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Nitrogen Heterocycles in Medicinal Chemistry
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Nitrogen Heterocycles in Medicinal Chemistry

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 64858

Special Issue Editors

Dr. Anna Carbone

E-Mail Website
Guest Editor
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università degli Studi di Palermo, Palermo, Italy
Interests: drug discovery; medicinal chemistry; synthesis of heterocyclic compounds; antitumor agents, kinases; marine alkaloids analogs; anti-fibrotic agents
Dr. Fabio Bertozzi

E-Mail Website
Guest Editor
D3-PharmaChemistry, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy
Interests: drug discovery; medicinal chemistry; synthesis of heterocyclic compounds; organic synthesis; new synthetic methodologies; anti-inflammatory agents; enzyme inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is a great pleasure and honor for us to invite you to contribute to the Special Issue entitled “Nitrogen heterocycles in Medicinal Chemistry”.

Nitrogen heterocycles represent a highly important class of compounds that are widespread in medicinal chemistry, receiving special attention in drug discovery. These heterocyclic rings are common structural units in many natural or synthetic agents and approximately 60% of FDA-approved drugs contain a nitrogen heterocycle in their structure.

They exhibit a very wide range of biological activities as antibiotic, antibacterial, antifungal, anticancer, anticonvulsant, anti-HIV, anti-inflammatory, analgesic, antitubercular, and antimalarial agents. Moreover, they also have applications as fungicides, herbicides, anticorrosives, agrochemicals, antioxidants, and play an important role in biochemical processes because they are key elements of DNA, RNA, and coenzymes.

Despite the extensive literature on N-heterocycles synthesis, there is great interest in the development of more innovative and efficient synthetic methodologies to obtain new chemical entities.

This Special Issue will accept original research papers and high-quality reviews in the fields of medicinal chemistry, organic chemistry, biochemistry, and pharmacology. The topic of the Special Issue will be focused on the drug design, new synthetic approaches, biosynthesis, isolation, and biological activity of new nitrogen heterocycle derivatives.

Dr. Anna Carbone
Dr. Fabio Bertozzi
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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

  • Nitrogen heterocycles
  • Drug discovery
  • Medicinal chemistry
  • New synthetic methodologies
  • Biosynthesis
  • Isolation
  • Biological activity
  • Natural compounds

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Published Papers (8 papers)

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Research

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10 pages, 1786 KiB  
Article
Two New Indole Alkaloids from Toad Venom of Bufo bufo gargarizans
by Yu-Lin Chen, Ying-Hui Dai, An-Dong Wang, Zi-Ying Zhou, Miao Lei, Jiao Liu, Bin Lin, Ming-Yu Xia and Dong Wang
Molecules 2020, 25(19), 4511; https://doi.org/10.3390/molecules25194511 - 1 Oct 2020
Cited by 9 | Viewed by 2798
Abstract
Two new indole alkaloids, Bufotenidine B (2) and Bufocarboline A (6), along with seven known indole alkaloids (1, 3–5, and 7–9) and three organic acids (10–12), were isolated from the water extract of [...] Read more.
Two new indole alkaloids, Bufotenidine B (2) and Bufocarboline A (6), along with seven known indole alkaloids (1, 3–5, and 7–9) and three organic acids (10–12), were isolated from the water extract of toad venom. The structures of the new alkaloids were elucidated by extensive spectroscopic methods. The absolute configurations of 4, 6, and 8 were determined for the first time by electronic circular dichroism (ECD) calculations. The cytotoxic activity of all compounds was tested against human malignant melanoma cells A375 by the MTT method, and no antitumor activity was observed. Full article
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
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12 pages, 2649 KiB  
Article
A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor
by Guanguan Li, Amanda N. Nieman, Md Yeunus Mian, Nicolas M. Zahn, Brandon N. Mikulsky, Michael M. Poe, Kashi R. Methuku, Yongfeng Liu, James M. Cook, Douglas C. Stafford and Leggy A. Arnold
Molecules 2020, 25(17), 3864; https://doi.org/10.3390/molecules25173864 - 25 Aug 2020
Cited by 8 | Viewed by 3471
Abstract
Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ [...] Read more.
Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC50 of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with 3H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABAAR) of the α1-3β2-3γ1-2 subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABAARs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors. Full article
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
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23 pages, 2481 KiB  
Article
Discovery of New Schiff Bases Tethered Pyrazole Moiety: Design, Synthesis, Biological Evaluation, and Molecular Docking Study as Dual Targeting DHFR/DNA Gyrase Inhibitors with Immunomodulatory Activity
by Ashraf S. Hassan, Ahmed A. Askar, Ahmed M. Naglah, Abdulrahman A. Almehizia and Ahmed Ragab
Molecules 2020, 25(11), 2593; https://doi.org/10.3390/molecules25112593 - 2 Jun 2020
Cited by 59 | Viewed by 4461
Abstract
A series of Bis-pyrazole Schiff bases (6a–d and 7a–d) and mono-pyrazole Schiff bases (8a–d and 9a–d) were designed and synthesized through the reaction of 5-aminopyrazoles 1a–d with aldehydes [...] Read more.
A series of Bis-pyrazole Schiff bases (6a–d and 7a–d) and mono-pyrazole Schiff bases (8a–d and 9a–d) were designed and synthesized through the reaction of 5-aminopyrazoles 1a–d with aldehydes 2–5 using mild reaction condition with a good yield percentage. The chemical structure of newly formed Schiff bases tethered pyrazole core was confirmed based on spectral and experimental data. All the newly formed pyrazole Schiff bases were evaluated against eight pathogens (Gram-positive, Gram-negative, and fungi). The result exhibited that, most of them have good and broad activities. Among those, only six Schiff bases (6b, 7b, 7c, 8a, 8d, and 9b) displayed MIC values (0.97–62.5 µg/mL) compared to Tetracycline (15.62–62.5 µg/mL) and Amphotericin B (15.62–31.25 µg/mL), MBC values (1.94–87.5 µg/mL) and selectivity to tumor cell than normal cells. Immunomodulatory activities showed that the promising Schiff bases increase the immunomodulator effect of defense cell and the Schiff base 8a is the highest one by (Intra. killing activity = 136.5 ± 0.3%) having a pyrazole moiety as well as amide function (O=C-NH2) and piperidinyl core. Furthermore, the most potent one exhibited broad activity depending on both MIC and MBC values. Moreover, to study the mechanism of these pyrazole Schiff bases, two active Schiff bases 8a and 9b from six derivatives were introduced to study the enzyme assay as dihydrofolate reductase (DHFR) on E. coli organism and DNA gyrase with two different organisms, S. aureus and B. subtilis, to determine the inhibitory activities with lower values in the case of DNA gyrase (8a and 9b) or nearly as DHFR compound 9b, while pyrazole 8a showed excellent inhibitory against all enzyme assay. The molecular docking study against dihydrofolate reductase and DNA gyrase were performed to study the binding between active site in the pocket with the two Schiff bases (8a and 9b) that exhibited good binding affinity with different bond types as H-bonding, aren-aren, and arene-cation interaction as well as study the physicochemical and pharmacokinetic properties of the two active Schiff bases 8a and 9b. Full article
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
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22 pages, 4823 KiB  
Article
Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity
by Sarra Boudriga, Saoussen Haddad, Vikneswaran Murugaiyah, Moheddine Askri, Michael Knorr, Carsten Strohmann and Christopher Golz
Molecules 2020, 25(8), 1963; https://doi.org/10.3390/molecules25081963 - 23 Apr 2020
Cited by 23 | Viewed by 3299
Abstract
A novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio- and diastereoselectivities under mild reaction conditions. The stereochemistry of [...] Read more.
A novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio- and diastereoselectivities under mild reaction conditions. The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies. Several synthetized compounds show higher inhibition on acetylcholinesterase (AChE) than butyrylcholinesterase (BChE). Of the 17 synthesized compounds tested, five exhibit good AChE inhibition with IC50 of 11.42 to 22.21 µM. A molecular docking study has also been undertaken for compound 4n possessing the most potent AChE inhibitory activity, disclosing its binding to the peripheral anionic site of AChE enzymes. Full article
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
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17 pages, 3160 KiB  
Article
Biological Evaluation and Molecular Docking with In Silico Physicochemical, Pharmacokinetic and Toxicity Prediction of Pyrazolo[1,5-a]pyrimidines
by Ahmed M. Naglah, Ahmed A. Askar, Ashraf S. Hassan, Tamer K. Khatab, Mohamed A. Al-Omar and Mashooq A. Bhat
Molecules 2020, 25(6), 1431; https://doi.org/10.3390/molecules25061431 - 21 Mar 2020
Cited by 47 | Viewed by 3965
Abstract
Pyrazolo[1,5-a]pyrimidines 5a–c, 9a–c and 13a–i were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory activity. The biological activities of pyrazolo[1,5-a]pyrimidines showed that the pyrazolo[1,5-a [...] Read more.
Pyrazolo[1,5-a]pyrimidines 5a–c, 9a–c and 13a–i were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory activity. The biological activities of pyrazolo[1,5-a]pyrimidines showed that the pyrazolo[1,5-a]pyrimidines (5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h) displayed promising antimicrobial and immunomodulatory activities. Studying the in silico predicted physicochemical, pharmacokinetic, ADMET and drug-likeness properties for the pyrazolo[1,5-a]pyrimidines 5a–c, 9a–c and 13a–i confirmed that most of the compounds (i) were within the range set by Lipinski’s rule of five, (ii) show higher gastrointestinal absorption and inhibition of some CYP isoforms, and (iii) have a carcinogenicity test that was predicted as negative and hERG test that presented medium risk. Moreover, the molecular docking study demonstrated that the compounds 5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h are potent inhibitors of 14-alpha demethylase, transpeptidase and alkaline phosphatase enzymes. This study could be valuable in the discovery of a new series of drugs. Full article
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
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Review

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32 pages, 5293 KiB  
Review
Natural Nitrogenous Sesquiterpenoids and Their Bioactivity: A Review
by De-Li Chen, Bo-Wen Wang, Zhao-Cui Sun, Jun-Shan Yang, Xu-Dong Xu and Guo-Xu Ma
Molecules 2020, 25(11), 2485; https://doi.org/10.3390/molecules25112485 - 27 May 2020
Cited by 18 | Viewed by 3111
Abstract
Nitrogenous sesquiterpenoids fromnatural sourcesare rare, so unsurprisingly neither the potentially valuable bioactivity nor thebroad structural diversity of nitrogenous sesquiterpenoids has been reviewed before. This report covers the progressduring the decade from 2010 to February 2020 on the isolation, identification, and bioactivity of 391 [...] Read more.
Nitrogenous sesquiterpenoids fromnatural sourcesare rare, so unsurprisingly neither the potentially valuable bioactivity nor thebroad structural diversity of nitrogenous sesquiterpenoids has been reviewed before. This report covers the progressduring the decade from 2010 to February 2020 on the isolation, identification, and bioactivity of 391 nitrogen-containing natural sesquiterpenes from terrestrial plant, marine organisms, and microorganisms. This complete and in-depth reviewshouldbe helpful for discovering and developing new drugs of medicinal valuerelated to natural nitrogenous sesquiterpenoids. Full article
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
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42 pages, 16889 KiB  
Review
A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications
by Nagaraju Kerru, Lalitha Gummidi, Suresh Maddila, Kranthi Kumar Gangu and Sreekantha B. Jonnalagadda
Molecules 2020, 25(8), 1909; https://doi.org/10.3390/molecules25081909 - 20 Apr 2020
Cited by 886 | Viewed by 32186
Abstract
The analogs of nitrogen-based heterocycles occupy an exclusive position as a valuable source of therapeutic agents in medicinal chemistry. More than 75% of drugs approved by the FDA and currently available in the market are nitrogen-containing heterocyclic moieties. In the forthcoming decade, a [...] Read more.
The analogs of nitrogen-based heterocycles occupy an exclusive position as a valuable source of therapeutic agents in medicinal chemistry. More than 75% of drugs approved by the FDA and currently available in the market are nitrogen-containing heterocyclic moieties. In the forthcoming decade, a much greater share of new nitrogen-based pharmaceuticals is anticipated. Many new nitrogen-based heterocycles have been designed. The number of novel N-heterocyclic moieties with significant physiological properties and promising applications in medicinal chemistry is ever-growing. In this review, we consolidate the recent advances on novel nitrogen-containing heterocycles and their distinct biological activities, reported over the past one year (2019 to early 2020). This review highlights the trends in the use of nitrogen-based moieties in drug design and the development of different potent and competent candidates against various diseases. Full article
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
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18 pages, 6367 KiB  
Review
Recent Advances in the Synthesis of Oxazole-Based Molecules via van Leusen Oxazole Synthesis
by Xunan Zheng, Wei Liu and Dawei Zhang
Molecules 2020, 25(7), 1594; https://doi.org/10.3390/molecules25071594 - 31 Mar 2020
Cited by 58 | Viewed by 9574
Abstract
Oxazole compounds, including one nitrogen atom and one oxygen atom in a five-membered heterocyclic ring, are present in various biological activities. Due to binding with a widespread spectrum of receptors and enzymes easily in biological systems through various non-covalent interactions, oxazole-based molecules are [...] Read more.
Oxazole compounds, including one nitrogen atom and one oxygen atom in a five-membered heterocyclic ring, are present in various biological activities. Due to binding with a widespread spectrum of receptors and enzymes easily in biological systems through various non-covalent interactions, oxazole-based molecules are becoming a kind of significant heterocyclic nucleus, which have received attention from researchers globally, leading them to synthesize diverse oxazole derivatives. The van Leusen reaction, based on tosylmethylisocyanides (TosMICs), is one of the most appropriate strategies to prepare oxazole-based medicinal compounds. In this review, we summarize the recent advances of the synthesis of oxazole-containing molecules utilizing the van Leusen oxazole synthesis from 1972, aiming to look for potential oxazole-based medicinal compounds, which are valuable information for drug discovery and synthesis. Full article
(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)
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