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Medicinal Chemistry: From Drug Design to Drug Development

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 7126

Special Issue Editors


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Guest Editor
Department of Pharmacy, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy
Interests: medicinal chemistry; antiproliferative agents; neuroprotective agents; phosphodiesterase inhibitors; antioxidant compounds; protein kinase inhibitors; antibacterial agents
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Pharmacy, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy
Interests: medicinal chemistry; antiproliferative agents; antiviral agents; molecular docking; antioxidant compounds; protein kinase inhibitors; antibacterial agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Medicinal chemistry and pharmaceutical chemistry represent a reference model capable of fueling a virtuous circuit between environment, growth and well-being. They are a multidisciplinary topics focused on design, optimization and development of new chemical compounds useful as drug. Over the last 20 years, drug design and drug development have proven fundamental for the treatment of many diseases, including cancer, cardiovascular, infectious and neurodegenerative diseases, which today represent the main cause of death in the Western world. This special issue therefore is aimed to collect the updates of medicinal and pharmaceutical chemistry that could support the pharmaceutical development of potential drug. In particular, it is focused on rational design of new organic and inorganic drugs, but also on organic synthesis and reactivity, photochemistry, synthesis of new multifunctional polymeric, metallic and nanostructured materials, advanced methodologies and pharmaceutical technology in the chemical and chemical-pharmaceutical fields. The results reported in the issue will further support medicinal chemistry research to exploit the pharmaceutical potential of new chemical entities.

Dr. Chiara Brullo
Dr. Andrea Spallarossa
Guest Editors

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Keywords

  • medicinal chemistry
  • biological targets
  • drug synthesis
  • drug discovery
  • pharmaceutical chemistry
  • structure-activity relationships

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Published Papers (4 papers)

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Research

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17 pages, 4873 KiB  
Article
Next-Generation Analogues of AC265347 as Positive Allosteric Modulators of the Calcium-Sensing Receptor: Pharmacological Investigation of Structural Modifications at the Stereogenic Centre
by Le Vi Dinh, Jesse Dangerfield, Aaron DeBono, Andrew N. Keller, Tracy M. Josephs, Karen J. Gregory, Katie Leach and Ben Capuano
Int. J. Mol. Sci. 2025, 26(6), 2580; https://doi.org/10.3390/ijms26062580 - 13 Mar 2025
Viewed by 384
Abstract
The calcium-sensing receptor (CaSR) is a validated therapeutic target in the treatment of hyperparathyroidism and related diseases. The CaSR ago-positive allosteric modulator (PAM), AC265347 (1), exhibits a chemically and pharmacologically unique profile compared to current approved CaSR PAM therapeutics. Herein, [...] Read more.
The calcium-sensing receptor (CaSR) is a validated therapeutic target in the treatment of hyperparathyroidism and related diseases. The CaSR ago-positive allosteric modulator (PAM), AC265347 (1), exhibits a chemically and pharmacologically unique profile compared to current approved CaSR PAM therapeutics. Herein, we report a series of ‘next-generation’ analogues of AC265347, investigating the impact of structural modifications at the stereogenic centre on CaSR PAM activity. Compounds 5 and 7b featuring the alcohol functional group showed ago-PAM profiles comparable to 1, whilst compounds 6, 7 and 9 devoid of this functionality were ‘pure’ PAMs with no intrinsic agonism. These novel chemical tools provide an opportunity to explore the therapeutic potential of AC265347-like PAMs as a function of affinity, cooperativity and intrinsic agonism. Full article
(This article belongs to the Special Issue Medicinal Chemistry: From Drug Design to Drug Development)
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14 pages, 2574 KiB  
Article
Design, Synthesis, Physicochemical Properties, and Biological Activity of Thymidine Compounds Attached to 5,8-Quinolinedione Derivatives as Potent DT-Diaphorase Substrates
by Monika Kadela-Tomanek
Int. J. Mol. Sci. 2024, 25(20), 11211; https://doi.org/10.3390/ijms252011211 - 18 Oct 2024
Viewed by 911
Abstract
After heart disease, cancer is the second-leading cause of death worldwide. The most effective method of cancer treatment is target therapy. One of the potential goals of therapy could be DT-diaphorase, which reduces quinone moiety to hydroquinone, and reactive oxygen species are create [...] Read more.
After heart disease, cancer is the second-leading cause of death worldwide. The most effective method of cancer treatment is target therapy. One of the potential goals of therapy could be DT-diaphorase, which reduces quinone moiety to hydroquinone, and reactive oxygen species are create as a byproduct. The obtaining of hybrid compounds containing the quinone moiety and other bioactive compounds leads to new derivatives which can activate DT-diaphorase. The aim of this research was the synthesis and characterization of new hybrids of 5,8-quinolinedione with thymidine derivatives. The analysis of the physicochemical properties shows a strong relationship between the structure and properties of the tested compounds. The enzymatic assay shows that hybrids are good substrates of NQO1 protein. The analysis of the structure–activity relationship shows that the localization of nitrogen atoms influences the enzymatic conversion rate. The analysis was supplemented by a molecular docking study. Comparing the results of the enzymatic assay and the molecular docking presents a strong correlation between the enzymatic conversion rate and the scoring value. Full article
(This article belongs to the Special Issue Medicinal Chemistry: From Drug Design to Drug Development)
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49 pages, 7765 KiB  
Article
Low-Basicity 5-HT6 Receptor Ligands from the Group of Cyclic Arylguanidine Derivatives and Their Antiproliferative Activity Evaluation
by Przemysław Zaręba, Anna K. Drabczyk, Artur Wnorowski, Maciej Maj, Katarzyna Malarz, Patryk Rurka, Gniewomir Latacz, Beata Duszyńska, Krzesimir Ciura, Katarzyna Ewa Greber, Anna Boguszewska-Czubara, Paweł Śliwa and Julia Kuliś
Int. J. Mol. Sci. 2024, 25(19), 10287; https://doi.org/10.3390/ijms251910287 - 24 Sep 2024
Cited by 1 | Viewed by 1704
Abstract
The serotonin 5-HT6 receptor (5-HT6R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT6R signaling with pathways involved in cancer progression, we decided to check [...] Read more.
The serotonin 5-HT6 receptor (5-HT6R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT6R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT6R ligands in the treatment of CNS tumors. For this purpose, a new group of low-base 5-HT6R ligands was developed, belonging to arylsulfonamide derivatives of cyclic arylguanidines. The selected group of molecules was also tested for their antiproliferative activity on astrocytoma (1321N1) and glioblastoma (U87MG, LN-229, U-251) cell lines. Some of the molecules were subjected to ADMET tests in vitro, including lipophilicity, drug binding to plasma proteins, affinity for phospholipids, drug–drug interaction (DDI), the penetration of the membrane (PAMPA), metabolic stability, and hepatotoxicity as well as in vivo cardiotoxicity in the Danio rerio model. Two antagonists with an affinity constant Ki < 50 nM (PR 68 Ki = 37 nM) were selected. These compounds were characterized by very high selectivity. An analysis of pharmacokinetic parameters for the lead compound PR 68 confirmed favorable properties for administration, including passive diffusion and acceptable metabolic stability (metabolized in 49%, MLMs). The compound did not exhibit the potential for drug–drug interactions. Full article
(This article belongs to the Special Issue Medicinal Chemistry: From Drug Design to Drug Development)
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Review

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34 pages, 7196 KiB  
Review
PDE4D: A Multipurpose Pharmacological Target
by Matteo Lusardi, Federica Rapetti, Andrea Spallarossa and Chiara Brullo
Int. J. Mol. Sci. 2024, 25(15), 8052; https://doi.org/10.3390/ijms25158052 - 24 Jul 2024
Cited by 5 | Viewed by 2999
Abstract
Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning [...] Read more.
Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties. Full article
(This article belongs to the Special Issue Medicinal Chemistry: From Drug Design to Drug Development)
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