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Development of Potential Drugs Based on Small Molecules

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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 (31 May 2020) | Viewed by 26491

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Special Issue Editor

Dr. Rachid Skouta

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Guest Editor

Laboratory of Medicinal Chemistry, Department of Biology, University of Massachusetts, Amherst, MA 01003-9297, USA
Interests: probing diseases with small molecules; development of novel bioactive compounds with better pharmaceutical properties; medicinal chemistry; structure–activity relationship study; in silico screening for drug development; in vitro assays; ADME/PK assays; programmed cell death (e.g., Ferroptosis and apoptosis)
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Special Issue Information

Dear Colleagues,

Small molecules, including natural and synthetic molecules, are the backbone of drug development. Drug development is a lengthy and expensive process. Several drug development approaches are used in academia and the industry for improving human health. Among these approaches are: (i) In silico screening of a large library of available small molecules against specific targets. (ii) In vitro high-throughput screening (HTS) of a library of available small molecules against specific cells. (iii) Medicinal chemistry and structure–activity relationship (SAR) of specific hits toward improving their pharmaceutical properties (e.g., solubility, bioavailability, plasma, and microsomal stability, selectivity, and toxicity). (iv) biochemical assays for target validation and (v) in vivo studies of the efficacy of potential small molecules. However, determining how accurate these approaches mimic diseases is one of the challenges that the drug discovery community is facing.

The lack of accuracy of some of these approaches may cause translational failures that explain the low rate of FDA approved drugs.

We hope to stimulate broad multidisciplinary investigations in drug discovery and provide a platform via this Special Issue that invites investigators to report their latest discoveries dealing with the creation of novel small molecules and suggest new approaches to overcome the low rate of drug development.

Dr. Rachid Skouta
Guest Editor

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

Efficient synthesis
Bioactive small molecules
In silico screening
HTS screening
Drug discovery
SAR study
In vitro biochemical assays
ADME/PK assays
In vivo assays
Target validation

Published Papers (7 papers)

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Research

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22 pages, 1685 KiB

Open AccessFeature PaperArticle

5-(4H)-Oxazolones and Their Benzamides as Potential Bioactive Small Molecules

by Evangelos Mavridis, Eleftherios Bermperoglou, Eleni Pontiki and Dimitra Hadjipavlou-Litina

Molecules 2020, 25(14), 3173; https://doi.org/10.3390/molecules25143173 - 11 Jul 2020

Cited by 17 | Viewed by 2802

Abstract

The five membered heterocyclic oxazole group plays an important role in drug discovery. Oxazolones present a wide range of biological activities. In this article the synthesis of 4-substituted-2-phenyloxazol-5(4H)-ones from the appropriate substituted aldehydes via an Erlenmeyer–Plochl reaction is reported. Subsequently, the corresponding benzamides were produced via a nucleophilic attack of a secondary amine on the oxazolone ring applying microwave irradiation. The compounds are obtained in good yields up to 94% and their structures were confirmed using IR, ¹H-NMR, ¹³C-NMR and LC/MS data. The in vitro anti-lipid peroxidation activity and inhibitory activity against lipoxygenase and trypsin induced proteolysis of the novel derivatives were studied. Inhibition of carrageenin-induced paw edema (CPE) and nociception was also determined for compounds 4a and 4c. Oxazolones 2a and 2c strongly inhibit lipid peroxidation, followed by oxazolones 2b and 2d with an average inhibition of 86.5%. The most potent lipoxygenase inhibitor was the bisbenzamide derivative 4c, with IC₅₀ 41 μM. The benzamides 3c, 4a–4e and 5c were strong inhibitors of proteolysis. The replacement of the thienyl moiety by a phenyl group does not favor the protection. Compound 4c inhibited nociception higher than 4a. The replacement of thienyl groups by phenyl ring led to reduced biological activity. Docking studies of the most potent LOX inhibitor highlight interactions through allosteric mechanism. All the potent derivatives present good oral bioavailability. Full article

(This article belongs to the Special Issue Development of Potential Drugs Based on Small Molecules)

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18 pages, 4286 KiB

Open AccessArticle

In Vitro Antimycobacterial Activity and Physicochemical Characterization of Diaryl Ether Triclosan Analogues as Potential InhA Reductase Inhibitors

by Tarek S. Ibrahim, Ehab S. Taher, Ebtihal Samir, Azizah M. Malebari, Ahdab N. Khayyat, Mamdouh F. A. Mohamed, Riham M. Bokhtia, Mohammed A. AlAwadh, Israa A. Seliem, Hani Z. Asfour, Nabil A. Alhakamy, Siva S. Panda and Amany M. M. AL-Mahmoudy

Molecules 2020, 25(14), 3125; https://doi.org/10.3390/molecules25143125 - 08 Jul 2020

Cited by 9 | Viewed by 2500

Abstract

Two sets of diphenyl ether derivatives incorporating five-membered 1,3,4-oxadiazoles, and their open-chain aryl hydrazone analogs were synthesized in good yields. Most of the synthesized compounds showed promising in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Three diphenyl ether derivatives, namely hydrazide 3, oxadiazole 4 and naphthylarylidene 8g exhibited pronounced activity with minimum inhibitory concentrations (MICs) of 0.61, 0.86 and 0.99 μg/mL, respectively compared to triclosan (10 μg/mL) and isoniazid (INH) (0.2 μg/mL). Compounds 3, 4, and 8g showed the InhA reductase enzyme inhibition with higher IC₅₀ values (3.28–4.23 µM) in comparison to triclosan (1.10 µM). Correlation between calculated physicochemical parameters and biological activity has been discussed which justifies a strong correlation with respect to the inhibition of InhA reductase enzyme. Molecular modeling and drug-likeness studies showed good agreement with the obtained biological evaluation. The structural and experimental information concerning these three InhA inhibitors will likely contribute to the lead optimization of new antibiotics for M. tuberculosis. Full article

(This article belongs to the Special Issue Development of Potential Drugs Based on Small Molecules)

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14 pages, 2852 KiB

Open AccessArticle

Self-Nanoemulsifying Drug Delivery Systems for Enhancing Solubility, Permeability, and Bioavailability of Sesamin

by Chih-Yuan Wang, Ching-Chi Yen, Mei-Chich Hsu and Yu-Tse Wu

Molecules 2020, 25(14), 3119; https://doi.org/10.3390/molecules25143119 - 08 Jul 2020

Cited by 17 | Viewed by 3472

Abstract

Sesamin (SSM) is a water-insoluble compound that is easily eliminated by liver metabolism. To improve the solubility and bioavailability of SSM, this study developed and characterized a self-nanoemulsifying drug delivery system (SNEDDS) for the oral delivery of SSM and conducted pharmacokinetic assessments. Oil and surfactant materials suitable for SNEDDS preparation were selected on the basis of their saturation solubility at 37 ± 0.5 °C. The mixing ratios of excipients were determined on the basis of their dispersibility, transmittance (%), droplet sizes, and polydispersity index. An SNEDDS (F10) formulation comprising glyceryl trioctanoate, polyoxyethylene castor oil, and Tween 20 at a ratio of 10:10:80 (w/w/w) was the optimal formulation. This formulation maintained over 90% of its contents in different storage environments for 12 weeks. After the self-emulsification of SNEDDS, the SSM dispersed droplet size was 66.4 ± 31.4 nm, intestinal permeability increased by more than three-fold, relative bioavailability increased by approximately 12.9-fold, and absolute bioavailability increased from 0.3% to 4.4%. Accordingly, the developed SNEDDS formulation can preserve SSM’s solubility, permeability, and bioavailability. Therefore, this SNEDDS formulation has great potential for the oral administration of SSM, which can enhance its pharmacological application value. Full article

(This article belongs to the Special Issue Development of Potential Drugs Based on Small Molecules)

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11 pages, 1773 KiB

Open AccessArticle

Protective Evaluation of Compounds Extracted from Root of Rhodiola rosea L. against Methylglyoxal-Induced Toxicity in a Neuronal Cell Line

by Cheng-Hao Wang, Safwan Safwan, Min-Chi Cheng, Te-Yu Liao, Lin-Chen Cheng, Ting-An Chen, Yueh-Hsiung Kuo, Yung-Feng Lin and Ching-Kuo Lee

Molecules 2020, 25(12), 2801; https://doi.org/10.3390/molecules25122801 - 17 Jun 2020

Cited by 10 | Viewed by 2806

Abstract

Rhodiola rosea L. (R. rosea) is one of the most beneficial medicinal plants and it is studied as an adaptogen. This study aims to evaluate the neuroprotective activity of compounds extracted from the root of R. rosea against methylglyoxal (MG)-induced apoptosis in neuro-2A (N2A) cells. The root of R. rosea was extracted with ethanol and partitioned with water, ethyl acetate, and n-butanol fractions to evaluate acetylcholinesterase (AChE) inhibitory activity and neuroprotective activity. The ethyl acetate fraction exhibited the highest values of AChE inhibitory activity (49.2% ± 3%) and cell viability (50.7% ± 4.8%) for neuroprotection. The structure identification of the most potential fraction (ethyl acetate fraction) revealed 15 compounds, consisting of three tannins, five flavonoids, and seven phenolics by infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All compounds were evaluated for their neuroprotective activity. Salidroside had the most potential neuroprotective activity. Gallic acid and methyl gallate had potential cytotoxicity in N2A cells. This study showed that R. rosea might have potential neuroprotective activities. Full article

(This article belongs to the Special Issue Development of Potential Drugs Based on Small Molecules)

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14 pages, 3118 KiB

Open AccessArticle

Angiotensin-I-Converting Enzyme Inhibitory Activity of Coumarins from Angelica decursiva

by Md Yousof Ali, Su Hui Seong, Hyun Ah Jung and Jae Sue Choi

Molecules 2019, 24(21), 3937; https://doi.org/10.3390/molecules24213937 - 31 Oct 2019

Cited by 28 | Viewed by 3872

Abstract

The bioactivity of ten traditional Korean Angelica species were screened by angiotensin-converting enzyme (ACE) assay in vitro. Among the crude extracts, the methanol extract of Angelica decursiva whole plants exhibited potent inhibitory effects against ACE. In addition, the ACE inhibitory activity of coumarins 1–5, 8–18 was evaluated, along with two phenolic acids (6, 7) obtained from A. decursiva. Among profound coumarins, 11–18 were determined to manifest marked inhibitory activity against ACE with IC₅₀ values of 4.68–20.04 µM. Compounds 12, 13, and 15 displayed competitive inhibition against ACE. Molecular docking studies confirmed that coumarins inhibited ACE via many hydrogen bond and hydrophobic interactions with catalytic residues and zinc ion of C- and N-domain ACE that blocked the catalytic activity of ACE. The results derived from these computational and in vitro experiments give additional scientific support to the anecdotal use of A. decursiva in traditional medicine to treat cardiovascular diseases such as hypertension. Full article

(This article belongs to the Special Issue Development of Potential Drugs Based on Small Molecules)

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Review

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22 pages, 629 KiB

Open AccessReview

Second-Generation Pharmacological Chaperones: Beyond Inhibitors

by My Lan Tran, Yves Génisson, Stéphanie Ballereau and Cécile Dehoux

Molecules 2020, 25(14), 3145; https://doi.org/10.3390/molecules25143145 - 09 Jul 2020

Cited by 31 | Viewed by 4607

Abstract

Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates. Full article

(This article belongs to the Special Issue Development of Potential Drugs Based on Small Molecules)

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25 pages, 6274 KiB

Open AccessFeature PaperReview

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

by Jyothi Dhuguru and Rachid Skouta

Molecules 2020, 25(7), 1615; https://doi.org/10.3390/molecules25071615 - 01 Apr 2020

Cited by 71 | Viewed by 5709

Abstract

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed. Full article

(This article belongs to the Special Issue Development of Potential Drugs Based on Small Molecules)

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