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Dear Colleagues,

Drug discovery is a time- and money-consuming process that requires the conception of smart shortcuts, to be improved. Many efforts have been done in the past and are ongoing for drug target identification and to accelerate and improve biological assays. At the same time, the usual medicinal chemistry approaches are continuously enhanced in the attempt to find more active and selective small molecules with a few or no side and unwanted effects. Molecular hybridization to find bidentate and multi-target ligands recently resulted in the PROTAC technique. Antibody-drug conjugates significantly improved drug delivery and allowed to recycle molecules that act as a cell poison. Repurposing and repositioning of known drugs into different therapeutic areas gained increasing success and laid the foundations to alternative use of pre-existing therapeutic agents. In the recent literature many other examples appeared that described advances in the identification of biologically active small molecules, either from natural sources or synthesis.

This Special Issue of the International Journal of Molecular Sciences is intended to collect original works or literature surveys dedicated to finding new putative drugs or diagnostic agents by application of innovative or improved drug design and identification approaches and techniques.

Prof. Dr. Fabrizio Manetti
Dr. Samuele Maramai
Guest Editor

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Keywords

Drug Discovery
Molecular Modelling
Biologically active compounds
Natural compounds
Structure-activity relationships
Molecular hybridization
Multi-target ligands
Biological evaluation
Drug repurposing and repositioning
Synthesis of small molecules
Hit identification
Hit-to-lead optimization

Published Papers (2 papers)

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Research

21 pages, 9384 KiB

Open AccessArticle

Novel Hybrid 1,2,4- and 1,2,3-Triazoles Targeting Mycobacterium Tuberculosis Enoyl Acyl Carrier Protein Reductase (InhA): Design, Synthesis, and Molecular Docking

by Maged A. El Sawy, Maram M. Elshatanofy, Yeldez El Kilany, Kamal Kandeel, Bassma H. Elwakil, Mohamed Hagar, Mohamed Reda Aouad, Fawzia Faleh Albelwi, Nadjet Rezki, Mariusz Jaremko and El Sayed H. El Ashry

Int. J. Mol. Sci. 2022, 23(9), 4706; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094706 - 24 Apr 2022

Cited by 13 | Viewed by 1962

Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis is still a serious public health concern around the world. More treatment strategies or more specific molecular targets have been sought by researchers. One of the most important targets is M. tuberculosis’ enoyl-acyl carrier protein reductase InhA which is considered a promising, well-studied target for anti-tuberculosis medication development. Our team has made it a goal to find new lead structures that could be useful in the creation of new antitubercular drugs. In this study, a new class of 1,2,3- and 1,2,4-triazole hybrid compounds was prepared. Click synthesis was used to afford 1,2,3-triazoles scaffold linked to 1,2,4-triazole by fixable mercaptomethylene linker. The new prepared compounds have been characterized by different spectroscopic tools. The designed compounds were tested in vitro against the InhA enzyme. At 10 nM, the inhibitors 5b, 5c, 7c, 7d, 7e, and 7f successfully and totally (100%) inhibited the InhA enzyme. The IC₅₀ values were calculated using different concentrations. With IC₅₀ values of 0.074 and 0.13 nM, 7c and 7e were the most promising InhA inhibitors. Furthermore, a molecular docking investigation was carried out to support antitubercular activity as well as to analyze the binding manner of the screened compounds with the target InhA enzyme’s binding site. Full article

(This article belongs to the Special Issue Recent Advances in the Identification of Biologically Active Natural and Synthetic Small Molecules)

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18 pages, 3843 KiB

Open AccessArticle

Ruthenium(II) and Platinum(II) Complexes with Biologically Active Aminoflavone Ligands Exhibit In Vitro Anticancer Activity

by Małgorzata Fabijańska, Maria M. Kasprzak and Justyn Ochocki

Int. J. Mol. Sci. 2021, 22(14), 7568; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147568 - 15 Jul 2021

Cited by 8 | Viewed by 2057

Abstract

Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of cis-dichlorobis(3-imino-2-methoxyflavanone)ruthenium(II), cis-dichlorobis(3-imino-2-ethoxyflavanone)ruthenium(II), and trans-dichlorobis(3-aminoflavone)platinum(II). Cisplatin was used as a reference compound. The cytotoxicity was investigated by MTT assay. The mechanism of proapoptotic activity of the tested compounds was investigated by evaluation of caspase-8 activity, cytometric analysis of annexin-V positive cells, and mitochondrial potential loss measurement. The results showed that ruthenium compounds break partially or completely the cisplatin resistance by activating the caspase 8-dependent apoptosis pathway and loss of mitochondrial membrane potential. Platinum compounds also have a cytostatic effect, but their action requires more exposure time. Potential mechanisms underlying drug resistance in the two pairs of cancer cell lines were investigated: total glutathione content, P-glycoprotein activity, and differences in the activity of DNA repair induced by nucleotide excision. Results showed that cisplatin-resistant cells have elevated glutathione levels relative to sensitive cells. Moreover, they indicated the mechanisms enabling cells to avoid apoptosis caused by DNA damage. Pg-P activity has no effect on the development of cisplatin resistance in the cell lines described. Full article

(This article belongs to the Special Issue Recent Advances in the Identification of Biologically Active Natural and Synthetic Small Molecules)

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