Recent Advances in the Development of Hybrid Drugs

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 20 April 2024 | Viewed by 30423

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Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal
Interests: organometallic/inorganic chemistry; peptide chemistry; metal–peptide conjugates; interaction studies with biomolecules; anti-cancer drug design and development; drug delivery; medicinal chemistry
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Guest Editor
Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal
Interests: carbohydrate chemistry; organic chemistry; medicinal chemistry; sugar-based drug discovery; antimicrobial resistance; antibiotic research; membrane-targeting drugs; drug-lipid interactions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hybrid drug development is a research field that is currently expanding. For a wide community of researchers around the world, the combination of two or more pharmacophores and/or drug-directing moieties in the same molecule is an attractive strategy for the design of new compounds with optimized pharmacodynamic profiles, and has already delivered promising results in the contexts of multidrug-resistant cancers, emerging antimicrobial-resistant bacteria, and others.

Molecular hybridization of several active fragments into the same molecular framework offers a unique opportunity to achieve additive and synergistic effects that would not otherwise be possible, hence opening new doors for enhanced drug potency, selectivity and, in some cases, drug susceptibility. As hybridized fragments share the same pharmacokinetic profile, this molecular design approach assures that the required concentrations of each pharmacophore are available near the target(s) at the exact same time—something that is often crucial for optimal results. 

Because of its undeniable potential, more and more researchers are integrating molecular hybridization into their strategic drug development approaches. Hence, this Special Issue of Pharmaceutics welcomes original research articles, communications and review articles dedicated to major advancements, breakthroughs and challenges in the design, synthesis and biological evaluation of organic, inorganic and organometallic hybrid drugs. Medicinal chemists working across all therapeutic areas are encouraged to contribute with research or literature overviews on this topic.

Dr. Tânia S. Morais
Dr. Ana M. de Matos
Guest Editors

Manuscript Submission Information

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Keywords

  • hybrid drugs
  • drug design
  • fragment-based drug discovery
  • molecular hybridization
  • therapeutic approaches
  • organic hybrid drugs
  • inorganic/organometallic hybrid drugs
  • targeting
  • selectivity

Published Papers (8 papers)

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Research

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19 pages, 2147 KiB  
Article
Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes
by Aleksandr Kazimir, Benedikt Schwarze, Peter Lönnecke, Sanja Jelača, Sanja Mijatović, Danijela Maksimović-Ivanić and Evamarie Hey-Hawkins
Pharmaceutics 2023, 15(2), 682; https://doi.org/10.3390/pharmaceutics15020682 - 17 Feb 2023
Cited by 5 | Viewed by 2009 | Correction
Abstract
The luminal A-subtype of breast cancer, where the oestrogen receptor α (ERα) is overexpressed, is the most frequent one. The prodrug tamoxifen (1) is the clinically used agent, inhibiting the ERα activity via the formation of several active metabolites, such as [...] Read more.
The luminal A-subtype of breast cancer, where the oestrogen receptor α (ERα) is overexpressed, is the most frequent one. The prodrug tamoxifen (1) is the clinically used agent, inhibiting the ERα activity via the formation of several active metabolites, such as 4-hydroxytamoxifen (2) or 4,4′-dihydroxytamoxifen (3). In this study, we present the tamoxifen derivative 4-[1,1-bis(4-methoxyphenyl)but-1-en-2-yl]-2,2′-bipyridine (4), which was combined with platinum or palladium dichloride, the former a well-known scaffold in anticancer treatment, to give [PtCl2(42N,N′)] (5) or [PdCl2(42N,N′] (6). To prevent fast exchange of weakly coordinating chlorido ligands in aqueous solution, a bulky, highly stable and hydrophobic nido-carborate(−2) ([C2B9H11]2−) was incorporated. The resulting complexes [3-(42N,N′)-3,1,2-PtC2B9H11] (7) and [3-(42N,N′)-3,1,2-PdC2B9H11] (8) exhibit a dramatic change in electronic and biological properties compared to 5 and 6. Thus, 8 is highly selective for triple-negative MDA-MB-231 cells (IC50 = 3.7 μM, MTT test), while 7 is completely inactive against this cell line. The observed cytotoxicity of compounds 46 and 8 against this triple-negative cell line suggests off-target mechanisms rather than only ERα inhibition, for which these compounds were originally designed. Spectroscopic properties and electronic structures of the metal complexes were investigated for possible explanations of the biological activities. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)
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20 pages, 2610 KiB  
Article
The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors
by Philipp Stockmann, Lydia Kuhnert, Wencke Leinung, Cathleen Lakoma, Birte Scholz, Svetlana Paskas, Sanja Mijatović, Danijela Maksimović-Ivanić, Walther Honscha and Evamarie Hey-Hawkins
Pharmaceutics 2023, 15(1), 241; https://doi.org/10.3390/pharmaceutics15010241 - 10 Jan 2023
Cited by 4 | Viewed by 1816
Abstract
The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer [...] Read more.
The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents’ pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)
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23 pages, 4993 KiB  
Article
Antioxidant and Cytotoxic Activity of New Polyphenolic Derivatives of Quinazolin-4(3H)-one: Synthesis and In Vitro Activities Evaluation
by Raluca Pele, Gabriel Marc, Ioana Ionuț, Cristina Nastasă, Ionel Fizeșan, Adrian Pîrnău, Laurian Vlase, Mariana Palage, Smaranda Oniga and Ovidiu Oniga
Pharmaceutics 2023, 15(1), 136; https://doi.org/10.3390/pharmaceutics15010136 - 30 Dec 2022
Cited by 3 | Viewed by 1571
Abstract
The development of hybrid molecules with significant human therapeutic properties is one of the main approaches of pharmaceutical research. One of the most important pharmacophores is the quinazolin-4(3H)-one heterocycle moiety, due to its wide range of biological activities. By its derivatization with polyphenolic [...] Read more.
The development of hybrid molecules with significant human therapeutic properties is one of the main approaches of pharmaceutical research. One of the most important pharmacophores is the quinazolin-4(3H)-one heterocycle moiety, due to its wide range of biological activities. By its derivatization with polyphenolic compounds, in our previous research, it proved to possess a good antiradical activity of ortho-diphenolic derivatives of quinazolin-4(3H)-one. In this study, we developed two new series of compounds, with an additional phenolic group or with a methyl group on the thioacetohydrazone fragment. The methods used to evaluate the activity of the compounds were radical scavenging, reduction of oxidizing reagents and transition metals’ ions chelation assays. Quantum descriptors were also calculated in order to evaluate the influence of substituents and their position on the activity of the compounds. The cytotoxic activity was evaluated using normal human foreskin fibroblast cells (BJ) and two cancerous cell lines, lung adenocarcinoma cells (A549) and prostate carcinoma cells (LNCaP). The results obtained for the pyrogallol derivatives showed a high antioxidant activity compared to ascorbic acid and Trolox. All the synthesized compounds displayed a higher cytotoxicity against the cancerous cell types and a high cytocompatibility with the normal cells. The antioxidant activity was deeply influenced by the addition of the third phenolic group in the synthesized molecules. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)
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20 pages, 2397 KiB  
Article
Resveratrol/Hydrazone Hybrids: Synthesis and Chemopreventive Activity against Colorectal Cancer Cells
by Wilson Castrillón-López, Angie Herrera-Ramírez, Gustavo Moreno-Quintero, Juan Carlos Coa, Tonny W. Naranjo and Wilson Cardona-Galeano
Pharmaceutics 2022, 14(11), 2278; https://doi.org/10.3390/pharmaceutics14112278 - 24 Oct 2022
Cited by 1 | Viewed by 1331
Abstract
A series of resveratrol/hydrazone hybrids were obtained and elucidated by spectroscopic analysis. All compounds were evaluated against colorectal cancer cells (SW480 and Sw620) and nonmalignant cell lines (HaCaT and CHO-K1) to establish the selectivity index. Among the hybrids evaluated, compounds 6e and 7 [...] Read more.
A series of resveratrol/hydrazone hybrids were obtained and elucidated by spectroscopic analysis. All compounds were evaluated against colorectal cancer cells (SW480 and Sw620) and nonmalignant cell lines (HaCaT and CHO-K1) to establish the selectivity index. Among the hybrids evaluated, compounds 6e and 7 displayed the highest cytotoxic activity with IC50 values of = 6.5 ± 1.9 µM and 19.0 ± 1.4 µM, respectively, on SW480 cells. In addition, hybrid 7 also exhibited activity on SW620 cells with an IC50 value of 38.41 ± 3.3 µM. Both compounds were even more toxic against these malignant cells in comparison to the nonmalignant ones, as evidenced by higher selectivity indices 48 h after treatment. These compounds displayed better activity and selectivity than parental compounds (PIH and Resveratrol) and the reference drug (5-FU). In addition, it was observed that both compounds caused antiproliferative activity probably exerted by cell cycle arrest at the G2/M or G0/G1 phases, with the formation of cells in the subG0/G1 phase. Furthermore, it was noticed that compound 7 induced mitochondrial depolarization in SW480 cells and positive staining for propidium iodide in both cancer cell lines, suggesting cell membrane damage involving either apoptosis or other processes of death. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)
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Review

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25 pages, 1375 KiB  
Review
Antibody–Drug Conjugates: Ushering in a New Era of Cancer Therapy
by Joshua Hurwitz, Lucy Roxana Haggstrom and Elgene Lim
Pharmaceutics 2023, 15(8), 2017; https://doi.org/10.3390/pharmaceutics15082017 - 26 Jul 2023
Cited by 4 | Viewed by 3644
Abstract
Antibody–drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancer, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development. The therapeutic benefits of [...] Read more.
Antibody–drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancer, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development. The therapeutic benefits of ADCs leverage the ability to selectively target cancer cells through antibody binding, resultant relative sparing of non-malignant tissues, and the targeted delivery of a cytotoxic payload. Consequently, this drug class has demonstrated activity in multiple malignancies refractory to standard therapeutic options. Despite this, limitations exist, including narrow therapeutic windows, unique toxicity profiles, development of therapeutic resistance, and appropriate biomarker selection. This review will describe the development of ADCs, their mechanisms of action, pivotal trials, and approved indications and identify common themes. Current challenges and opportunities will be discussed for this drug class in cancer therapeutics at a time when significant developments in antibody therapies, immunotherapy, and targeted agents are occurring. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)
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14 pages, 1242 KiB  
Review
Anticancer Drug Conjugates Incorporating Estrogen Receptor Ligands
by Darius P. Zlotos, Thales Kronenberger and Stefan A. Laufer
Pharmaceutics 2023, 15(1), 67; https://doi.org/10.3390/pharmaceutics15010067 - 26 Dec 2022
Cited by 1 | Viewed by 1648
Abstract
Hormone-dependent cancers, such as certain types of breast cancer are characterized by over-expression of estrogen receptors (ERs). Anticancer drug conjugates combining ER ligands with other classes of anticancer agents may not only benefit from dual action at both anti-cancer targets but also from [...] Read more.
Hormone-dependent cancers, such as certain types of breast cancer are characterized by over-expression of estrogen receptors (ERs). Anticancer drug conjugates combining ER ligands with other classes of anticancer agents may not only benefit from dual action at both anti-cancer targets but also from selective delivery of cytotoxic agents to ER-positive tumor cells resulting in less toxicity and adverse effects. Moreover, they could also take advantage of overcoming resistance typical for anti-hormonal monotherapy such as tamoxifen. In this review, we discuss the design, structures and pharmacological effects of numerous series of drug conjugates containing ER ligands such as selective ER modulators (tamoxifen, 4-hydroxytamoxifen, endoxifen), selective ER degraders (ICI-164384) and ER agonists (estradiol) linked to diverse anti-cancer agents including histone-deacetylase inhibitors, DNA-alkylating agents, antimitotic agents and epidermal growth factor receptor inhibitors. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)
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19 pages, 5515 KiB  
Review
FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis
by Davide Benedetto Tiz, Luana Bagnoli, Ornelio Rosati, Francesca Marini, Claudio Santi and Luca Sancineto
Pharmaceutics 2022, 14(11), 2538; https://doi.org/10.3390/pharmaceutics14112538 - 21 Nov 2022
Cited by 19 | Viewed by 16393
Abstract
This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for [...] Read more.
This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases. The diverse small molecules are described according to the date of approval and their syntheses is discussed. This review comprises classical chemical scaffolds together with innovative drugs such as a deuterium-containing drug. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)
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Other

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2 pages, 433 KiB  
Correction
Correction: Kazimir et al. Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes. Pharmaceutics 2023, 15, 682
by Aleksandr Kazimir, Benedikt Schwarze, Peter Lönnecke, Sanja Jelača, Sanja Mijatović, Danijela Maksimović-Ivanić and Evamarie Hey-Hawkins
Pharmaceutics 2023, 15(6), 1769; https://doi.org/10.3390/pharmaceutics15061769 - 19 Jun 2023
Viewed by 713
Abstract
In the original publication [...] Full article
(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)
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