages with the N-heterocyclic chemical salts in acetonitrile reached 2.2 V under a fixed current value. Charge-discharge experiments were performed in the electrochemical capacitor with an anion-exchange membrane using a non-aqueous electrolyte prepared with a synthesized N-heterocyclic salt in acetonitrile. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of N-Heterocyclic Derivatives and Related Compounds)
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13 pages, 1113 KiB  
Article
Microwave-Assisted Synthesis, Proton Dissociation Processes, and Anticancer Evaluation of Novel D-Ring-Fused Steroidal 5-Amino-1-Arylpyrazoles
by Gergő Mótyán, Ádám Baji, Małgorzata Anna Marć, Mohana Krishna Gopisetty, Dóra I. Adamecz, Mónika Kiricsi, Éva A. Enyedy and Éva Frank
Appl. Sci. 2020, 10(1), 229; https://doi.org/10.3390/app10010229 - 27 Dec 2019
Cited by 6 | Viewed by 2767
Abstract
Taking into account the pharmacological relevance of heterocycle-fused natural steroids, the objective of the current study was to develop a multistep reaction sequence for the efficient synthesis of novel D-ring-condensed 5-amino-1-arylpyrazoles from dehydroepiandrosterone (DHEA). A condensation reaction of 16-formyl-DHEA with hydroxylamine afforded the [...] Read more.
Taking into account the pharmacological relevance of heterocycle-fused natural steroids, the objective of the current study was to develop a multistep reaction sequence for the efficient synthesis of novel D-ring-condensed 5-amino-1-arylpyrazoles from dehydroepiandrosterone (DHEA). A condensation reaction of 16-formyl-DHEA with hydroxylamine afforded the corresponding oxime, which was demonstrated to be stable in one of its cyclic isoxazoline forms due to possible ring-chain tautomerism. The subsequent base-induced dehydration to a diastereomeric β-ketonitrile, followed by microwave-assisted heterocyclization with different arylhydrazines led to the desired pyrazoles. The generally good yields of the products depended slightly on the electronic character of the substituent present on the aromatic ring of the reagent. The proton dissociation processes of the DHEA-derived heterocycles were investigated in aqueous solution by UV-visible spectrophotometric titrations to reveal their actual chemical forms at physiological pH. The determined pKa values attributed to the pyrazole NH+ moiety were low (1.8–4.0) and varied by the different substituents of the benzene ring. The antiproliferative effects of the structurally similar compounds were screened in vitro on human cancer cells (namely on HeLa, U2Os, MCF-7, PC-3, and A549), along with a noncancerous cell line (MRC-5). The IC50 values of the most active derivative were determined on all cell lines. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of N-Heterocyclic Derivatives and Related Compounds)
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20 pages, 1953 KiB  
Article
Photophysicochemical Properties and In Vitro Phototherapeutic Effects of Iodoquinoline- and Benzothiazole-Derived Unsymmetrical Squaraine Cyanine Dyes
by Sofia Friães, Eurico Lima, Renato E. Boto, Diana Ferreira, José R. Fernandes, Luis F. V. Ferreira, Amélia M. Silva and Lucinda V. Reis
Appl. Sci. 2019, 9(24), 5414; https://doi.org/10.3390/app9245414 - 11 Dec 2019
Cited by 15 | Viewed by 4487
Abstract
The search to replace conventional cancer treatment therapies, such as chemotherapy, radiotherapy and surgery has led over the last ten years, to a substantial effort in the development of several classes of photodynamic therapy photosensitizers with desired photophysicochemical and photobiological properties. Herein we [...] Read more.
The search to replace conventional cancer treatment therapies, such as chemotherapy, radiotherapy and surgery has led over the last ten years, to a substantial effort in the development of several classes of photodynamic therapy photosensitizers with desired photophysicochemical and photobiological properties. Herein we report the synthesis of 6-iodoquinoline- and benzothiazole-based unsymmetrical squaraine cyanine dyes functionalized with amine groups located in the four-membered central ring. Their photodegradation and singlet oxygen production ability, as well as their in vitro photocytotoxicity against Caco-2 and HepG2 cell lines using a 630.8 ± 0.8 nm centered light-emitting diode system, were also investigated. All photosensitizer candidates displayed strong absorption within the tissue transparency spectral region (650–850 nm). The synthesized dyes were found to have moderate light stability. The potential of these compounds is evidenced by their cytotoxic activity against both tumor cell lines, highlighting the zwitterionic unsubstituted dye, which showed more intense photodynamic activity. Although the singlet oxygen quantum yields of these iodinated derivatives are considered low, it could be concluded that their introduction into the quinoline heterocycle was highly advantageous as it played a role in increasing selective cytotoxicity in the presence of light. Thus, the novel synthesized dyes present photophysicochemical and in vitro photobiological properties that make them excellent photosensitizer candidates for photodynamic therapy. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of N-Heterocyclic Derivatives and Related Compounds)
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