Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
6.7
4.6
Journals
Molecules
Special Issues
Designing Next-Generation Drug-Like Molecules for Medicinal Applications
molecules-logo
Submit to Molecules Review for Molecules Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Designing Next-Generation Drug-Like Molecules for Medicinal Applications

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 50043

Special Issue Editors

Dr. Imtiaz Khan

E-Mail Website
Guest Editor
Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
Interests: organic (organometallic) synthesis; new reaction methodology; catalysis; C‒H functionalizations; bioactive heterocycles; multistep organic synthesis; drug design
Special Issues, Collections and Topics in MDPI journals
Dr. Sumera Zaib

E-Mail Website1 Website2
Guest Editor
Department of Basic & Applied Chemistry, Faculty of Science & Technology, University of Central Punjab, Lahore, Pakistan
Interests: medicinal chemistry; enzymology; expression and purification of proteins; virtual screening; homology modeling; molecular modeling and dynamic simulations; in vivo animal model systems; in vitro biological assays; clinical biochemistry; enzyme inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of new drugs/drug candidates for medical treatment remains an exciting but challenging process as only a limited number of synthetic compounds fit well into the discovery and development process after multiple experimentation and screening for their preclinical properties. Over the years, this continuous demand has been fueled by the use of organic/synthetic chemistry protocols that deliver new molecules or improve the existing toolbox diversifying libraries of pharmacophores of medicinal interest. The application of new methodologies particularly employing green and sustainable commercial feedstock chemicals for the discovery and development of biological therapeutics opens up new avenues of research. In parallel, the discovery and development of new organic molecules have always proved effective in designing drugs while overcoming critical challenges to the pharmaceutical industry and providing innovative solutions toward commercialized medicines.

This Special Issue aims to provide a far-reaching overview of the most recent developments in synthetic methodologies as well as medicinal chemistry applications of small molecule inhibitors. We invite contributions including short communications, full papers, and authoritative/tutorial reviews from colleagues working in organic chemistry and sustainable synthesis. In particular, we invite papers on the development of new drug inhibitors for medicinal applications. Furthermore, the scope of this Special Issue will cover exciting developments in the design strategies of new drugs/drug molecules, structure–activity relationships, in vitro and in silico analyses, and pharmacokinetic properties. We look forward to reading your contributions.

Dr. Imtiaz Khan
Dr. Sumera Zaib
Guest Editors

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. 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.

Related Special Issue

Published Papers (18 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

4 pages, 191 KiB  
Editorial
Designing Next-Generation Drug-like Molecules for Medicinal Applications
by Imtiaz Khan and Sumera Zaib
Molecules 2023, 28(4), 1860; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28041860 - 16 Feb 2023
Cited by 1 | Viewed by 1037
Abstract
The development of new drugs/drug candidates for medical treatment remains an exciting but challenging process as only a limited number of synthetic compounds fit well into the discovery and development process after multiple experiments and screening for their preclinical properties [...] Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)

Research

Jump to: Editorial, Review

20 pages, 6841 KiB  
Article
Ring-Modified Histidine-Containing Cationic Short Peptides Exhibit Anticryptococcal Activity by Cellular Disruption
by Komal Sharma, Shams Aaghaz, Indresh Kumar Maurya, Shreya Singh, Shivaprakash M. Rudramurthy, Vinod Kumar, Kulbhushan Tikoo and Rahul Jain
Molecules 2023, 28(1), 87; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28010087 - 22 Dec 2022
Cited by 4 | Viewed by 1453
Abstract
Delineation of clinical complications secondary to fungal infections, such as cryptococcal meningitis, and the concurrent emergence of multidrug resistance in large population subsets necessitates the need for the development of new classes of antifungals. Herein, we report a series of ring-modified histidine-containing short [...] Read more.
Delineation of clinical complications secondary to fungal infections, such as cryptococcal meningitis, and the concurrent emergence of multidrug resistance in large population subsets necessitates the need for the development of new classes of antifungals. Herein, we report a series of ring-modified histidine-containing short cationic peptides exhibiting anticryptococcal activity via membrane lysis. The N-1 position of histidine was benzylated, followed by iodination at the C-5 position via electrophilic iodination, and the dipeptides were obtained after coupling with tryptophan. In vitro analysis revealed that peptides Trp-His[1-(3,5-di-tert-butylbenzyl)-5-iodo]-OMe (10d, IC50 = 2.20 μg/mL; MIC = 4.01 μg/mL) and Trp-His[1-(2-iodophenyl)-5-iodo)]-OMe (10o, IC50 = 2.52 μg/mL; MIC = 4.59 μg/mL) exhibit promising antifungal activities against C. neoformans. When administered in combination with standard drug amphotericin B (Amp B), a significant synergism was observed, with 4- to 16-fold increase in the potencies of both peptides and Amp B. Electron microscopy analysis with SEM and TEM showed that the dipeptides primarily act via membrane disruption, leading to pore formation and causing cell lysis. After entering the cells, the peptides interact with the intracellular components as demonstrated by confocal laser scanning microscopy (CLSM). Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

24 pages, 3695 KiB  
Article
Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies
by Mariangela Agamennone, Marialuigia Fantacuzzi, Simone Carradori, Anél Petzer, Jacobus P. Petzer, Andrea Angeli, Claudiu T. Supuran and Grazia Luisi
Molecules 2022, 27(22), 7884; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27227884 - 15 Nov 2022
Cited by 6 | Viewed by 1337
Abstract
The involvement of human carbonic anhydrase (hCA) IX/XII in the pathogenesis and progression of many types of cancer is well acknowledged, and more recently human monoamine oxidases (hMAOs) A and B have been found important contributors to tumor development and aggressiveness. With a [...] Read more.
The involvement of human carbonic anhydrase (hCA) IX/XII in the pathogenesis and progression of many types of cancer is well acknowledged, and more recently human monoamine oxidases (hMAOs) A and B have been found important contributors to tumor development and aggressiveness. With a view of an enzymatic dual-blockade approach, in this investigation, new coumarin-based amino acyl and (pseudo)-dipeptidyl derivatives were synthesized and firstly evaluated in vitro for inhibitory activity and selectivity against membrane-bound and cytosolic hCAs (hCA IX/XII over hCA I/II), as well as the hMAOs, to estimate their potential as anticancer agents. De novo design of peptide-coumarin conjugates was subsequently carried out and involved the combination of the widely explored coumarin nucleus with the unique biophysical and structural properties of native or modified peptides. All compounds displayed nanomolar inhibitory activities towards membrane-anchored hCAs, whilst they were unable to block the ubiquitous CA I and II isoforms. Structural features pertinent to potent and selective CA inhibitory activity are discussed, and modeling studies were found to support the biological data. Lower potency inhibition of the hMAOs was observed, with most compounds showing preferential inhibition of hMAO-A. The binding of the most potent ligands (6 and 16) to the hydrophobic active site of hMAO-A was investigated in an attempt to explain selectivity on the molecular level. Calculated Ligand Efficiency values indicate that compound 6 has the potential to serve as a lead compound for developing innovative anticancer agents based on the dual inhibition strategy. This information may help design new coumarin-based peptide molecules with diverse bioactivities. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Figure 1

25 pages, 4916 KiB  
Article
Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2
by Reda G. Yousef, Wagdy M. Eldehna, Alaa Elwan, Abdelaziz S. Abdelaziz, Ahmed B. M. Mehany, Ibraheem M. M. Gobaara, Bshra A. Alsfouk, Eslam B. Elkaeed, Ahmed M. Metwaly and Ibrahim H. Eissa
Molecules 2022, 27(13), 4079; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27134079 - 24 Jun 2022
Cited by 11 | Viewed by 2200
Abstract
VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be [...] Read more.
VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, 1H-NMR, and 13C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound 8 exhibited the strongest anti-proliferative activities with IC50 values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound 8 was the most potent VEGFR-2 inhibitor with an IC50 value of 77.02 nM (compare to sorafenib: IC50 = 53.65 nM). Treatment of HCT-116 cells with compound 8 produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound 8 caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound 8 on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound 8 has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Figure 1

25 pages, 8474 KiB  
Article
Ligand and Structure-Based In Silico Determination of the Most Promising SARS-CoV-2 nsp16-nsp10 2′-o-Methyltransferase Complex Inhibitors among 3009 FDA Approved Drugs
by Ibrahim H. Eissa, Mohamed S. Alesawy, Abdulrahman M. Saleh, Eslam B. Elkaeed, Bshra A. Alsfouk, Abdul-Aziz M. M. El-Attar and Ahmed M. Metwaly
Molecules 2022, 27(7), 2287; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072287 - 31 Mar 2022
Cited by 32 | Viewed by 2399
Abstract
As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (2′OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (PDB [...] Read more.
As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (2′OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2′-o-methyltransferase (PDB ID: (6W4H) was conducted through a multi-step screening approach. At the beginning, molecular fingerprints experiment with SAM (S-Adenosylmethionine), the co-crystallized ligand of the targeted enzyme, unveiled the resemblance of 147 drugs. Then, a structural similarity experiment recommended 26 compounds. Therefore, the 26 compounds were docked against 2′OMTase to reveal the potential inhibitory effect of seven promising compounds (Protirelin, (1187), Calcium folinate (1913), Raltegravir (1995), Regadenoson (2176), Ertapenem (2396), Methylergometrine (2532), and Thiamine pyrophosphate hydrochloride (2612)). Out of the docked ligands, Ertapenem (2396) showed an ideal binding mode like that of the co-crystallized ligand (SAM). It occupied all sub-pockets of the active site and bound the crucial amino acids. Accordingly, some MD simulation experiments (RMSD, RMSF, Rg, SASA, and H-bonding) have been conducted for the 2′OMTase—Ertapenem complex over 100 ns. The performed MD experiments verified the correct binding mode of Ertapenem against 2′OMTase exhibiting low energy and optimal dynamics. Finally, MM-PBSA studies indicated that Ertapenem bonded advantageously to the targeted protein with a free energy value of −43 KJ/mol. Furthermore, the binding free energy analysis revealed the essential amino acids of 2′OMTase that served positively to the binding. The achieved results bring hope to find a treatment for COVID-19 via in vitro and in vivo studies for the pointed compounds. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

17 pages, 2046 KiB  
Article
Rhodamine 101 Conjugates of Triterpenoic Amides Are of Comparable Cytotoxicity as Their Rhodamine B Analogs
by Niels V. Heise, Daniel Major, Sophie Hoenke, Marie Kozubek, Immo Serbian and René Csuk
Molecules 2022, 27(7), 2220; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072220 - 29 Mar 2022
Cited by 13 | Viewed by 2093
Abstract
Pentacyclic triterpenoic acids (betulinic, oleanolic, ursolic, and platanic acid) were selected and subjected to acetylation followed by the formation of amides derived from either piperazine or homopiperazine. These amides were coupled with either rhodamine B or rhodamine 101. All of these compounds were [...] Read more.
Pentacyclic triterpenoic acids (betulinic, oleanolic, ursolic, and platanic acid) were selected and subjected to acetylation followed by the formation of amides derived from either piperazine or homopiperazine. These amides were coupled with either rhodamine B or rhodamine 101. All of these compounds were screened for their cytotoxic activity in SRB assays. As a result, the cytotoxicity of the parent acids was low but increased slightly upon their acetylation while a significant increase in cytotoxicity was observed for piperazinyl and homopiperazinyl amides. A tremendous improvement in cytotoxicity was observed; however, for the rhodamine B and rhodamine 101 conjugates, and compound 27, an ursolic acid derived homopiperazinyl amide holding a rhodamine 101 residue showed an EC50 = 0.05 µM for A2780 ovarian cancer cells while being less cytotoxic for non-malignant fibroblasts. To date, the rhodamine 101 derivatives presented here are the first examples of triterpene derivatives holding a rhodamine residue different from rhodamine B. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

11 pages, 3295 KiB  
Article
Virtual Screening, Synthesis and Biological Evaluation of Streptococcus mutans Mediated Biofilm Inhibitors
by Lubna Atta, Ruqaiya Khalil, Khalid Mohammed Khan, Moatter Zehra, Faiza Saleem, Mohammad Nur-e-Alam and Zaheer Ul-Haq
Molecules 2022, 27(4), 1455; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27041455 - 21 Feb 2022
Cited by 3 | Viewed by 2795
Abstract
Dental caries, a global oral health concern, is a biofilm-mediated disease. Streptococcus mutans, the most prevalent oral microbiota, produces extracellular enzymes, including glycosyltransferases responsible for sucrose polymerization. In bacterial communities, the biofilm matrix confers resistance to host immune responses and antibiotics. Thus, in [...] Read more.
Dental caries, a global oral health concern, is a biofilm-mediated disease. Streptococcus mutans, the most prevalent oral microbiota, produces extracellular enzymes, including glycosyltransferases responsible for sucrose polymerization. In bacterial communities, the biofilm matrix confers resistance to host immune responses and antibiotics. Thus, in cases of chronic dental caries, inhibiting bacterial biofilm assembly should prevent demineralization of tooth enamel, thereby preventing tooth decay. A high throughput screening was performed in the present study to identify small molecule inhibitors of S. mutans glycosyltransferases. Multiple pharmacophore models were developed, validated with multiple datasets, and used for virtual screening against large chemical databases. Over 3000 drug-like hits were obtained that were analyzed to explore their binding mode. Finally, six compounds that showed good binding affinities were further analyzed for ADME (absorption, distribution, metabolism, and excretion) properties. The obtained in silico hits were evaluated for in vitro biofilm formation. The compounds displayed excellent antibiofilm activities with minimum inhibitory concentration (MIC) values of 15.26–250 µg/mL. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Figure 1

14 pages, 2778 KiB  
Article
Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors
by Kashif Rafiq, Najeeb Ur Rehman, Sobia Ahsan Halim, Majid Khan, Ajmal Khan and Ahmed Al-Harrasi
Molecules 2022, 27(3), 816; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030816 - 26 Jan 2022
Cited by 3 | Viewed by 2839
Abstract
Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we [...] Read more.
Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-β-alanine 1,3,4-oxadiazole hybrids (4a–l), characterized by 1H- and 13C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-β-alanine 1,3,4-oxadiazole derivatives 4a–l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC50 value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Figure 1

12 pages, 2623 KiB  
Article
Approach for the Design of Covalent Protein Kinase Inhibitors via Focused Deep Generative Modeling
by Atsushi Yoshimori, Filip Miljković and Jürgen Bajorath
Molecules 2022, 27(2), 570; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27020570 - 17 Jan 2022
Cited by 8 | Viewed by 3798
Abstract
Deep machine learning is expanding the conceptual framework and capacity of computational compound design, enabling new applications through generative modeling. We have explored the systematic design of covalent protein kinase inhibitors by learning from kinome-relevant chemical space, followed by focusing on an exemplary [...] Read more.
Deep machine learning is expanding the conceptual framework and capacity of computational compound design, enabling new applications through generative modeling. We have explored the systematic design of covalent protein kinase inhibitors by learning from kinome-relevant chemical space, followed by focusing on an exemplary kinase of interest. Covalent inhibitors experience a renaissance in drug discovery, especially for targeting protein kinases. However, computational design of this class of inhibitors has thus far only been little investigated. To this end, we have devised a computational approach combining fragment-based design and deep generative modeling augmented by three-dimensional pharmacophore screening. This approach is thought to be particularly relevant for medicinal chemistry applications because it combines knowledge-based elements with deep learning and is chemically intuitive. As an exemplary application, we report for Bruton’s tyrosine kinase (BTK), a major drug target for the treatment of inflammatory diseases and leukemia, the generation of novel candidate inhibitors with a specific chemically reactive group for covalent modification, requiring only little target-specific compound information to guide the design efforts. Newly generated compounds include known inhibitors and characteristic substructures and many novel candidates, thus lending credence to the computational approach, which is readily applicable to other targets. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Figure 1

15 pages, 3286 KiB  
Article
Development of Sustained Release Baricitinib Loaded Lipid-Polymer Hybrid Nanoparticles with Improved Oral Bioavailability
by Md. Khalid Anwer, Essam A. Ali, Muzaffar Iqbal, Mohammed Muqtader Ahmed, Mohammed F. Aldawsari, Ahmed Al Saqr, Mohd Nazam Ansari and M. Ali Aboudzadeh
Molecules 2022, 27(1), 168; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27010168 - 28 Dec 2021
Cited by 22 | Viewed by 2880
Abstract
Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid [...] Read more.
Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (−36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer–Peppas kinetic model (R2 = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

16 pages, 3451 KiB  
Article
Structural Bases for Hesperetin Derivatives: Inhibition of Protein Tyrosine Phosphatase 1B, Kinetics Mechanism and Molecular Docking Study
by Md Yousof Ali, Susoma Jannat, Hyun-Ah Jung and Jae-Sue Choi
Molecules 2021, 26(24), 7433; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26247433 - 08 Dec 2021
Cited by 10 | Viewed by 2587
Abstract
In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5- [...] Read more.
In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5-O-glucoside, a single-glucose-containing flavanone glycoside, significantly inhibited PTP1B with an IC50 value of 37.14 ± 0.07 µM. Hesperetin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC50 = 9.65 ± 0.01 µM). The most active flavanone hesperetin 5-O-glucoside suggested that the position of a sugar moiety at the C-5-position influences the PTP1B inhibition. It was observed that the ability to inhibit PTP1B is dependent on the nature, position, and number of sugar moieties in the flavonoid structure, as well as conjugation. In the kinetic study of PTP1B enzyme inhibition, hesperetin 5-O-glucoside led to mixed-type inhibition. Molecular docking studies revealed that hesperetin 5-O-glucoside had a higher binding affinity with key amino residues, suggesting that this molecule best fits the PTP1B allosteric site cavity. The data reported here support hesperetin 5-O-glucoside as a hit for the design of more potent and selective inhibitors against PTP1B in the search for a new anti-diabetic treatment. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Figure 1

14 pages, 2762 KiB  
Article
Fabrication and Biological Assessment of Antidiabetic α-Mangostin Loaded Nanosponges: In Vitro, In Vivo, and In Silico Studies
by Faisal Usman, Hamid Saeed Shah, Sumera Zaib, Sirikhwan Manee, Jahanzeb Mudassir, Ajmal Khan, Gaber El-Saber Batiha, Khamael M. Abualnaja, Dalal Alhashmialameer and Imtiaz Khan
Molecules 2021, 26(21), 6633; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216633 - 01 Nov 2021
Cited by 11 | Viewed by 3043
Abstract
Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this [...] Read more.
Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this perspective, xanthone compounds in the pericarp of the mangosteen fruit, especially α-mangostin (MGN), have been recognized to restore damaged pancreatic β-cells for optimal insulin release. Therefore, taking advantage of the robust use of nanotechnology for targeted drug delivery, we herein report the preparation of MGN loaded nanosponges for anti-diabetic therapeutic applications. The nanosponges were prepared by quasi-emulsion solvent evaporation method. Physico-chemical characterization of formulated nanosponges with satisfactory outcomes was performed with Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Zeta potential, hydrodynamic diameter, entrapment efficiency, drug release properties, and stability studies at stress conditions were also tested. Molecular docking analysis revealed significant interactions of α-glucosidase and MGN in a protein-ligand complex. The maximum inhibition by nanosponges against α-glucosidase was observed to be 0.9352 ± 0.0856 µM, 3.11-fold higher than acarbose. In vivo studies were conducted on diabetic rats and plasma glucose levels were estimated by HPLC. Collectively, our findings suggest that MGN-loaded nanosponges may be beneficial in the treatment of diabetes since they prolong the antidiabetic response in plasma and improve patient compliance by slowly releasing MGN and requiring less frequent doses, respectively. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

23 pages, 4935 KiB  
Article
Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis
by Sumera Zaib, Rubina Munir, Muhammad Tayyab Younas, Naghmana Kausar, Aliya Ibrar, Sehar Aqsa, Noorma Shahid, Tahira Tasneem Asif, Hashem O. Alsaab and Imtiaz Khan
Molecules 2021, 26(21), 6573; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216573 - 30 Oct 2021
Cited by 22 | Viewed by 3049
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

8 pages, 3328 KiB  
Article
Evaluation of the Inhibitory Effects of Pyridylpyrazole Derivatives on LPS-Induced PGE2 Productions and Nitric Oxide in Murine RAW 264.7 Macrophages
by Mahmoud M. Gamal El-Din, Mohammed I. El-Gamal, Young-Do Kwon, Su-Yeon Kim, Hee-Soo Han, Sang-Eun Park, Chang-Hyun Oh, Kyung-Tae Lee and Hee-Kwon Kim
Molecules 2021, 26(21), 6489; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216489 - 27 Oct 2021
Cited by 1 | Viewed by 1537
Abstract
A series of thirteen triarylpyrazole analogs were investigated as inhibitors of lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) and nitric oxide (NO) production in RAW 264.7 macrophages. The target compounds 1a–m have first been assessed for cytotoxicity against RAW 264.7 [...] Read more.
A series of thirteen triarylpyrazole analogs were investigated as inhibitors of lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) and nitric oxide (NO) production in RAW 264.7 macrophages. The target compounds 1a–m have first been assessed for cytotoxicity against RAW 264.7 macrophages to determine their non-cytotoxic concentration(s) for anti-inflammatory testing to make sure that the inhibition of PGE2 and NO production would not be caused by cytotoxicity. It was found that compounds 1f and 1m were the most potent PGE2 inhibitors with IC50 values of 7.1 and 1.1 μM, respectively. In addition, these compounds also showed inhibitory effects of 11.6% and 37.19% on LPS-induced NO production, respectively. The western blots analysis of COX-2 and iNOS showed that the PGE2 and NO inhibitory effect of compound 1m are attributed to inhibition of COX-2 and iNOS protein expression through inactivation of p38. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

20 pages, 15502 KiB  
Article
Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents
by Abdullah Mohammed Al-Majid, M. Ali, Mohammad Shahidul Islam, Saeed Alshahrani, Abdullah Saleh Alamary, Sammer Yousuf, M. Iqbal Choudhary and Assem Barakat
Molecules 2021, 26(20), 6305; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26206305 - 19 Oct 2021
Cited by 13 | Viewed by 2280
Abstract
A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, [...] Read more.
A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a–f to afford the target di-spirooxindole compounds 4a–n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC50 = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC50 = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO2 substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC50 = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Figure 1

Review

Jump to: Editorial, Research

85 pages, 448309 KiB  
Review
Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects
by Mohammed I. El-Gamal, Seyed-Omar Zaraei, Moustafa M. Madkour and Hanan S. Anbar
Molecules 2022, 27(1), 330; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27010330 - 05 Jan 2022
Cited by 23 | Viewed by 5754
Abstract
Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based [...] Read more.
Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011–2020). Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

31 pages, 6647 KiB  
Review
A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors
by Mohammed I. El-Gamal, Nada H. Mewafi, Nada E. Abdelmotteleb, Minnatullah A. Emara, Hamadeh Tarazi, Rawan M. Sbenati, Moustafa M. Madkour, Seyed-Omar Zaraei, Afnan I. Shahin and Hanan S. Anbar
Molecules 2021, 26(23), 7376; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26237376 - 05 Dec 2021
Cited by 23 | Viewed by 4068
Abstract
HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed [...] Read more.
HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed in many human tissues, both adult and fetal. It is important to understand the role of HER4 in the treatment of many disorders. Many studies were also conducted on the role of HER4 in tumors and its tumor suppressor function. Mostly, overexpression of HER4 kinase results in cancer development. In the present article, we reviewed the structure, location, ligands, physiological functions of HER4, and its relationship to different cancer types. HER4 inhibitors reported mainly from 2016 to the present were reviewed as well. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Graphical abstract

24 pages, 4660 KiB  
Review
Phytochemistry, Ethnopharmacological Uses, Biological Activities, and Therapeutic Applications of Cassia obtusifolia L.: A Comprehensive Review
by Md Yousof Ali, Seongkyu Park and Munseog Chang
Molecules 2021, 26(20), 6252; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26206252 - 15 Oct 2021
Cited by 17 | Viewed by 3235
Abstract
Cassia obtusifolia L., of the Leguminosae family, is used as a diuretic, laxative, tonic, purgative, and natural remedy for treating headache, dizziness, constipation, tophobia, and lacrimation and for improving eyesight. It is commonly used in tea in Korea. Various anthraquinone derivatives make up [...] Read more.
Cassia obtusifolia L., of the Leguminosae family, is used as a diuretic, laxative, tonic, purgative, and natural remedy for treating headache, dizziness, constipation, tophobia, and lacrimation and for improving eyesight. It is commonly used in tea in Korea. Various anthraquinone derivatives make up its main chemical constituents: emodin, chrysophanol, physcion, obtusifolin, obtusin, au rantio-obtusin, chryso-obtusin, alaternin, questin, aloe-emodin, gluco-aurantio-obtusin, gluco-obtusifolin, naphthopyrone glycosides, toralactone-9-β-gentiobioside, toralactone gentiobioside, and cassiaside. C. obtusifolia L. possesses a wide range of pharmacological properties (e.g., antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and neuroprotective properties) and may be used to treat Alzheimer’s disease, Parkinson’s disease, and cancer. In addition, C. obtusifolia L. contributes to histamine release and antiplatelet aggregation. This review summarizes the botanical, phytochemical, and pharmacological features of C. obtusifolia and its therapeutic uses. Full article
(This article belongs to the Special Issue Designing Next-Generation Drug-Like Molecules for Medicinal Applications)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-18
Back to TopTop