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Pharmaceuticals
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Multitargeted Compounds: A Promising Approach in Medicinal Chemistry
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Multitargeted Compounds: A Promising Approach in Medicinal Chemistry

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

Deadline for manuscript submissions: 25 November 2025 | Viewed by 9794

Special Issue Editor

Prof. Dr. Abdallah Hamze

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, Paris-Saclay University, Orsay, France
Interests: medicinal chemistry; drug discovery; anticancer agents; antibody drug conjugate (ADC); Histone deacetylase inhibitors (HDAC); protein kinase (PKs) inhibitors

Special Issue Information

Dear Colleagues,

In recent years, the development of novel therapeutic agents with the ability to interact with multiple targets simultaneously has drawn significant attention in the field of medicinal chemistry. These multitargeted compounds offer a new paradigm for drug discovery and hold immense potential for addressing complex diseases with intricate molecular mechanisms. This proposed Special Issue aims to explore the design, synthesis, and application of multitargeted compounds as a promising strategy in the field of medicinal chemistry.

Rational Design of Multitargeted Compounds:

This section aims to explore the rational design principles employed in the creation of multitargeted compounds. It will highlight the importance of structural modifications, molecular docking studies, and computational approaches to optimize the interactions between a compound and multiple targets.

Mechanistic Insights and Synergistic Effects:

Here, the focus will be on elucidating the mechanisms of action of multitargeted compounds. Understanding how these compounds simultaneously modulate multiple targets can provide valuable insights into the synergistic effects and enhanced therapeutic outcomes they offer. The section will showcase case studies that demonstrate the mechanistic basis of multitargeted compound activity.

Therapeutic Applications of Multitargeted Compounds:

This section will explore the diverse therapeutic applications of multitargeted compounds across various disease areas. Examples encompass cancer, neurodegenerative disorders, cardiovascular diseases, infectious diseases, and inflammation. Special emphasis will be placed on the advantages and challenges associated with multitargeted compounds compared to traditional single-target drugs.

Future Perspectives and Emerging Technologies:

The final section will provide an outlook on the future of multitargeted compounds in medicinal chemistry. It will explore emerging technologies, such as artificial intelligence, machine learning, and high-throughput screening, that can facilitate the discovery and optimization of multitargeted compounds. Additionally, potential strategies for translating multitargeted compounds from bench to bedside will be examined.

Prof. Dr. Abdallah Hamze
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • multitargeted compounds
  • medicinal chemistry
  • rational design
  • drug discovery
  • synergistic effects
  • emerging technologies
  • therapeutic applications
  • dual compounds

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Published Papers (4 papers)

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Research

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25 pages, 7088 KiB  
Article
Discovery of Dual TRPA1 and TRPV1 Antagonists as Novel Therapeutic Agents for Pain
by Nayeon Do, Dongxu Zuo, Miri Kim, Minseok Kim, Hee-Jin Ha, Peter M. Blumberg, Jihyae Ann, Sun Wook Hwang and Jeewoo Lee
Pharmaceuticals 2024, 17(9), 1209; https://doi.org/10.3390/ph17091209 - 13 Sep 2024
Cited by 4 | Viewed by 2950
Abstract
Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and [...] Read more.
Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and TRPV1 simultaneously with dual antagonists offers a promising approach to pain relief. In this study, we investigated a series of hybrid analogs of TRPA1 and TRPV1 antagonists to discover novel therapeutic agents for pain. Among these compounds synthesized by a condensation reaction forming 1,2,4-oxadiazole between the A- and C-regions, compound 50 exhibited substantial dual-acting antagonism to TRPA1 and TRPV1 with IC50 values of 1.42, 2.84, 2.13, and 5.02 μM for hTRPA1, mTRPA1, hTRPV1, and rTRPV1, respectively. In the formalin test, compound 50 demonstrated dose-dependent analgesic activity with an ED50 of 85.9 mg/kg in phase 1 and 21.6 mg/kg in phase 2, respectively, and was able to inhibit pain behavior completely at a dose of 100 mg/kg. This study presents the discovery and characterization of a novel dual TRPA1/TRPV1 antagonist, highlighting its potential as a therapeutic agent for pain management. Full article
(This article belongs to the Special Issue Multitargeted Compounds: A Promising Approach in Medicinal Chemistry)
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20 pages, 2702 KiB  
Article
Quercetin and Kaempferol as Multi-Targeting Antidiabetic Agents against Mouse Model of Chemically Induced Type 2 Diabetes
by Muhammad Ali, Mudassir Hassan, Siddique Akber Ansari, Hamad M. Alkahtani, Lamees S. Al-Rasheed and Shoeb Anwar Ansari
Pharmaceuticals 2024, 17(6), 757; https://doi.org/10.3390/ph17060757 - 8 Jun 2024
Cited by 16 | Viewed by 3808
Abstract
Diabetes, a multifactorial metabolic disorder, demands the discovery of multi-targeting drugs with minimal side effects. This study investigated the multi-targeting antidiabetic potential of quercetin and kaempferol. The druggability and binding affinities of both compounds towards multiple antidiabetic targets were explored using pharmacokinetic and [...] Read more.
Diabetes, a multifactorial metabolic disorder, demands the discovery of multi-targeting drugs with minimal side effects. This study investigated the multi-targeting antidiabetic potential of quercetin and kaempferol. The druggability and binding affinities of both compounds towards multiple antidiabetic targets were explored using pharmacokinetic and docking software (AutoDock Vina 1.1.2). Our findings showed that quercetin and kaempferol obey Lipinski’s rule of five and exhibit desirable ADMET (absorption, distribution, metabolism excretion, and toxicity) profiles. Both compounds showed higher binding affinities towards C-reactive protein (CRP), interleukin-1 (IL-1), dipeptidyl peptidase-4 (DPP-IV), peroxisome proliferator-activated receptor gamma (PPARG), protein tyrosine phosphatase (PTP), and sodium–glucose co-transporter-1 (SGLT-1) compared to metformin (the positive control). Both quercetin and kaempferol inhibited α-amylase activity (in vitro) up to 20.30 ± 0.49 and 37.43 ± 0.42%, respectively. Their oral supplementation significantly reduced blood glucose levels (p < 0.001), improved lipid profile (p < 0.001), and enhanced total antioxidant status (p < 0.01) in streptozotocin–nicotinamide (STZ-NA)-induced diabetic mice. Additionally, both compounds significantly inhibited the proliferation of Huh-7 and HepG2 (cancer cells) (p < 0.0001) with no effect on the viability of Vero cell line (non-cancer). In conclusion, quercetin and kaempferol demonstrated higher binding affinities towards multiple targets than metformin. In vitro and in vivo antidiabetic potential along with the anticancer activities of both compounds suggest promise for further development in diabetes management. The combination of both drugs did not show a synergistic effect, possibly due to their same target on the receptors. Full article
(This article belongs to the Special Issue Multitargeted Compounds: A Promising Approach in Medicinal Chemistry)
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19 pages, 4178 KiB  
Article
Dual Antitubercular and Antileishmanial Profiles of Quinoxaline Di-N-Oxides Containing an Amino Acidic Side Chain
by Juan F. González, María-Auxiliadora Dea-Ayuela, Lena Huck, José María Orduña, Francisco Bolás-Fernández, Elena de la Cuesta, Nazia Haseen, Ashraf Ali Mohammed and J. Carlos Menéndez
Pharmaceuticals 2024, 17(4), 487; https://doi.org/10.3390/ph17040487 - 11 Apr 2024
Viewed by 1465
Abstract
We present a new category of quinoxaline di-N-oxides (QdNOs) containing amino acid side chains with dual antituberculosis and antileishmanial activity. These compounds were synthesized by combining a regioselective 2,5-piperazinedione opening and a Beirut reaction and were screened for their activity against Mycobacterium tuberculosis [...] Read more.
We present a new category of quinoxaline di-N-oxides (QdNOs) containing amino acid side chains with dual antituberculosis and antileishmanial activity. These compounds were synthesized by combining a regioselective 2,5-piperazinedione opening and a Beirut reaction and were screened for their activity against Mycobacterium tuberculosis and the promastigote and amastigote forms of representative species of the Leishmania genus. Most QdNOs exhibited promising antitubercular activity with IC50 values ranging from 4.28 to 49.95 μM, comparable to clinically established drugs. Structure–activity relationship analysis emphasized the importance of substituents on the aromatic ring and the side chain. Antileishmanial tests showed that some selected compounds exhibited activity comparable to the positive control miltefosine against promastigotes of Leishmania amazonensis and Leishmania donovani. Notably, some compounds were found to be also more potent and less toxic than miltefosine in intracellular amastigote assays against Leishmania amazonensis. The compound showing the best dual antitubercular and leishmanicidal profile and a good selectivity index, 4h, can be regarded as a hit compound that opens up new opportunities for the development of integrated therapies against co-infections. Full article
(This article belongs to the Special Issue Multitargeted Compounds: A Promising Approach in Medicinal Chemistry)
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Review

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46 pages, 6291 KiB  
Review
Recent Advancements in the Development of HDAC/Tubulin Dual-Targeting Inhibitors
by Christine Tran and Abdallah Hamze
Pharmaceuticals 2025, 18(3), 341; https://doi.org/10.3390/ph18030341 - 27 Feb 2025
Viewed by 958
Abstract
Histone deacetylases (HDACs) have become one of the main targets in cancer therapy due to their involvement in various biological processes, including gene regulation, cell proliferation, and differentiation. Microtubules, as key elements of the cell cytoskeleton, also represent important therapeutic targets in anticancer [...] Read more.
Histone deacetylases (HDACs) have become one of the main targets in cancer therapy due to their involvement in various biological processes, including gene regulation, cell proliferation, and differentiation. Microtubules, as key elements of the cell cytoskeleton, also represent important therapeutic targets in anticancer drugs research. These proteins are involved in diverse cellular functions, especially mitosis, cell signaling, and intracellular trafficking. With the emergence of multi-target therapy during the last decades, the combination of HDAC and tubulin inhibitors has been envisioned as a practical approach for optimizing the therapeutic efficacy of antitumor molecules. HDAC/tubulin dual-targeting inhibitors offer the advantages of the synergistic action of both compounds, along with a significant decrease in their respective toxicities and drug resistance. This review will detail the major recent advancements in the development of HDAC/tubulin dual inhibitors over the last decade and their impact on anticancer drugs discovery. Full article
(This article belongs to the Special Issue Multitargeted Compounds: A Promising Approach in Medicinal Chemistry)
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