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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 2023) | Viewed by 10886

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Dr. Manoj K. Pandey

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Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
Interests: multiple myeloma; drug design; leukemia, drug development; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of a novel medicine starts when researchers learn of a biological target, such as a protein, gene, receptor, etc., which plays a critical role in diseases such as cancers, diabetes, or neurological disorders. This Special Issue will cover the discovery and development of a variety of novel agents. Here, we will cover the discovery and development of entirely new agents, those with a mode of action different from already approved medicines and intended for clinical translations. Our aim is to publish the recent advancement in the area of drug discovery and development. One overall theme of our Special Issue is to report the preclinical or clinical studies of novel agents and understand their design, synthesis, and characterization. This Special Issue will facilitate the translation of new agents to the next level. As editors of the journal, we encourage the submission of research reports that provide data relevant to this Special Issue.

Dr. Manoj K. Pandey
Guest Editor

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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.

Keywords

medicinal chemistry
pharmaceuticals
nutraceuticals
drug design
drug development
cancer
inflammations

Published Papers (7 papers)

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Research

19 pages, 1132 KiB

Open AccessArticle

Chemotherapeutic Activities of New η⁶-p-Cymene Ruthenium(II) and Osmium(II) Complexes with Chelating SS and Tridentate SNS Ligands

by David O. Ywaya, Halliru Ibrahim, Holger B. Friedrich, Muhammad D. Bala, Lynette Soobramoney, Aliscia Daniels and Moganavelli Singh

Molecules 2024, 29(5), 944; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29050944 - 21 Feb 2024

Viewed by 1128

Abstract

A series of new chelating bidentate (SS) alkylimidazole-2-thione-Ru(II)/Os(II) complexes (3a_i, 3a_ii, 3a_iii, 3b_ii/4a_iii, 4b_i, 4b_ii), and the tridentate (SNS) pyridine-2,6-diylimidazole-2-thione-Ru(II)/Os(II) complexes (5b_i, 5c_iv/6bi, 6c_i, 6c_iv) in the forms [M^II(cym)(L)Cl]PF₆ and [M^II(cym)(L)]PF₆ (M = Ru or Os, cym = η⁶-p-cymene, and L = heterocyclic derivatives of thiourea) respectively, were successfully synthesized. Spectroscopic and analytical methods were used to characterize the complexes and their ligands. Solid-state single-crystal X-ray diffraction analyses revealed a “piano-stool” geometry around the Ru(II) or Os(II) centers in the respective complexes. The complexes were investigated for in vitro chemotherapeutic activities against human cervical carcinoma (HeLa) and the non-cancerous cell line (Hek293) using the MTT assay. The compounds 3a_ii, 5c_iv, 5b_i, 4a_iii, 6c_i, 6c_iv, and the reference drug, 5-fluorouracil were found to be selective toward the tumor cells; the compounds 3a_i, 3a_iii, 3b_ii, 4b_i, 4b_ii, and 6b_i, which were found not to be selective between normal and tumor cell lines. The IC₅₀ value of the tridentate half-sandwich complex 5b_i (86 ± 9 μM) showed comparable anti-proliferative activity with the referenced commercial anti-cancer drug, 5-fluorouracil (87 ± 15 μM). The pincer (SNS) osmium complexes 6c_i (36 ± 10 μM) and 6c_iv (40 ± 4 μM) were twice as effective as the reference drug 5-fluorouracil at the respective dose concentrations. However, the analogous pincer (SNS) ruthenium complex 5c_iv was ineffective and did not show anti-proliferative activity, even at a higher concentration of 147 ± 1 μM. These findings imply that the higher stability of the chelating (SS) and the pincer (SNS) ligand architectures in the complexes improves the biological (anti-proliferative) activity of the complexes by reducing the chance of ligand dissociation under physiological conditions. In general, the pincer (SNS) osmium complexes were found to be more cytotoxic than their ruthenium analogues, suggesting that the anti-proliferative activity of the imidazole-2-thione-Ru/Os complexes depends on the ligand’s spatial coordination, the nature of the metal center, and the charge of the metal complex ions. Full article

(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drugs)

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12 pages, 752 KiB

Open AccessArticle

Multi-Gram Scale Synthesis and Characterization of Mometasone Furoate EP Impurity C

by Riccardo Ronchetti, Luigi Alfonso Pannone, Bruno Cerra, Emidio Camaioni, Gianfranco Lopopolo, Emanuele Attolino and Antimo Gioiello

Molecules 2023, 28(23), 7859; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28237859 - 30 Nov 2023

Viewed by 1016

Abstract

Mometasone furoate is a synthetic corticosteroid used in the treatment of skin inflammatory conditions, hay fever and asthma. The industrial manufacturing routes to mometasone furoate are generally accompanied by the formation of numerous process impurities that need to be detected and quantified, as requested by regulatory authorities. The ready availability of such impurities in the required quantity and purity is therefore essential for toxicological studies, analytical method development and process validation. Herein, we report the multi-gram scale preparation of 21′-chloro-(16′α-methyl-3′,11′,20′-trioxo-pregna-1′,4′-dien-17′-yl)-furan-2-carboxylate (mometasone furoate EP impurity C), one of the known impurities of mometasone furoate. This study also includes the systematic investigation of the final acylation step, as well as the characterization of the difuroate enol ether intermediate and its conversion to the target impurity C. Full article

(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drugs)

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11 pages, 1746 KiB

Open AccessArticle

A Novel Betulinic Acid Analogue: Synthesis, Solubility, Antitumor Activity and Pharmacokinetic Study in Rats

by Yucen Liang, Meixuan Zhu, Tao Xu, Weimin Ding, Min Chen, Yang Wang and Jian Zheng

Molecules 2023, 28(15), 5715; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28155715 - 28 Jul 2023

Cited by 1 | Viewed by 1093

Abstract

Betulinic acid (BA) and betulin (BE) are naturally pentacyclic triterpenes with documented biological activities, especially antitumor and anti-inflammatory activity. However, their bioavailability in vivo is not satisfactory in terms of medical applications. Thus, to improve the solubility and bioavailability so as to improve the efficacy, 28-O-succinyl betulin (SBE), a succinyl derivative of BE, was synthesized and its solubility, in vitro and in vivo anti-tumor activities, the apoptosis pathway as well as the pharmacokinetic properties were investigated. The results showed that SBE exhibited significantly higher solubility in most of the tested solvents, and showed a maximum solubility of 7.19 ± 0.66 g/L in n-butanol. In vitro and in vivo anti-tumor activity assays indicated both BA and SBE exhibited good anti-tumor activities, and SBE demonstrated better potential compared to BA. An increase in the ratio of Bad/Bcl-xL and activation of caspase 9 was found in SBE treated Hela cells, suggesting that the intrinsic mitochondrial pathway is involved in SBE induced apoptosis. Compared with BA, SBE showed much-improved absorption and bioavailability in pharmacokinetic studies. Full article

(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drugs)

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17 pages, 6067 KiB

Open AccessArticle

The Antileishmanial Activity of Eugenol Associated with Lipid Storage Reduction Rather Than Membrane Properties Alterations

by Kristelle Hughes, Thanh Binh Le, Patrick Van Der Smissen, Donatienne Tyteca, Marie-Paule Mingeot-Leclercq and Joëlle Quetin-Leclercq

Molecules 2023, 28(9), 3871; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28093871 - 4 May 2023

Cited by 2 | Viewed by 1426

Abstract

Leishmaniasis is a neglected tropical disease that still infects thousands of people per year throughout the world. The occurrence of resistance against major treatments for this disease causes a healthcare burden in low-income countries. Eugenol is a phenylpropanoid that has shown in vitro antileishmanial activity against Leishmania mexicana mexicana (Lmm) promastigotes with an IC₅₀ of 2.72 µg/mL and a high selectivity index. Its specific mechanism of action has yet to be studied. We prepared large unilamellar vesicles (LUVs), mimicking Lmm membranes, and observed that eugenol induced an increase in membrane permeability and a decrease in membrane fluidity at concentrations much higher than IC₅₀. The effect of eugenol was similar to the current therapeutic antibiotic, amphotericin B, although the latter was effective at lower concentrations than eugenol. However, unlike amphotericin B, eugenol also affected the permeability of LUVs without sterol. Its effect on the membrane fluidity of Lmm showed that at high concentrations (≥22.5× IC₅₀), eugenol increased membrane fluidity by 20–30%, while no effect was observed at lower concentrations. Furthermore, at concentrations below 10× IC₅₀, a decrease in metabolic activity associated with the maintenance of membrane integrity revealed a leishmaniostatic effect after 24 h of incubation with Lmm promastigotes. While acidocalcisomes distribution and abundance revealed by Trypanosoma brucei vacuolar H⁺ pyrophosphatase (TbVP1) immunolabeling was not modified by eugenol, a dose-dependent decrease of lipid droplets assessed by the Nile Red assay was observed. We hereby demonstrate that the antileishmanial activity of eugenol might not directly involve plasma membrane sterols such as ergosterol, but rather target the lipid storage of Lmm. Full article

(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drugs)

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18 pages, 5073 KiB

Open AccessArticle

Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study

by Krzysztof Marciniec, Zuzanna Rzepka, Elwira Chrobak, Stanisław Boryczka, Małgorzata Latocha, Dorota Wrześniok and Artur Beberok

Molecules 2023, 28(6), 2509; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28062509 - 9 Mar 2023

Cited by 2 | Viewed by 2000

Abstract

Cancer cells need to carefully regulate their metabolism to keep them growing and dividing under the influence of different nutrients and oxygen levels. Muscle isoform 2 of pyruvate kinase (PKM2) is a key glycolytic enzyme involved in the generation of ATP and is critical for cancer metabolism. PKM2 is expressed in many human tumors and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various modulators regulate PKM2, shifting it between highly active and less active states. In the presented work, a series of 8-quinolinesulfonamide derivatives of PKM2 modulators were designed using molecular docking and molecular dynamics techniques. New compounds were synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Compound 9a was identified in in silico studies as a potent modulator of muscle isoform 2 of pyruvate kinase. The results obtained from in vitro experiments confirmed the ability of compound 9a to reduce the intracellular pyruvate level in A549 lung cancer cells with simultaneous impact on cancer cell viability and cell-cycle phase distribution. Moreover, compound 9a exhibited more cytotoxicity on cancer cells than normal cells, pointing to high selectivity in the mode of action. These findings indicate that the introduction of another quinolinyl fragment to the modulator molecule may have a significant impact on pyruvate levels in cancer cells and provides further directions for future research to find novel analogs suitable for clinical applications in cancer treatment. Full article

(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drugs)

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12 pages, 2994 KiB

Open AccessArticle

Synthesis and Evaluation of Reactive Oxygen Species Sensitive Prodrugs of a NAMPT Inhibitor FK866

by Zili Xu, Huihui Wang, Haixia Liu, Hongli Chen and Biao Jiang

Molecules 2023, 28(1), 169; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28010169 - 25 Dec 2022

Viewed by 1811

Abstract

NAMPT is an attractive target in cancer therapy and numerous NAMPT inhibitors have been developed. However, the clinical activities of NAMPT inhibitors have displayed disappointing results in clinical trials for their dose-limiting toxicities. In this study, reactive oxygen species (ROS)-responsive prodrugs of a NAMPT inhibitor FK866 were designed and synthesized. A short synthesis method was developed to shield the activity of FK866 through a quaternary ammonium connection. Two prodrugs, with boronic acid as a responsive group to ROS, were prepared and one of the prodrugs 122-066 also contained a fluorescence carrier. Both of the prodrugs released the active compound by the treatment of H₂O_2,, and the biological evaluation showed that they exhibited a higher potency in cells with high levels of ROS. Moreover, prodrug 122-066 had the ability to release FK866 and simultaneously induce the fluorescence activation under the stimulation of H₂O₂. This method has the potential to improve the therapeutic window of NAMPT inhibitors. Full article

(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drugs)

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19 pages, 4763 KiB

Open AccessArticle

Novel Phthalazin-1(2H)-One Derivatives Displaying a Dithiocarbamate Moiety as Potential Anticancer Agents

by Noemí Vila, Pedro Besada, José Brea, María Isabel Loza and Carmen Terán

Molecules 2022, 27(23), 8115; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27238115 - 22 Nov 2022

Cited by 2 | Viewed by 1624

Abstract

Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6–8, which display the dithiocarbamate scaffold at N2, and compounds 9, in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H₃PO₄, and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6–8 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e, 8e, 6g, 9a–b, 9d, and 9g with IC₅₀ values less than 10 µM were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively. Full article

(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drugs)

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