Nitrogen Containing Scaffolds in Medicinal Chemistry 2023

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 2856

Special Issue Editors

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Rome, Italy
Interests: drug design and synthesis; medicinal chemistry; organic synthesis; antimicrobial agents; structure–activity relationship; antiviral agents; antiparasitic agents; anticancer agents; antiprotozoal agents
Special Issues, Collections and Topics in MDPI journals
1. Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy
2. Dipartimento di biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy
Interests: drug design; anticancer agents; antiviral and antiretroviral agents; antiprotozoal agents; antimicrobial agents; structure–activity relationship study; organic synthesis; medicinal chemistry

Special Issue Information

Dear Colleagues,

Most of the organic compounds used as therapeutics, as well as intermediates utilized for their synthesis, contain heterocyclic motifs. A heterocycle is a ring with at least one atom that is not carbon. Nitrogen, oxygen, and sulfur are the primary elements seen in common heterocycles and play a critical role in drug discovery. In detail, nitrogen heterocycles contain at least one nitrogen atom in the ring. Based on the size of the ring, there are three, four, five, six, seven and eight-membered rings, as well as fused, bicyclic and macrocyclic heterocycles of nitrogen. Furthermore, these may be described as aromatic, saturated or unsaturated. Depending on the structure and on the type of bonds, such compounds show different acid–base properties and can contain one, two or more nitrogen atoms. Nitrogen-containing scaffolds are among the most significant structural components of therapeutic agents. Furthermore, there are a plethora of natural products which are nitrogen-containing heterocyclic that serve as the basis for many different substances, including alkaloids, vitamins, hormones, dyes, antibiotics, herbicides, or nutraceuticals.  Over the past decades, much attention has been devoted to the development of and pharmacological studies into heteroaromatic organic compounds (such as benzimidazoles, benzothiazoles, indole, oxadiazole, imidazole, isoxazole, pyrazole, triazoles, quinolines and quinazolines) that are currently considered privileged scaffolds for different therapeutic agents. Indeed, they show a wide range of biological activities, representing nearly 60% of all FDA-approved drugs, with more than 880 nitrogen-based heterocyclic drugs approved by the US FDA. For instance, nitrogen-based heterocyclic compounds are widely reported in the literature as anticancer agents and represented 73% of the approved anticancer drugs in 2015. This Special Issue will publish research papers with topics including, but not limited to, the preparation of aromatic and non-aromatic nitrogen-containing heterocycles endowed with any biological action. We also welcome contributions that highlight the importance of the nitrogen-based scaffolds that are widely found in agrochemicals, dyes, cosmetics and functional materials. The aim of the present Special Issue is primarily to present an overview primarily of the state of the art of synthetic methods and recent advances in the synthesis of nitrogen-based heterocycles.

Dr. Valentina Noemi Madia
Dr. Valeria Tudino
Guest Editors

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Keywords

  • nitrogen-based heterocycles
  • bioactive compounds
  • structure-based drug design
  • structure-activity relationship
  • in silico studies
  • ADMET properties
  • microwave-assisted synthesis
  • green chemistry
  • multicomponent reactions
  • phytochemicals

Published Papers (3 papers)

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Research

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15 pages, 2694 KiB  
Article
Synthesis and Biological Activity of Piperidinothiosemicarbazones Derived from Aminoazinecarbonitriles
by Dagmara Ziembicka, Katarzyna Gobis, Małgorzata Szczesio, Ewa Augustynowicz-Kopeć, Agnieszka Głogowska, Izabela Korona-Głowniak and Krzysztof Bojanowski
Pharmaceuticals 2023, 16(9), 1267; https://doi.org/10.3390/ph16091267 - 07 Sep 2023
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Abstract
To investigate how structural modifications affect tuberculostatic potency, we synthesized seven new piperidinothiosemicrabazone derivatives 814, in which three of them had a pyrazine ring replacing the pyridine ring. Derivatives 89 and 1314 exhibited significant activity against [...] Read more.
To investigate how structural modifications affect tuberculostatic potency, we synthesized seven new piperidinothiosemicrabazone derivatives 814, in which three of them had a pyrazine ring replacing the pyridine ring. Derivatives 89 and 1314 exhibited significant activity against the standard strain (minimum inhibitory concentration (MIC) 2–4 μg/mL) and even greater activity against the resistant M. tuberculosis strain (MIC 0.5–4 μg/mL). Additionally, the effects of compounds 89 were entirely selective (MIC toward other microorganisms ≥ 1000 μg/mL) and non-toxic (IC50 to HaCaT cells 5.8 to >50 μg/mL). The antimycobacterial activity of pyrazine derivatives 1112 was negligible (MIC 256 to >500 μg/mL), indicating that replacing the aromatic ring was generally not a promising line of research in this case. The zwitterionic structure of compound 11 was determined using X-ray crystallography. Absorption, distribution, metabolism, and excretion (ADME) calculations showed that all compounds, except 11, could be considered for testing as future drugs. An analysis of the structure–activity relationship was carried out, indicating that the higher basicity of the substituent located at the heteroaromatic ring might be of particular importance for the antituberculous activity of the tested groups of compounds. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry 2023)
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16 pages, 3936 KiB  
Article
In Vitro Analyses of the Multifocal Effects of Natural Alkaloids Berberine, Matrine, and Tabersonine against the O’nyong-nyong Arthritogenic Alphavirus Infection and Inflammation
by Anne-Laure Sandenon Seteyen, Pascale Guiraud, Philippe Gasque, Emmanuelle Girard-Valenciennes and Jimmy Sélambarom
Pharmaceuticals 2023, 16(8), 1125; https://doi.org/10.3390/ph16081125 - 09 Aug 2023
Cited by 1 | Viewed by 836
Abstract
O’nyong-nyong virus (ONNV) is a member of the reemerging arthritogenic alphaviruses that cause chronic debilitating polyarthralgia and/or polyarthritis via their tropism for the musculoskeletal system. Thus, the discovery of dual antiviral and anti-inflammatory drugs is a great challenge in this field. We investigated [...] Read more.
O’nyong-nyong virus (ONNV) is a member of the reemerging arthritogenic alphaviruses that cause chronic debilitating polyarthralgia and/or polyarthritis via their tropism for the musculoskeletal system. Thus, the discovery of dual antiviral and anti-inflammatory drugs is a great challenge in this field. We investigated the effects of the common plant-derived alkaloids berberine (isoquinoline), matrine (quinolizidine), and tabersonine (indole) at a non-toxic concentration (10 μM) on a human fibroblast cell line (HS633T) infected by ONNV (MOI 1). Using qRT-PCR analyses, we measured the RNA levels of the gene coding for the viral proteins and for the host cell immune factors. These alkaloids demonstrated multifocal effects by the inhibition of viral replication, as well as the regulation of the type-I interferon antiviral signaling pathway and the inflammatory mediators and pathways. Berberine and tabersonine proved to be the more valuable compounds. The results supported the proposal that these common alkaloids may be useful scaffolds for drug discovery against arthritogenic alphavirus infection. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry 2023)
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Review

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14 pages, 611 KiB  
Review
Five-Membered Nitrogen Heterocycles Angiotensin-Converting Enzyme (ACE) Inhibitors Induced Angioedema: An Underdiagnosed Condition
by Niki Papapostolou, Stamatios Gregoriou, Alexander Katoulis and Michael Makris
Pharmaceuticals 2024, 17(3), 360; https://doi.org/10.3390/ph17030360 - 10 Mar 2024
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Abstract
Angiotensin-converting enzyme (ACE) inhibitors are used primarily in the treatment of hypertension, heart failure, and in the acute phase of myocardial infarction. Lisinopril [N2-[(1S)-1-car-boxy-3-phenylpropyl]-L-lysyl-L-proline], enalapril [(S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline] and ramipril [2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid] are all five-membered heterocycles and three of the most prevalent ACE [...] Read more.
Angiotensin-converting enzyme (ACE) inhibitors are used primarily in the treatment of hypertension, heart failure, and in the acute phase of myocardial infarction. Lisinopril [N2-[(1S)-1-car-boxy-3-phenylpropyl]-L-lysyl-L-proline], enalapril [(S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline] and ramipril [2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid] are all five-membered heterocycles and three of the most prevalent ACE inhibitors in clinical use worldwide. ACE inhibitor-induced angioedema (AE) is clinically characterized by self-limited edema of the dermis and subcutaneous lipid tissue, localized on face skin, oral mucosa and tongue in most cases. However, severe episodes of intestinal AE misdiagnosed as acute appendicitis and laryngeal AE requiring incubation have been reported. The pathophysiology of ACE inhibitor-induced angioedema is attributed to the accumulation of bradykinin, which is a potent vasodilator with proinflammatory activity that is normally degraded by angiotensin-converting enzyme (ACE) and aminopeptidase P; however, a small proportion of treated patients is affected. Given that patients do not respond to anti-H1 antihistamines and steroids, early clinical recognition and discontinuation of the ACE inhibitors are the treatments of choice for the long-term management of ACE inhibitor- induced angioedema. The search period of the present review was set up until November 2023, and its aim is to shed light on the broader context of ACE inhibitor-induced angioedema, exploring aspects such as clinical presentation, pathophysiology, and therapeutic considerations in this potentially life-threatening condition. The exploration of alternative drug options such as angiotensin II receptor blockers, the potential association of coadministration of DPP-4 inhibitors with ACE inhibitors, the presentation of angioedema and the significant clinical importance of this condition are also discussed. By focusing on the chemical structure of ACE inhibitors, specifically their nitrogen-based heterocycles—an attribute shared by over 880 drugs approved by the FDA within the pharmaceutical industry—this review emphasizes the pivotal role of nitrogen scaffolds in drug design and underscores their relevance in ACE inhibitor pharmacology. Full article
(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry 2023)
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