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Molecules
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Design and Synthesis of Novel Anti-Inflammatory Agents
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Design and Synthesis of Novel Anti-Inflammatory Agents

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

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 9988

Special Issue Editors

Dr. Eleni Pontiki

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
Interests: medicinal chemistry; natural products; antioxidants; anti-inflammatory activity; pharmacokinetics; drug design; structure–activity relationships
Special Issues, Collections and Topics in MDPI journals
Dr. Katerina Peperidou

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Interests: design, synthesis and pharmaceutical evaluation of hybrids of cinnamic acid with multiple biological profile

Special Issue Information

Dear Colleagues,

Inflammation is a physiological immune response to harmful stimuli. It is a protective mechanism which is phylogenetically highly conserved among humans and many other animal species and initiates the healing process to promote tissue recovery. Despite inflammation’s alliance with lifelong homeostasis, prolonged inflammation could be detrimental to health. Inflammatory mediators are associated with tissue damage and a compromised tissue repair process.

Inflammation is classified into acute and chronic depending on various inflammatory processes and cellular mechanisms. Recent findings suggest the important role of inadequate or chronic inflammation in the progression of chronic diseases and pathological conditions, such as arthritis, cancer, diabetes, cardiovascular diseases, eye disorders, obesity, autoimmune diseases, atherosclerosis, heart failure, and inflammatory bowel disease.

Two enzymes are implicated in the inflammatory process: cyclooxygenases and lipoxygenases. Additionally, it has been found that inflammation is associated with free radicals. During the inflammatory process, free radical homeostasis is disturbed. Free radicals are extremely reactive molecules with short lifetimes which react with different macromolecules such as nucleic acids, lipids, and proteins.

In recent years, ongoing research has been carried out regarding the discovery of novel potential anti-inflammatory agents. In this Special Issue, we aim to promote original research and reviews exploring recent progress in this field. Proposed topics include, among others, novel anti-inflammatory agents (natural or synthetic) and their evaluation and the clarification of molecular and biological mechanisms, enzymes, and targets implicated in anti-inflammatory responses.

Dr. Eleni Pontiki
Dr. Katerina Peperidou
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

  • anti-inflammatory agents
  • natural products
  • drug development
  • structure–activity relationships
  • interleukins
  • cyclooxygenase
  • lipoxygenase
  • chronic diseases

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Published Papers (5 papers)

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Research

12 pages, 1845 KiB  
Article
Enhancing Aseptic Inflammation Resolution with 1-(2-Ethoxyethyl)-4-(pent-1-yn-1-yl)piperidin-4-yl Propionate: A Novel β-Cyclodextrin Complex as a Therapeutic Agent
by Symbat Zhumakova, Aliya Tokusheva, Tolganay Zharkynbek, Marina Balabekova, Sulev Koks, Tulegen Seilkhanov, Valery Dembitsky, Alexey Zazybin, Murat Aydemir, Ulan Kemelbekov, Gulgul Kairanbayeva and Valentina Yu
Molecules 2024, 29(21), 5135; https://doi.org/10.3390/molecules29215135 - 30 Oct 2024
Viewed by 218
Abstract
The synthesized compound, 1-(2-ethoxyethyl)-4-(pent-1-yn-1-yl)piperidin-4-yl propionate (EPPP), and its 1:1 complex with β-cyclodextrin (EPPPβCD) have been characterized for the first time through a comprehensive suite of analytical methods. This study explores the therapeutic potential of EPPPβCD in modulating immune responses [...] Read more.
The synthesized compound, 1-(2-ethoxyethyl)-4-(pent-1-yn-1-yl)piperidin-4-yl propionate (EPPP), and its 1:1 complex with β-cyclodextrin (EPPPβCD) have been characterized for the first time through a comprehensive suite of analytical methods. This study explores the therapeutic potential of EPPPβCD in modulating immune responses and accelerating the resolution of septic inflammation induced by chromium and vanadium ions in outbred male rats. The research highlights the significant impact of EPPPβCD on the dynamics of regulatory T lymphocytes (Tregs), notably causing a reduction in the CD4+CD25+ fractions at the onset of inflammation. This effect is attributed to the inhibition of Treg proliferation, which is crucial in hastening the resolution of inflammation. These findings underscore the potential of EPPPβCD as a promising therapeutic agent in controlling and mitigating inflammation mediated by heavy metal exposure, thereby offering a new avenue for the development of anti-inflammatory treatments. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Anti-Inflammatory Agents)
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23 pages, 4698 KiB  
Article
Design, Synthesis, and Biological Evaluation of Novel Phenoxy Acetic Acid Derivatives as Selective COX-2 Inhibitors Coupled with Comprehensive Bio-Pharmacological Inquiry, Histopathological Profiling, and Toxicological Scrutiny
by Najla A. Alshaye, Mohamed K. Elgohary, Mahmoud S. Elkotamy and Hatem A. Abdel-Aziz
Molecules 2024, 29(6), 1309; https://doi.org/10.3390/molecules29061309 - 15 Mar 2024
Cited by 2 | Viewed by 1404
Abstract
COX-2 plays a key role in converting arachidonic acid into prostaglandins. This makes it a significant target for treating inflammation. Selective COX-2 inhibitors have marked a new phase in inflammatory treatment, providing significant effectiveness while reducing negative side effects. Herein, we aimed at [...] Read more.
COX-2 plays a key role in converting arachidonic acid into prostaglandins. This makes it a significant target for treating inflammation. Selective COX-2 inhibitors have marked a new phase in inflammatory treatment, providing significant effectiveness while reducing negative side effects. Herein, we aimed at the design and synthesis of new anti-inflammatory agents 5a–f, 7a–b, 10a–f, and 13a–b with expected selective inhibition for COX-2. Compounds 5d–f, 7b, and 10c–f showed significant COX-2 inhibition with IC50 in the range of 0.06–0.09 μM, indicating powerful pharmacological potential. In light of this, eight compounds were selected for further testing in vivo to assess their selectivity toward COX-1/COX-2 enzymes with the ability to reduce paw thickness. Compounds 5f and 7b showed significant anti-inflammatory effects without causing stomach ulcers, as they showed significant in vivo inhibition for paw thickness at 63.35% and 46.51%, as well as paw weight at 68.26% and 64.84%. Additionally, the tested compounds lowered TNF-α by 61.04% and 64.88%, as well as PGE-2 by 60.58% and 57.07%, respectively. Furthermore, these potent compounds were thoroughly analyzed for their pain-relieving effects, histological changes, and toxicological properties. Assessing renal and stomach function, as well as measuring liver enzymes AST and ALT, together with kidney indicators creatinine and urea, offered valuable information on their safety profiles. Molecular modeling studies explain the complex ways in which the strong interacts with the COX-2 enzyme. This comprehensive strategy emphasizes the therapeutic potential and safety profiling of these new analogues for managing inflammation. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Anti-Inflammatory Agents)
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20 pages, 5261 KiB  
Article
Development of Novel Pyrrole Derivatives and Their Cinnamic Hybrids as Dual COX-2/LOX Inhibitors
by Viola Noti, Eleni Pontiki and Dimitra Hadjipavlou-Litina
Molecules 2023, 28(24), 7958; https://doi.org/10.3390/molecules28247958 - 5 Dec 2023
Viewed by 1387
Abstract
Molecular hybridization has emerged as a promising approach in the treatment of diseases exhibiting multifactorial etiology. With regard to this, dual cyclooxygenase-2/lipoxygenase (COX-2/LOX) inhibitors could be considered a safe alternative to traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs) for the [...] Read more.
Molecular hybridization has emerged as a promising approach in the treatment of diseases exhibiting multifactorial etiology. With regard to this, dual cyclooxygenase-2/lipoxygenase (COX-2/LOX) inhibitors could be considered a safe alternative to traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs) for the treatment of inflammatory conditions. Taking this into account, six novel pyrrole derivatives and pyrrole–cinnamate hybrids were developed as potential COX-2 and soybean LOX (sLOX) inhibitors with antioxidant activity. In silico calculations were performed to predict their ADMET (absorption, distribution, metabolism, excretion, toxicity) properties and drug-likeness, while lipophilicity was experimentally determined as RM values. All synthesized compounds (1–4, 5–8) could be described as drug-like. The results from the docking studies on COX-2 were in accordance with the in vitro studies. According to molecular docking studies on soybean LOX, the compounds displayed allosteric interactions with the enzyme. Pyrrole 2 appeared to be the most potent s-LOX inhibitor (IC50 = 7.5 μM). Hybrids 5 and 6 presented a promising combination of in vitro LOX (IC50 for 5 = 30 μM, IC50 for 6 = 27.5 μM) and COX-2 (IC50 for 5 = 0.55 μM, IC50 for 6 = 7.0 μM) inhibitory activities, and therefore could be used as the lead compounds for the synthesis of more effective multi-target agents. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Anti-Inflammatory Agents)
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18 pages, 3743 KiB  
Article
Preparation and In Vitro and In Vivo Evaluation of Rectal In Situ Gel of Meloxicam Hydroxypropyl-β-cyclodextrin Inclusion Complex
by Xiaomeng Lei, Guansheng Zhang, Tao Yang, Yuhuan Wu, Ying Peng, Tiantian Wang, Dongxun Li, Qian Liu, Canjian Wang and Guosong Zhang
Molecules 2023, 28(10), 4099; https://doi.org/10.3390/molecules28104099 - 15 May 2023
Cited by 2 | Viewed by 1653
Abstract
Meloxicam (MLX) is one of the most effective NSAIDs, but its poor water solubility and low bioavailability limit its clinical application. In this study, we designed a thermosensitive in situ gel of the hydroxypropyl-β-cyclodextrin inclusion complex (MLX/HP-β-CD-ISG) for rectal delivery to improve bioavailability. [...] Read more.
Meloxicam (MLX) is one of the most effective NSAIDs, but its poor water solubility and low bioavailability limit its clinical application. In this study, we designed a thermosensitive in situ gel of the hydroxypropyl-β-cyclodextrin inclusion complex (MLX/HP-β-CD-ISG) for rectal delivery to improve bioavailability. The best method for preparing MLX/HP-β-CD was the saturated aqueous solution method. The optimal inclusion prescription was optimized using an orthogonal test, and the inclusion complex was evaluated via PXRD, SEM, FTIR and DSC. Then, MLX/HP-β-CD-ISG was characterized regarding the gel properties, release in vitro, and pharmacokinetics in vivo. The inclusion rate of the inclusion complex obtained via the optimal preparation process was 90.32 ± 3.81%. The above four detection methods show that MLX is completely embedded in the HP-β-CD cavity. The developed MLX/HP-β-CD-ISG formulation has a suitable gelation temperature of 33.40 ± 0.17 °C, a gelation time of 57.33 ± 5.13 s, pH of 7.12 ± 0.05, good gelling ability and meets the requirements of rectal preparations. More importantly, MLX/HP-β-CD-ISG significantly improved the absorption and bioavailability of MLX in rats, prolonging the rectal residence time without causing rectal irritation. This study suggests that the MLX/HP-β-CD-ISG can have a wide application prospect with superior therapeutic benefits. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Anti-Inflammatory Agents)
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24 pages, 3812 KiB  
Article
New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation
by Riham M. Bokhtia, Siva S. Panda, Adel S. Girgis, Nermin Samir, Mona F. Said, Anwar Abdelnaser, Soad Nasr, Mohamed S. Bekheit, Abdelhameed S. Dawood, Horrick Sharma, Margaret Wade, Swapnil K. Sharma and Amany M. Ghanim
Molecules 2023, 28(4), 1945; https://doi.org/10.3390/molecules28041945 - 17 Feb 2023
Cited by 11 | Viewed by 4486
Abstract
New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and [...] Read more.
New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Anti-Inflammatory Agents)
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