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Biomolecules
Special Issues
Small-Molecule Drug Discovery
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Small-Molecule Drug Discovery

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 4768

Special Issue Editors

Dr. Takashi Kurihara

E-Mail Website
Guest Editor
Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
Interests: pain; itch; emotional disorders; drug discovery
Dr. Takasaki Ichiro

E-Mail Website
Guest Editor
Department of Pharmacology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan
Interests: pain; itch; cancer; drug discovery

Special Issue Information

Dear Colleagues,

Small-molecule drugs are low-molecular-weight organic compounds that help to regulate biological processes and diagnose, treat or prevent diseases. Many are derived from natural sources, including plants, fungi, bacteria and marine organisms. Until today, small-molecule drugs have been the mainstay of the pharmaceutical industry. Because of their low-molecular-weight, small-molecule drugs have some distinct advantages as therapeutics: most can be administered orally and some of them can even pass through cell membranes to reach intracellular targets. The identification and development of new small-molecule drugs could open new avenues to target challenging disease pathways that have previously been considered undruggable.

This Special Issue aims to highlight recent research in various therapeutic areas. In particular, this Special Issue aims to present the most recent advances in the design and synthetic strategies of small molecules, and biophysical/pharmacological methods to screen useful druggable small molecules.

This Special Issue will accept original research papers and high-quality reviews on:

  • Synthetic strategies underlying the building of small molecules and their chemical libraries useful for drug discovery;
  • Biophysical methods to screen small molecules/chemical libraries;
  • The pharmacological evaluation of small molecules endowed with biological activity;
  • The isolation and identification of small molecules from natural sources; and
  • The evaluation of molecular mechanisms by newly synthesized small molecules.
We hope that this Special Issue will make an important contribution to our knowledge of small molecules for drug discoveries to target complex disease pathways.

Dr. Takashi Kurihara
Dr. Takasaki Ichiro
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. Biomolecules is an international peer-reviewed open access monthly 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 molecules
  • drug design
  • synthetic strategies
  • structure–activity relationship
  • docking studies
  • in vivo, in vitro and ex vivo evaluation
  • biological activity

Published Papers (3 papers)

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Research

15 pages, 3084 KiB  
Article
Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators
by Kenneth Sue, Melissa M. Cadelis, Florent Rouvier, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel and Brent R. Copp
Biomolecules 2024, 14(3), 261; https://doi.org/10.3390/biom14030261 - 22 Feb 2024
Viewed by 848
Abstract
Small molecules that can restore the action of legacy antibiotics toward drug-resistant bacteria represent an area of ongoing research interest. We have previously reported indole-3-glyoxylamido and indole-3-acetamido-polyamine conjugates that exhibit intrinsic activity toward bacterial and fungal species, and the ability to enhance the [...] Read more.
Small molecules that can restore the action of legacy antibiotics toward drug-resistant bacteria represent an area of ongoing research interest. We have previously reported indole-3-glyoxylamido and indole-3-acetamido-polyamine conjugates that exhibit intrinsic activity toward bacterial and fungal species, and the ability to enhance the action of doxycycline toward the Gram-negative bacteria Pseudomonas aeruginosa; however, these desirable activities were commonly associated with unfavorable cytotoxicity and/or red blood cell hemolytic properties. In this paper, we report the synthesis and biological investigation of a new class of α,ω-di(indole-3-carboxamido)polyamine derivatives, leading to the identification of several analogues that exhibit antimicrobial- and antibiotic-potentiating activities without detectable cytotoxic or hemolytic properties. 5-Bromo-substituted indole analogues 3 and 12–18 were generally more broad-spectrum in their activity than others in the set, with 13b (polyamine PA-3-6-3) being particularly notable for its anti-Staphylococcus aureus, Acinetobacter baumannii, and Cryptococcus neoformans activities (MIC ≤ 0.28 µM). The same analogue also restored the action of doxycycline toward P. aeruginosa with a 21-fold enhancement, while the corresponding 5-bromo-indole-3-carboxamide-PA3-7-3 analogue was able to enhance the action of both doxycycline and erythromycin toward P. aeruginosa and Escherichia coli, respectively. The analogue 13b was capable of disrupting the bacterial membrane of both S. aureus and methicillin-resistant S. aureus (MRSA) and the outer membrane of P. aeruginosa, suggesting that membrane perturbation could be a mechanism of action of both intrinsic antimicrobial activities and antibiotic potentiation. Full article
(This article belongs to the Special Issue Small-Molecule Drug Discovery)
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16 pages, 1778 KiB  
Article
Characterization and Investigation of Novel Benzodioxol Derivatives as Antidiabetic Agents: An In Vitro and In Vivo Study in an Animal Model
by Mohammed Hawash, Derar Al-Smadi, Anil Kumar, Barbara Olech, Paulina Maria Dominiak, Nidal Jaradat, Sarah Antari, Sarah Mohammed, Ala’a Nasasrh, Murad Abualhasan, Ahmed Musa, Shorooq Suboh, İrfan Çapan, Mohammad Qneibi and Hiba Natsheh
Biomolecules 2023, 13(10), 1486; https://doi.org/10.3390/biom13101486 - 6 Oct 2023
Cited by 1 | Viewed by 1815
Abstract
In this study, we synthesized benzodioxol carboxamide derivatives and investigated their antidiabetic potential. The synthesized compounds (Ia-Ic and IIa-IId) underwent characterization via HRMS, 1H-, 13CAPT-NMR, and MicroED. Their efficacy against α-amylase was assessed in vitro, while MTS assays were [...] Read more.
In this study, we synthesized benzodioxol carboxamide derivatives and investigated their antidiabetic potential. The synthesized compounds (Ia-Ic and IIa-IId) underwent characterization via HRMS, 1H-, 13CAPT-NMR, and MicroED. Their efficacy against α-amylase was assessed in vitro, while MTS assays were employed to gauge cytotoxicity across cancer and normal cell lines. Additionally, the antidiabetic impact of compound IIc was evaluated in vivo using a streptozotocin-induced diabetic mice model. Notably, IIa and IIc displayed potent α-amylase inhibition (IC50 values of 0.85 and 0.68 µM, respectively) while exhibiting a negligible effect on the Hek293t normal cell line (IC50 > 150 µM), suggesting their safety. Compound IId demonstrated significant activity against four cancer cell lines (26–65 µM). In vivo experiments revealed that five doses of IIc substantially reduced mice blood glucose levels from 252.2 mg/dL to 173.8 mg/dL in contrast to the control group. The compelling in vitro anticancer efficacy of IIc and its safety for normal cells underscores the need for further in vivo assessment of this promising compound. This research highlights the potential of benzodioxol derivatives as candidates for the future development of synthetic antidiabetic drugs. Full article
(This article belongs to the Special Issue Small-Molecule Drug Discovery)
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13 pages, 2950 KiB  
Article
Sensitive Quantitative In Vivo Assay for Evaluating the Effects of Biomolecules on Hair Growth and Coloring Using Direct Microinjections into Mouse Whisker Follicles
by Lipeng Gao, He-Li Zhang, Xiao-Yang Tan, Yan-Ge Wang, Hongzhi Song, Vicky Lan Yuan and Xin-Hua Liao
Biomolecules 2023, 13(7), 1076; https://doi.org/10.3390/biom13071076 - 5 Jul 2023
Viewed by 1673
Abstract
Many people suffer from hair loss and abnormal skin pigmentation, highlighting the need for simple assays to support drug discovery research. Current assays have various limitations, such as being in vitro only, not sensitive enough, or unquantifiable. We took advantage of the bilateral [...] Read more.
Many people suffer from hair loss and abnormal skin pigmentation, highlighting the need for simple assays to support drug discovery research. Current assays have various limitations, such as being in vitro only, not sensitive enough, or unquantifiable. We took advantage of the bilateral symmetry and large size of mouse whisker follicles to develop a novel in vivo assay called “whisker follicle microinjection assay”. In this assay, we plucked mouse whiskers and then injected molecules directly into one side of the whisker follicles using microneedles that were a similar size to the whiskers, and we injected solvent on the other side as a control. Once the whiskers grew out again, we quantitatively measured their length and color intensity to evaluate the effects of the molecules on hair growth and coloring. Several chemicals and proteins were used to test this assay. The chemicals minoxidil and ruxolitinib, as well as the protein RSPO1, promoted hair growth. The effect of the clinical drug minoxidil could be detected at a concentration as low as 0.001%. The chemical deoxyarbutin inhibited melanin production. The protein Nbl1 was identified as a novel hair-growth inhibitor. In conclusion, we successfully established a sensitive and quantitative in vivo assay to evaluate the effects of chemicals and proteins on hair growth and coloring and identified a novel regulator by using this assay. This whisker follicle microinjection assay will be useful when investigating protein functions and when developing drugs to treat hair loss and abnormal skin pigmentation. Full article
(This article belongs to the Special Issue Small-Molecule Drug Discovery)
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