Hybrid Drugs: Design and Applications

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

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 22587

Special Issue Editors

School of Chemistry, University of KwaZulu-Natal, Durban, South Africa
Interests: synthetic methodology; computational chemistry and molecular modelling; pharmacophore design; medicinal Chemistry; ligand–protein interactions; peptide folding; docking
Special Issues, Collections and Topics in MDPI journals
Department of Chemistry, Guru Nanak Dev University, Amritsar, India
Interests: molecular hybridization; anti-plasmodials; anti-mycobacterials; bio-organometallic chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A general belief that agents modulating multiple biological targets could outperform single target drugs paved the way for the introduction of molecular hybridization as an efficient technique in drug discovery and development. The goal of this approach is to combine two (or more) pharmacophoric/bioactive subunits into a new, single chemical entity known as a hybrid molecule. When compared to the parent drugs, the new hybrid molecule may have higher affinity and efficacy, a modified selectivity profile with improved pharmacokinetic and pharmacodynamic restrictions, dual or multiple modes of action, reduced undesirable side effects, decreased drug–drug interactions, reduced emergence or spread of drug resistance in pathogens, and lower cost.

Trioxaquines, for example, are antimalarial hybrid drugs that are effective against multiresistant strains of Plasmodium falciparum. The antimalarial activity of its two separate precursors is limited, demonstrating the synergistic effect of their covalent binding. Palumed has prepared over 100 trioxaquines, and the trioxaquine PA1103-SAR116242 was selected as a candidate for preclinical development in 2007 in collaboration with Sanofi-Aventis. Estramustine is an anticancer drug that is a combination of a steroid and nitrogen mustard. This is an effective treatment for metastatic and/or progressive prostate cancer. Panobinostat (LBH-589) is a marketed drug used to treat multiple myeloma because it inhibits multiple histone deacetylase enzymes, causing apoptosis to malignant cells.

The major challenges in developing new molecular hybrids that target complex diseases include selecting the right target combination and achieving balanced activity while retaining drug-like properties. Nonetheless, hybridization is gaining popularity in academia and industry as a valuable tool for developing new drugs for diseases such as cancer, malaria, tuberculosis, Alzheimer's, and others.

Prof. Dr. Parvesh Singh
Prof. Dr. Vipan Kumar
Guest Editors

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Keywords

  • molecular hybrids
  • anticancer
  • neglected tropical diseases
  • anti-Alzheimer
  • anti-HIV

Published Papers (9 papers)

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Editorial

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3 pages, 184 KiB  
Editorial
Special Issue “Hybrid Drugs: Design and Applications”
Pharmaceuticals 2023, 16(10), 1358; https://doi.org/10.3390/ph16101358 - 26 Sep 2023
Cited by 2 | Viewed by 638
Abstract
The widely held belief in the potential superiority of agents capable of modulating multiple biological targets has led to the adoption of molecular hybridization as an effective technique in the realm of drug discovery and development [...] Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)

Research

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20 pages, 4703 KiB  
Article
Discovery of New Boswellic Acid Hybrid 1H-1,2,3-Triazoles for Diabetic Management: In Vitro and In Silico Studies
Pharmaceuticals 2023, 16(2), 229; https://doi.org/10.3390/ph16020229 - 02 Feb 2023
Cited by 3 | Viewed by 1319
Abstract
A series of 24 new 1H-1,2,3-triazole hybrids of 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA (1)) and 11-keto-β-boswellic acid (β-KBA (2)) was designed and synthesized by employing “click” chemistry in a highly efficient manner. The 1,3-dipolar cycloaddition reaction between [...] Read more.
A series of 24 new 1H-1,2,3-triazole hybrids of 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA (1)) and 11-keto-β-boswellic acid (β-KBA (2)) was designed and synthesized by employing “click” chemistry in a highly efficient manner. The 1,3-dipolar cycloaddition reaction between β-AKBA-propargyl ester intermediate 3 or β-KBA-propargyl ester intermediate 4 with substituted aromatic azides 5a–5k in the presence of copper iodide (CuI) and Hünig’s base furnished the desired products—1H-1,2,3-triazole hybrids of β-AKBA (6a–6k) and β-KBA (7a–7k)—in high yields. All new synthesized compounds were characterized by 1H-, 13C-NMR spectroscopy, and HR-ESI-MS spectrometry. Furthermore, their α-glucosidase-inhibitory activity was evaluated in vitro. Interestingly, the results obtained from the α-glucosidase-inhibitory assay revealed that all the synthesized derivatives are highly potent inhibitors, with IC50 values ranging from 0.22 to 5.32 µM. Among all the compounds, 6f, 7h, 6j, 6h, 6g, 6c, 6k, 7g, and 7k exhibited exceptional inhibitory potency and were found to be several times more potent than the parent compounds 1 and 2, as well as standard acarbose. Kinetic studies of compounds 6g and 7h exhibited competitive and mixed types of inhibition, with ki values of 0.84 ± 0.007 and 1.18 ± 0.0012 µM, respectively. Molecular docking was carried out to investigate the binding modes of these compounds with α-glucosidase. The molecular docking interactions indicated that that all compounds are well fitted in the active site of α-glucosidase, where His280, Gln279, Asp215, His351, Arg442, and Arg315 mainly stabilize the binding of these compounds. The current study demonstrates the usefulness of incorporating a 1H-1,2,3-triazole moiety into the medicinally fascinating boswellic acids skeleton. Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)
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29 pages, 5887 KiB  
Article
Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells
Pharmaceuticals 2022, 15(10), 1299; https://doi.org/10.3390/ph15101299 - 21 Oct 2022
Cited by 8 | Viewed by 1835
Abstract
A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against [...] Read more.
A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against SW480 and SW620 cells with IC50 values of 62.73 ± 7.26 µM and 50.58 ± 1.33 µM, respectively; compound 4g induced cytotoxicity in SW620 cells with an IC50 value of 36.84 ± 0.71 µM. These compounds were even more selective than genistein alone, the reference drug (5-FU) and the equimolar mixture of genistein plus 5-FU. In addition, hybrids 4a and 4g induced time- and concentration-dependent antiproliferative activity and cell cycle arrest at the S-phase and G2/M. It was also observed that hybrid 4a induced apoptosis in SW620 cells probably triggered by the extrinsic pathway in response to the activation of p53, as evidenced by the increase in the levels of caspases 3/8 and the tumor suppressor protein (Tp53). Molecular docking studies suggest that the most active compound 4a would bind efficiently to proapoptotic human caspases 3/8 and human Tp53, which in turn could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. On the other hand, molecular dynamics (MD) studies provided strong evidence of the conformational stability of the complex between caspase-3 and hybrid 4a obtained throughout 100 ns all-atom MD simulation. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analyses of the complex with caspase-3 showed that the interaction between the ligand and the target protein is stable. Altogether, the results suggest that the active hybrids, mainly compound 4a, might act by modulating caspase-3 activity in a colorectal cancer model, making it a privileged scaffold that could be used in future investigations. Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)
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30 pages, 20432 KiB  
Article
α-Glucosidase and α-Amylase Inhibitory Potentials of Quinoline–1,3,4-oxadiazole Conjugates Bearing 1,2,3-Triazole with Antioxidant Activity, Kinetic Studies, and Computational Validation
Pharmaceuticals 2022, 15(8), 1035; https://doi.org/10.3390/ph15081035 - 22 Aug 2022
Cited by 10 | Viewed by 2147
Abstract
Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase while preventing oxidative [...] Read more.
Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase while preventing oxidative stress is deemed a practicable strategy for regulating postprandial glucose levels in DM patients. We report herein the α-glucosidase and α-amylase inhibition and antioxidant profile of quinoline hybrids 4at and 12at bearing 1,3,4-oxadiazole and 1,2,3-triazole cores, respectively. Overall, compound 4i with a bromopentyl sidechain exhibited the strongest α-glucosidase inhibition (IC50 = 15.85 µM) relative to reference drug acarbose (IC50 = 17.85 µM) and the best antioxidant profile in FRAP, DPPH, and NO scavenging assays. Compounds 4a and 12g also emerged as the most potent NO scavengers (IC50 = 2.67 and 3.01 µM, respectively) compared to gallic acid (IC50 = 728.68 µM), while notable α-glucosidase inhibition was observed for p-fluorobenzyl compound 4k (IC50 = 23.69 µM) and phenyl-1,2,3-triazolyl compound 12k (IC50 = 22.47 µM). Moreover, kinetic studies established the mode of α-glucosidase inhibition as non-competitive, thus classifying the quinoline hybrids as allosteric inhibitors. Molecular docking and molecular dynamics simulations then provided insights into the protein–ligand interaction profile and the stable complexation of promising hybrids at the allosteric site of α-glucosidase. These results showcase these compounds as worthy scaffolds for developing more potent α-glucosidase inhibitors with antioxidant activity for effective DM management. Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)
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20 pages, 2920 KiB  
Article
The Effect of 1,2,4-Triazole-3-thiol Derivatives Bearing Hydrazone Moiety on Cancer Cell Migration and Growth of Melanoma, Breast, and Pancreatic Cancer Spheroids
Pharmaceuticals 2022, 15(8), 1026; https://doi.org/10.3390/ph15081026 - 20 Aug 2022
Cited by 14 | Viewed by 1763
Abstract
4-Phenyl-3-[2-(phenylamino)ethyl]-1H-1,2,4-triazole-5(4H)-thione was used as a starting compound for the synthesis of the corresponding 1,2,4-triazol-3-ylthioacetohydrazide, which reacts with isatins and various aldehydes bearing aromatic and heterocyclic moieties provided target hydrazones. Their cytotoxicity was tested by the MTT assay against human [...] Read more.
4-Phenyl-3-[2-(phenylamino)ethyl]-1H-1,2,4-triazole-5(4H)-thione was used as a starting compound for the synthesis of the corresponding 1,2,4-triazol-3-ylthioacetohydrazide, which reacts with isatins and various aldehydes bearing aromatic and heterocyclic moieties provided target hydrazones. Their cytotoxicity was tested by the MTT assay against human melanoma IGR39, human triple-negative breast cancer (MDA-MB-231), and pancreatic carcinoma (Panc-1) cell lines. The selectivity of compounds towards cancer cells was also studied. In general, the synthesized compounds were more cytotoxic against the melanoma cell line. N′-(2-oxoindolin-3-ylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide, N′-((1H-pyrrol-2-yl)methylene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide and N′-(2-hydroxy-5-nitrobenzylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide were identified as the most active among all synthesized compounds in 3D cell cultures. N′-(4-(dimethylamino)benzylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide inhibited all cancer cell migration, was characterized as relatively more selective towards cancer cells, and could be further tested as an antimetastatic candidate. Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)
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Review

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42 pages, 31284 KiB  
Review
An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors
Pharmaceuticals 2023, 16(2), 254; https://doi.org/10.3390/ph16020254 - 07 Feb 2023
Cited by 9 | Viewed by 2390
Abstract
The world’s health system is plagued by cancer and a worldwide effort is underway to find new drugs to treat cancer. There has been a significant improvement in understanding the pathogenesis of cancer, but it remains one of the leading causes of death. [...] Read more.
The world’s health system is plagued by cancer and a worldwide effort is underway to find new drugs to treat cancer. There has been a significant improvement in understanding the pathogenesis of cancer, but it remains one of the leading causes of death. The imperative 1,3,4-oxadiazole scaffold possesses a wide variety of biological activities, particularly for cancer treatment. In the development of novel 1,3,4-oxadiazole-based drugs, structural modifications are important to ensure high cytotoxicity towards malignant cells. These structural modification strategies have shown promising results when combined with outstanding oxadiazole scaffolds, which selectively interact with nucleic acids, enzymes, and globular proteins. A variety of mechanisms, such as the inhibition of growth factors, enzymes, and kinases, contribute to their antiproliferative effects. The activity of different 1,3,4-oxadiazole conjugates were tested on the different cell lines of different types of cancer. It is demonstrated that 1,3,4-oxadiazole hybridization with other anticancer pharmacophores have different mechanisms of action by targeting various enzymes (thymidylate synthase, HDAC, topoisomerase II, telomerase, thymidine phosphorylase) and many of the proteins that contribute to cancer cell proliferation. The focus of this review is to highlight the anticancer potential, molecular docking, and SAR studies of 1,3,4-oxadiazole derivatives by inhibiting specific cancer biological targets, such as inhibiting telomerase activity, HDAC, thymidylate synthase, and the thymidine phosphorylase enzyme. The purpose of this review is to summarize recent developments and discoveries in the field of anticancer drugs using 1,3,4-oxadiazoles. Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)
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28 pages, 6451 KiB  
Review
Hybrid Molecules as Potential Drugs for the Treatment of HIV: Design and Applications
Pharmaceuticals 2022, 15(9), 1092; https://doi.org/10.3390/ph15091092 - 31 Aug 2022
Cited by 3 | Viewed by 2000
Abstract
Human immunodeficiency virus (HIV) infection is a major problem for humanity because HIV is constantly changing and developing resistance to current drugs. This necessitates the development of new anti-HIV drugs that take new approaches to combat an ever-evolving virus. One of the promising [...] Read more.
Human immunodeficiency virus (HIV) infection is a major problem for humanity because HIV is constantly changing and developing resistance to current drugs. This necessitates the development of new anti-HIV drugs that take new approaches to combat an ever-evolving virus. One of the promising alternatives to combination antiretroviral therapy (cART) is the molecular hybrid strategy, in which two or more pharmacophore units of bioactive scaffolds are combined into a single molecular structure. These hybrid structures have the potential to have higher efficacy and lower toxicity than their parent molecules. Given the potential advantages of the hybrid molecular approach, the development and synthesis of these compounds are of great importance in anti-HIV drug discovery. This review focuses on the recent development of hybrid compounds targeting integrase (IN), reverse transcriptase (RT), and protease (PR) proteins and provides a brief description of their chemical structures, structure–activity relationship, and binding mode. Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)
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93 pages, 41287 KiB  
Review
Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids
Pharmaceuticals 2022, 15(9), 1071; https://doi.org/10.3390/ph15091071 - 28 Aug 2022
Cited by 38 | Viewed by 5133
Abstract
Cancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single [...] Read more.
Cancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single molecule. The hybrid molecule acts through distinct modes of action on several targets at a given time with more efficacy and less susceptibility to resistance. Thus, there is a huge scope for using hybrid compounds to tackle the present difficulties in cancer medicine. Recent work has applied this technique to uncover some interesting molecules with substantial anticancer properties. In this study, we report data on numerous promising hybrid anti-proliferative/anti-tumor agents developed over the previous 10 years (2011–2021). It includes quinazoline, indole, carbazole, pyrimidine, quinoline, quinone, imidazole, selenium, platinum, hydroxamic acid, ferrocene, curcumin, triazole, benzimidazole, isatin, pyrrolo benzodiazepine (PBD), chalcone, coumarin, nitrogen mustard, pyrazole, and pyridine-based anticancer hybrids produced via molecular hybridization techniques. Overall, this review offers a clear indication of the potential benefits of merging pharmacophoric subunits from multiple different known chemical prototypes to produce more potent and precise hybrid compounds. This provides valuable knowledge for researchers working on complex diseases such as cancer. Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)
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35 pages, 11656 KiB  
Review
A Mini Review on Isatin, an Anticancer Scaffold with Potential Activities against Neglected Tropical Diseases (NTDs)
Pharmaceuticals 2022, 15(5), 536; https://doi.org/10.3390/ph15050536 - 27 Apr 2022
Cited by 23 | Viewed by 3561
Abstract
Isatin, chemically an indole-1H-2,3-dione, is recognised as one of the most attractive therapeutic fragments in drug design and development. The template has turned out to be exceptionally useful for developing new anticancer scaffolds, as evidenced by the increasing number of isatin-based [...] Read more.
Isatin, chemically an indole-1H-2,3-dione, is recognised as one of the most attractive therapeutic fragments in drug design and development. The template has turned out to be exceptionally useful for developing new anticancer scaffolds, as evidenced by the increasing number of isatin-based molecules which are either in clinical use or in trials. Apart from its promising antiproliferative properties, isatin has shown potential in treating Neglected Tropical Diseases (NTDs) not only as a parent core, but also by attenuating the activities of various pharmacophores. The objective of this mini-review is to keep readers up to date on the latest developments in the biological potential of isatin-based scaffolds, targeting cancer and NTDs such as tuberculosis, malaria, and microbial infections. Full article
(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)
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