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Molecules
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Design, Synthesis and Evaluation of Small Molecule Drugs
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Design, Synthesis and Evaluation of Small Molecule Drugs

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

Deadline for manuscript submissions: closed (1 March 2025) | Viewed by 5946

Special Issue Editors

Dr. Elisa Magli

E-Mail Website
Guest Editor
Department of Public Health, University of Naples Federico II, Naples, Italy
Interests: drug design; synthesis and characterization of molecules; medicinal chemistry; serotoninergic ligands; NCX isoform modulators
Prof. Dr. Beatrice Severino

E-Mail Website
Guest Editor
Department of Pharmacy, University of Naples Federico II, Naples, Italy
Interests: drug design; synthesis and characterization of molecules; medicinal chemistry; NCX isoform modulators; H2S donors

Special Issue Information

Dear Colleagues,

Small molecule drugs have been the mainstay of the pharmaceutical industry for nearly a century. Defined as any organic compound with a low molecular weight, small molecule drugs have some distinct advantages as therapeutics: most can be administered orally, and they can pass through cell membranes to reach intracellular targets. They can also be designed to engage biological targets by various modes of action and their distribution can further be tailored, for example, to allow for systemic exposure with or without brain penetration. The rapid advancement of biopharmaceutical research and technology opens up possibilities for innovative and creative new approaches to developing small molecule drugs. Based on these considerations, this Special Issue aims to provide a platform for original research papers, short communications, and review articles on the latest advances in small molecule drugs. These papers may cover multidisciplinary aspects (such as drug design, synthesis, and pharmacological evaluation) of novel small molecule drugs with potential therapeutic innovations.

Dr. Elisa Magli
Prof. Dr. Beatrice Severino
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.

Keywords

  • small molecule drugs
  • synthesis
  • characterization
  • medicinal chemistry
  • biological activity
  • drug delivery

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (4 papers)

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Research

14 pages, 4018 KiB  
Article
Synthesis and Biological Evaluation of New cis-Restricted Triazole Analogues of Combretastatin A-4
by Lidia Prieto, Daniel Gaviña, Marcos Escolano, María Cánovas-Belchí, María Sánchez-Roselló, Carlos del Pozo, Eva Falomir and Santiago Díaz-Oltra
Molecules 2025, 30(2), 317; https://doi.org/10.3390/molecules30020317 - 15 Jan 2025
Viewed by 1033
Abstract
The natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive trans stilbenes. In this [...] Read more.
The natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive trans stilbenes. In this study, we have prepared a series of 18 cis-restricted triazole analogues of combretastatin A-4 (CA-4), maintaining, in all cases, the 3,4,5-trimethoxy phenyl ring A, with the aim of investigating the substitution pattern on the B-ring in a systematic way. To this end, cytotoxic activities of the cis-restricted analogues of CA-4 prepared were determined in two tumor cell lines, namely, HT-29 and A-549, as well as in the non-tumor cell line HEK-293, to pre-evaluate the selectivity profile of the compounds for the tumor cell lines. The main conclusion was the essential presence of methoxyl or ethoxyl groups at the para position of the B-ring in order to obtain good antitumor activities. Thus, the more active compounds in our study displayed IC50 values in the nanomolar range for the tumor cell lines but not for the normal cells. Consequently, these triazole analogues of CA-4 could serve as promising alternatives to the natural product, although further studies about their biological activity are essential in order to fully determine their viability as therapeutic agents in the treatment of cancer. Full article
(This article belongs to the Special Issue Design, Synthesis and Evaluation of Small Molecule Drugs)
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23 pages, 2663 KiB  
Article
Synthesis and Anticancer Activity of 3,4-Diaryl-1,2-dihydro- and 1,2,3,4-Tetrahydroquinolines
by Santosh Rajput, Valerio Falasca, Mohan Bhadbhade, David StC Black and Naresh Kumar
Molecules 2024, 29(17), 4273; https://doi.org/10.3390/molecules29174273 - 9 Sep 2024
Viewed by 1193
Abstract
Tetrahydroquinolines are key structures in a variety of natural products with diverse pharmacological utilities and other applications. A series of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolines were synthesized in good yield by reacting 3-aryl-5,7-dimethoxy-2,3-dihydroquinolin-4-ones with different Grignard reagents followed by the dehydration of the intermediate phenolic compounds. Subsequent [...] Read more.
Tetrahydroquinolines are key structures in a variety of natural products with diverse pharmacological utilities and other applications. A series of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolines were synthesized in good yield by reacting 3-aryl-5,7-dimethoxy-2,3-dihydroquinolin-4-ones with different Grignard reagents followed by the dehydration of the intermediate phenolic compounds. Subsequent reduction and deprotection were carried out to achieve the desired tetrahydroquinolone moiety. The lead compound 3c showed low micromolar inhibition of various cancer cell lines. Demethylation under different reaction conditions was also investigated to afford the corresponding monohydroxy analogues. Full article
(This article belongs to the Special Issue Design, Synthesis and Evaluation of Small Molecule Drugs)
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16 pages, 2873 KiB  
Article
2-Amino-N-Phenethylbenzamides for Irritable Bowel Syndrome Treatment
by Miglena Milusheva, Mihaela Stoyanova, Vera Gledacheva, Iliyana Stefanova, Mina Todorova, Mina Pencheva, Kirila Stojnova, Slava Tsoneva, Paraskev Nedialkov and Stoyanka Nikolova
Molecules 2024, 29(14), 3375; https://doi.org/10.3390/molecules29143375 - 18 Jul 2024
Cited by 1 | Viewed by 1547
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain or discomfort. Mebeverine is an antispasmodic that has been widely used in clinical practice to relieve the symptoms of IBS. However, its systemic use usually leads to side effects. [...] Read more.
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain or discomfort. Mebeverine is an antispasmodic that has been widely used in clinical practice to relieve the symptoms of IBS. However, its systemic use usually leads to side effects. Therefore, the current paper aimed to synthesize more effective medicines for IBS treatment. We used ring opening of isatoic anhydride for the synthesis in reaction with 2-phenylethylamine. In silico simulation predicted spasmolytic activity for 2-amino-N-phenethylbenzamides. The newly synthesized compounds demonstrated a relaxation effect similar to mebeverine but did not affect the serotonin or Ca2+-dependent signaling pathway of contractile activity (CA) in contrast. Having in mind the anti-inflammatory potential of antispasmodics, the synthesized molecules were tested in vitro and ex vivo for their anti-inflammatory effects. Four of the newly synthesized compounds demonstrated very good activity by preventing albumin denaturation compared to anti-inflammatory drugs/agents well-established in medicinal practice. The newly synthesized compounds also inhibited the expression of interleukin-1β and stimulated the expression of neuronal nitric oxide synthase (nNOS), and, consequently, nitric oxide (NO) synthesis by neurons of the myenteric plexus. This characterizes the newly synthesized compounds as biologically active relaxants, offering a cleaner and more precise application in pharmacological practice, thereby enhancing their potential therapeutic value. Full article
(This article belongs to the Special Issue Design, Synthesis and Evaluation of Small Molecule Drugs)
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10 pages, 1824 KiB  
Article
3-Nitroatenolol: First Synthesis, Chiral Resolution and Enantiomers’ Absolute Configuration
by Rosa Sparaco, Pierfrancesco Cinque, Antonia Scognamiglio, Angela Corvino, Giuseppe Caliendo, Ferdinando Fiorino, Elisa Magli, Elisa Perissutti, Vincenzo Santagada, Beatrice Severino, Paolo Luciano, Marcello Casertano, Anna Aiello, Gustavo Yuri Martins Viegas, Gilberto De Nucci and Francesco Frecentese
Molecules 2024, 29(7), 1598; https://doi.org/10.3390/molecules29071598 - 3 Apr 2024
Cited by 2 | Viewed by 1239
Abstract
4-Nitro and 7-nitro propranolol have been recently synthesized and characterized by us. (±)-4-NO2-propranolol has been shown to act as a selective antagonist of 6-nitrodopamine (6-ND) receptors in the right atrium of rats. As part of our follow-up to this study, herein, [...] Read more.
4-Nitro and 7-nitro propranolol have been recently synthesized and characterized by us. (±)-4-NO2-propranolol has been shown to act as a selective antagonist of 6-nitrodopamine (6-ND) receptors in the right atrium of rats. As part of our follow-up to this study, herein, we describe the first synthesis of (±)-3-nitroatenolol as a probe to evaluate the potential nitration of atenolol by endothelium. Chiral chromatography was used to produce pure enantiomers. By using Riguera’s method, which is based on the sign distribution of ΔδH, the absolute configuration of the secondary alcohol was determined. Full article
(This article belongs to the Special Issue Design, Synthesis and Evaluation of Small Molecule Drugs)
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