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Discovery, Synthesis and Evaluation of Bioactive Compounds

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 20408

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Prof. Dr. Constantinos Athanassopoulos

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Department of Chemistry, University of Patras, GR-26504 Rion, Patras, Greece
Interests: discovery and development of small organic molecules and of natural product analogues or derivatives with anticancer, antibacterial and antiparasitic activity; synthesis of multitarget inhibitors and of hybrids or bioconjugates aiming at improvement of the pharmacological profile of one or more bioactive molecules
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Carlo Siciliano

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Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, I-87036 Arcavacata di Rende, Italy
Interests: high-resolution instrumental analysis of complex vegetable and animal matrices; synthesis of biomolecules and their analogues; amino acid and peptide chemistry; modification of natural amino acids; chiral templates; design and synthesis of protease inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Many useful drugs, biosensors, and medical applications of organic compounds result from broad collaboration between synthetic chemists and biologists. In this field, organic synthesis has a primary role in new drug discovery, as well as the design, realization, and characterization of bioactive low-molecular-weight compounds. At present, a plethora of synthetic strategies help organic chemists in collecting a large number of molecules, often having templates directly inspired by nature. As a consequence, the development of new methods that can be applied in preparing new and powerful bioactive compounds is a fundamental need in translational research projects.

In this Special Issue, we wish to focus on the most recent research efforts, towards the discovery of lead compounds and the development of drug candidates for successful therapies against major and severe contemporary diseases. Special attention will be given to interdisciplinary studies on novel therapeutic agents (anticancer, antiviral, antibacterial, antiparasitic, antidiabetic, etc.), having specific receptors, enzymes, or cellular pathways as targets.

Original research articles, reviews, and focus papers will be welcome, with the aim of collecting the most recent insights and results on new and straightforward synthetic approaches to bioactive organic compounds, the preparation of molecular templates for combinatorial chemistry, as well as the application of computational methods for the rational design and synthesis of novel lead drug candidates.

Prof. Dr. Constantinos Athanassopoulos
Prof. Dr. Carlo Siciliano
Guest Editors

Manuscript Submission Information

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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.

Keywords

Bioactive compounds
Drug discovery
Multitarget drugs
Pathway inhibitors
Drug candidates
Modification of natural products
Rational drug design
Lead compound optimization
Enzyme inhibitors

Published Papers (9 papers)

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Research

14 pages, 1309 KiB

Open AccessArticle

Synthesis and Antiproliferative Activity of Novel Dehydroabietic Acid-Chalcone Hybrids

by Sophia Grigoropoulou, Dimitra Manou, Antonia I. Antoniou, Artemis Tsirogianni, Carlo Siciliano, Achilleas D. Theocharis and Constantinos M. Athanassopoulos

Molecules 2022, 27(11), 3623; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27113623 - 05 Jun 2022

Cited by 8 | Viewed by 2280

Abstract

Dehydroabietic Acid (DHA, 1) derivatives are known for their antiproliferative properties, among others. In the context of this work, DHA was initially modified to two key intermediates bearing a C18 methyl ester, a phenol moiety at C12, and an acetyl or formyl group at C13 position. These derivatives allowed us to synthesize a series of DHA-chalcone hybrids, suitable for structure–activity relationship studies (SARS), following their condensation with a variety of aryl-aldehydes and methyl ketones. The antiproliferative evaluation of the synthesized DHA-chalcone hybrids against three breast cancer cell lines (the estrogen-dependent MCF-7 and the estrogen-independent MDA-MB-231 and Hs578T) showed that eight derivatives (33, 35, 37, 38, 39, 41, 43, 44) exhibit low micromolar activity levels (IC₅₀ 2.21–11.5 μΜ/MCF-7). For instance, some of them showed better activity compared to the commercial anticancer drug 5-FU against MCF-7 cells (33, 41, 43, 44) and against MDA-MB231 (33 and 41). Hybrid 38 is a promising lead compound for the treatment of MCF-7 breast cancer, exhibiting comparable activity to 5-FU and being 12.9 times less toxic (SI = 22.7). Thus, our findings suggest that DHA-chalcone hybrids are drug candidates worth pursuing for further development in the search for novel breast cancer therapies. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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19 pages, 2117 KiB

Open AccessArticle

Chemoselective Preparation of New Families of Phenolic-Organoselenium Hybrids—A Biological Assessment

by Paloma Begines, Sergio Martos, Irene Lagunes, Inés Maya, José M. Padrón, Óscar López and José G. Fernández-Bolaños

Molecules 2022, 27(4), 1315; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27041315 - 15 Feb 2022

Cited by 2 | Viewed by 1821

Abstract

Being aware of the enormous biological potential of organoselenium and polyphenolic compounds, we have accomplished the preparation of novel hybrids, combining both pharmacophores in order to obtain new antioxidant and antiproliferative agents. Three different families have been accessed in a straightforward and chemoselective fashion: carbohydrate-containing N-acylisoselenoureas, N-arylisoselenocarbamates and N-arylselenocarbamates. The nature of the organoselenium framework, number and position of phenolic hydroxyl groups and substituents on the aromatic scaffolds afforded valuable structure–activity relationships for the biological assays accomplished: antioxidant properties (antiradical activity, DNA-protective effects, Glutathione peroxidase (GPx) mimicry) and antiproliferative activity. Regarding the antioxidant activity, selenocarbamates 24–27 behaved as excellent mimetics of GPx in the substoichiometric elimination of H₂O₂ as a Reactive Oxygen Species (ROS) model. Isoselenocarbamates and particularly their selenocarbamate isomers exhibited potent antiproliferative activity against non-small lung cell lines (A549, SW1573) in the low micromolar range, with similar potency to that shown by the chemotherapeutic agent cisplatin (cis-diaminodichloroplatin, CDDP) and occasionally with more potency than etoposide (VP-16). Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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19 pages, 4503 KiB

Open AccessArticle

New Analogs of Polyamine Toxins from Spiders and Wasps: Liquid Phase Fragment Synthesis and Evaluation of Antiproliferative Activity

by Christos Vassileiou, Stefania Kalantzi, Eleanna Vachlioti, Constantinos M. Athanassopoulos, Christos Koutsakis, Zoi Piperigkou, Nikos Karamanos, Theodora Stivarou, Peggy Lymberi, Konstantinos Avgoustakis and Dionissios Papaioannou

Molecules 2022, 27(2), 447; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27020447 - 10 Jan 2022

Cited by 3 | Viewed by 1815

Abstract

Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic carboxylic acids, which have been recently shown to present antiproliferative activity. Ten analogs of the spider PATs Agel 416, HO-416b, and JSTX-3 and the wasp PAT PhTX-433 were synthesized with changes in the lipophilic head group and/or the PA chain, and their antiproliferative activity was evaluated on MCF-7 and MDA-MB-231 breast cancer cells, using Agel 416 and HO-416b as reference compounds. All five analogs of PhTX-433 were of very low activity on both cell lines, whereas the two analogs of JSTX-3 were highly active only on the MCF-7 cell line with IC₅₀ values of 2.63–2.81 μΜ. Of the remaining three Agel 416 or HO-416b analogs, only the one with the spermidine chain was highly active on both cells with IC₅₀ values of 3.15–12.6 μM. The two most potent compounds in this series, Agel 416 and HO-416b, with IC₅₀ values of 0.09–3.98 μΜ for both cell lines, were found to have a very weak cytotoxic effect on the MCF-12A normal breast cells. The present study points out that the structure of both the head group and the PA chain determine the strength of the antiproliferative activity of PATs and their selectivity towards different cells. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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16 pages, 2180 KiB

Open AccessArticle

Biophysical Evaluation and In Vitro Controlled Release of Two Isomeric Adamantane Phenylalkylamines with Antiproliferative/Anticancer and Analgesic Activity

by Marilena Vlachou, Angeliki-Sofia Foscolos, Angeliki Siamidi, Angeliki Syriopoulou, Nikitas Georgiou, Aikaterini Dedeloudi, Antonis D. Tsiailanis, Andreas G. Tzakos, Thomas Mavromoustakos and Ioannis P. Papanastasiou

Molecules 2022, 27(1), 7; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27010007 - 21 Dec 2021

Viewed by 2148

Abstract

The aqueous dissolution profile of the isomeric synthetic adamantane phenylalkylamine hydrochlorides I and II was probed. These adducts have shown significant antiproliferative/anticancer activity associated with an analgesic profile against neuropathic pain. They are both devoid of toxic effects and show appreciable enzymatic human plasma stability. The structures of these two compounds have been elucidated using 2D NMR experiments, which were used to study their predominant conformations. Compound II’s scaffold appeared more flexible, as shown by the NOE spatial interactions between the alkyl bridge chain, the aromatic rings, and the adamantane nucleus. Conversely, compound I appeared very rigid, as it did not share significant NOEs between the aforementioned structural segments. MD simulations confirmed the NOE results. The aqueous dissolution profile of both molecules fits well with their minimum energy conformers’ features, which stem from the NOE data; this was nicely demonstrated, especially in the case of compound II. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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28 pages, 9996 KiB

Open AccessArticle

Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi

by Lorraine Martins Rocha Orlando, Guilherme Curty Lechuga, Leonardo da Silva Lara, Byanca Silva Ferreira, Cynthia Nathalia Pereira, Rafaela Corrêa Silva, Maurício Silva dos Santos and Mirian Claudia S. Pereira

Molecules 2021, 26(21), 6742; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216742 - 08 Nov 2021

Cited by 7 | Viewed by 2365

Abstract

Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC₅₀ values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure–activity relationship (SAR) analysis revealed increased potency of 1-aryl-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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9 pages, 1676 KiB

Open AccessFeature PaperArticle

Convenient Preparation and Spectroscopic Characterization of 7R-Hydroxymatairesinol

by Eleonora Colombo, Giuseppe Paladino, Umberto Ciriello and Daniele Passarella

Molecules 2021, 26(19), 5838; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195838 - 26 Sep 2021

Cited by 2 | Viewed by 1281

Abstract

The preparation of 7R-HMR (allo-hydroxymatairesinol) is reported by: (a) NaBH₄ kinetic reduction of 7R/7S diastereomeric mixture; and (b) epimerization of the C7 hydroxyl group by Mitsunobu reaction and subsequent ester hydrolysis. The availability of highly pure target compound (7R-HMR) made it possible to confirm the structure of the target compound and to complete the full spectroscopic characterization. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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21 pages, 2720 KiB

Open AccessArticle

Preliminary Insight of Pyrrolylated-Chalcones as New Anti-Methicillin-Resistant Staphylococcus aureus (Anti-MRSA) Agents

by Mohanapriya Gunasekharan, Tae-Ik Choi, Yaya Rukayadi, Muhammad Alif Mohammad Latif, Thiruventhan Karunakaran, Siti Munirah Mohd Faudzi and Cheol-Hee Kim

Molecules 2021, 26(17), 5314; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26175314 - 01 Sep 2021

Cited by 6 | Viewed by 2428

Abstract

Bacterial infections are regarded as one of the leading causes of fatal morbidity and death in patients infected with diseases. The ability of microorganisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), to develop resistance to current drugs has evoked the need for a continuous search for new drugs with better efficacies. Hence, a series of non-PAINS associated pyrrolylated-chalcones (1–15) were synthesized and evaluated for their potency against MRSA. The hydroxyl-containing compounds (8, 9, and 10) showed the most significant anti-MRSA efficiency, with the MIC and MBC values ranging from 0.08 to 0.70 mg/mL and 0.16 to 1.88 mg/mL, respectively. The time-kill curve and SEM analyses exhibited bacterial cell death within four hours after exposure to 9, suggesting its bactericidal properties. Furthermore, the docking simulation between 9 and penicillin-binding protein 2a (PBP2a, PDB ID: 6Q9N) suggests a relatively similar bonding interaction to the standard drug with a binding affinity score of −7.0 kcal/mol. Moreover, the zebrafish model showed no toxic effects in the normal embryonic development, blood vessel formation, and apoptosis when exposed to up to 40 µM of compound 9. The overall results suggest that the pyrrolylated-chalcones may be considered as a potential inhibitor in the design of new anti-MRSA agents. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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17 pages, 2631 KiB

Open AccessArticle

Methoxy-Substituted Tyramine Derivatives Synthesis, Computational Studies and Tyrosinase Inhibitory Kinetics

by Yasir Nazir, Hummera Rafique, Naghmana Kausar, Qamar Abbas, Zaman Ashraf, Pornchai Rachtanapun, Kittisak Jantanasakulwong and Warintorn Ruksiriwanich

Molecules 2021, 26(9), 2477; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092477 - 23 Apr 2021

Cited by 8 | Viewed by 2194

Abstract

Targeting tyrosinase for melanogenesis disorders is an established strategy. Hydroxyl-substituted benzoic and cinnamic acid scaffolds were incorporated into new chemotypes that displayed in vitro inhibitory effects against mushroom and human tyrosinase for the purpose of identifying anti-melanogenic ingredients. The most active compound 2-((4-methoxyphenethyl)amino)-2-oxoethyl (E)-3-(2,4-dihydroxyphenyl) acrylate (Ph9), inhibited mushroom tyrosinase with an IC₅₀ of 0.059 nM, while 2-((4-methoxyphenethyl)amino)-2-oxoethyl cinnamate (Ph6) had an IC₅₀ of 2.1 nM compared to the positive control, kojic acid IC₅₀ 16700 nM. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound (Ph9) and Ph6 exhibited 94.6% and 92.2% inhibitory activity respectively while the positive control kojic acid showed 72.9% inhibition. Enzyme kinetics reflected a mixed type of inhibition for inhibitor Ph9 (K_i 0.093 nM) and non-competitive inhibition for Ph6 (K_i 2.3 nM) revealed from Lineweaver–Burk plots. In silico docking studies with mushroom tyrosinase (PDB ID:2Y9X) predicted possible binding modes in the catalytic site for these active compounds. Ph9 displayed no PAINS (pan-assay interference compounds) alerts. Our results showed that compound Ph9 is a potential candidate for further development of tyrosinase inhibitors. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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22 pages, 4641 KiB

Open AccessArticle

Synthesis, Docking, Computational Studies, and Antimicrobial Evaluations of New Dipeptide Derivatives Based on Nicotinoylglycylglycine Hydrazide

by Hemat S. Khalaf, Ahmed M. Naglah, Mohamed A. Al-Omar, Gaber O. Moustafa, Hassan M. Awad and Ahmed H. Bakheit

Molecules 2020, 25(16), 3589; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25163589 - 07 Aug 2020

Cited by 22 | Viewed by 2938

Abstract

Within a series of dipeptide derivatives (5–11), compound 4 was refluxed with d-glucose, d-xylose, acetylacetone, diethylmalonate, carbon disulfide, ethyl cyanoacetate, and ethyl acetoacetate which yielded 5–11, respectively. The candidates 5–11 were characterized and their biological activities were evaluated where they showed different anti-microbial inhibitory activities based on the type of pathogenic microorganisms. Moreover, to understand modes of binding, molecular docking was used of Nicotinoylglycine derivatives with the active site of the penicillin-binding protein 3 (PBP3) and sterol 14-alpha demethylase’s (CYP51), and the results, which were achieved via covalent and non-covalent docking, were harmonized with the biological activity results. Therefore, it was extrapolated that compounds 4, 7, 8, 9, and 10 had good potential to inhibit sterol 14-alpha demethylase and penicillin-binding protein 3; consequently, these compounds are possibly suitable for the development of a novel antibacterial and antifungal therapeutic drug. In addition, in silico properties of absorption, distribution, metabolism, and excretion (ADME) indicated drug likeness with low to very low oral absorption in most compounds, and undefined blood–brain barrier permeability in all compounds. Furthermore, toxicity (TOPKAT) prediction showed probability values for all carcinogenicity models were medium to pretty low for all compounds. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Evaluation of Bioactive Compounds)

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