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Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors

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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: 31 July 2024 | Viewed by 10068

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Dr. Letizia Giampietro

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Department of Pharmacy, University “G. D’Annunzio”, Chieti-Pescara, Italy
Interests: bioactive compounds; PPAR agonists; anticancer activity; neuroprotection; antioxidants; aromatase inhibitors; NOS; small molecules; medicinal chemistry; organic synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

New pharmacological therapies aim to use small-molecule inhibitors to improve their inherent properties. These little compounds are able to cross biological barriers and modulate different organic targets. In particular, the inhibition effects of different small molecules can also cause many pharmacological effects. For these reasons, in recent years small-molecule inhibitors were developed to regulate many biological districts and represent an interesting instrument for the development of potential new therapeutic agents.

In this context, the aim of this Special Issue is to focus our attention on the most recent studies in the design and synthesis of small-molecule inhibitors, as well as on the discovery of naturally occurring small molecules that are able to inhibit biological targets and are useful as potential therapeutics.

This Special Issue will accept original research papers and high-quality reviews that cover multiple aspects of small molecule inhibitors focusing on:

The design, synthesis, and identification of new small molecule inhibitors;
The biological evaluation of small molecules endowed with biological activity as inhibitors;
The isolation and identification of small-molecule inhibitors from natural sources;
The evaluation of molecular mechanisms and biological targets of new small molecule inhibitors.

This Special Issue will serve as an important contribution to the knowledge of the importance of small-molecule inhibitors in drug discovery and pharmacology.

Dr. Letizia Giampietro
Guest Editor

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 molecules
inhibitors
natural products
drug design
synthetic strategies
structure-activity relationship
docking studies
drug delivery
in vivo, in vitro and ex vivo evaluation
biological activity
molecular mechanisms

Published Papers (9 papers)

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Research

34 pages, 5254 KiB

Open AccessArticle

Functional Activity of Enantiomeric Oximes and Diastereomeric Amines and Cyano Substituents at C9 in 3-Hydroxy-N-phenethyl-5-phenylmorphans

by Hudson G. Roth, Madhurima Das, Agnieszka Sulima, Dan Luo, Sophia Kaska, Thomas E. Prisinzano, Andrew T. Kerr, Arthur E. Jacobson and Kenner C. Rice

Molecules 2024, 29(9), 1926; https://doi.org/10.3390/molecules29091926 - 23 Apr 2024

Viewed by 292

Abstract

The synthesis of stereochemically pure oximes, amines, saturated and unsaturated cyanomethyl compounds, and methylaminomethyl compounds at the C9 position in 3-hydroxy-N-phenethyl-5-phenylmorphans provided μ-opioid receptor (MOR) agonists with varied efficacy and potency. One of the most interesting compounds, (2-((1S,5R,9R)-5-(3-hydroxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-yl)acetonitrile), was found to be a potent partial MOR agonist (EC₅₀ = 2.5 nM, %E_max = 89.6%), as determined in the forskolin-induced cAMP accumulation assay. Others ranged in potency and efficacy at the MOR, from nanomolar potency with a C9 cyanomethyl compound (EC₅₀ = 0.85 nM) to its totally inactive diastereomer, and three compounds exhibited weak MOR antagonist activity (the primary amine 3, the secondary amine 8, and the cyanomethyl compound 41). Many of the compounds were fully efficacious; their efficacy and potency were affected by both the stereochemistry of the molecule and the specific C9 substituent. Most of the MOR agonists were selective in their receptor interactions, and only a few had δ-opioid receptor (DOR) or κ-opioid receptor (KOR) agonist activity. Only one compound, a C9-methylaminomethyl-substituted phenylmorphan, was moderately potent and fully efficacious as a KOR agonist (KOR EC₅₀ = 18 nM (% E_max = 103%)). Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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17 pages, 5213 KiB

Open AccessArticle

Synthesis, Anti-Inflammatory Activities, and Molecular Docking Study of Novel Pyxinol Derivatives as Inhibitors of NF-κB Activation

by Shuai Tan, Zongji Zou, Xuwen Luan, Cheng Chen, Shuang Li, Zhen Zhang, Mengran Quan, Xiang Li, Wei Zhu and Gangqiang Yang

Molecules 2024, 29(8), 1711; https://doi.org/10.3390/molecules29081711 - 10 Apr 2024

Viewed by 443

Abstract

Pyxinol, an active metabolite of ginsenosides in human hepatocytes, exhibits various pharmacological activities. Here, a series of C-3 modified pyxinol derivatives was designed and virtually screened by molecular docking with the key inflammation-related proteins of the nuclear factor kappa B (NF-κB) pathway. Some of the novel derivatives were synthesized to assess their effects in inhibiting the production of nitric oxide (NO) and mitochondrial reactive oxygen species (MtROS) in lipopolysaccharide-triggered RAW264.7 cells. Derivative 2c exhibited the highest NO and MtROS inhibitory activities with low cytotoxicity. Furthermore, 2c decreased the protein levels of interleukin 1β, tumor necrosis factor α, inducible nitric oxide synthase, and cyclooxygenase 2 and suppressed the activation of NF-κB signaling. Cellular thermal shift assays indicated that 2c could directly bind with p65 and p50 in situ. Molecular docking revealed that 2c’s binding to the p65–p50 heterodimer and p50 homodimer was close to their DNA binding sites. In summary, pyxinol derivatives possess potential for development as NF-κB inhibitors. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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11 pages, 1311 KiB

Open AccessArticle

Camel-Derived Nanobodies as Potent Inhibitors of New Delhi Metallo-β-Lactamase-1 Enzyme

by Rahma Ben Abderrazek, Emna Hamdi, Alessandra Piccirilli, Sayda Dhaouadi, Serge Muyldermans, Mariagrazia Perilli and Balkiss Bouhaouala-Zahar

Molecules 2024, 29(7), 1431; https://doi.org/10.3390/molecules29071431 - 22 Mar 2024

Viewed by 623

Abstract

The injudicious usage of antibiotics during infections caused by Gram-negative bacteria leads to the emergence of β-lactamases. Among them, the NDM-1 enzyme poses a serious threat to human health. Developing new antibiotics or inhibiting β-lactamases might become essential to reduce and prevent bacterial infections. Nanobodies (Nbs), the smallest antigen-binding single-domain fragments derived from Camelidae heavy-chain-only antibodies, targeting enzymes, are innovative alternatives to develop effective inhibitors. The biopanning of an immune VHH library after phage display has helped to retrieve recombinant antibody fragments with high inhibitory activity against recombinant-NDM-1 enzyme. Nb02NDM-1, Nb12NDM-1, and Nb17NDM-1 behaved as uncompetitive inhibitors against NDM-1 with K_i values in the nM range. Remarkably, IC₅₀ values of 25.0 nM and 8.5 nM were noted for Nb02NDM-1 and Nb17NDM-1, respectively. The promising inhibition of NDM-1 by Nbs highlights their potential application in combating particular Gram-negative infections. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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20 pages, 3837 KiB

Open AccessArticle

Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer’s Disease: AChE, MAO-B, and COX-2 as Molecular Targets

by Saira Asghar, Nousheen Mushtaq, Ahsaan Ahmed, Laila Anwar, Rabya Munawar and Shamim Akhtar

Molecules 2024, 29(2), 490; https://doi.org/10.3390/molecules29020490 - 19 Jan 2024

Viewed by 944

Abstract

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer’s disease (AD) treatment due to a growing understanding of AD’s complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC₅₀ values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC₅₀ = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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13 pages, 3417 KiB

Open AccessArticle

Experimental and Theoretical Biological Probing of Schiff Bases as Esterase Inhibitors: Structural, Spectral and Molecular Insights

by Muhammad Asam Raza, Muhammad Waseem Mumtaz, Seyhan Öztürk, Muhammad Latif, Aisha, Adnan Ashraf, Necmi Dege, Onur Erman Dogan, Erbil Agar, Shafiq Ur Rehman and Awal Noor

Molecules 2023, 28(15), 5703; https://doi.org/10.3390/molecules28155703 - 28 Jul 2023

Cited by 1 | Viewed by 935

Abstract

The present study was designed to evaluate the in vitro and in silico potential of the Schiff bases (Z)-4-ethoxy-N-((5-nitrothiophen-2-yl)methylene)benzenamine (1) and (Z)-2,4-diiodo-6-((2-methyl-3-nitrophenylimino)methyl)phenol (2). These Schiff bases were synthesized according to a reported method using ethanol as a solvent, and each reaction was monitored on a TLC until completion of the reaction. The structures of both compounds were elucidated using spectroscopic techniques such as UV–Vis, FTIR, ¹H NMR and ¹³C NMR. Molecular structure was determined using single-crystal XRD, which revealed that compounds 1 and 2 were monoclinic and triclinic, respectively. Hirshfeld surface analysis (HS) and 2D fingerprint plots were used to determine the intermolecular interactions along the contact contribution in the crystalline molecules. The structures of both compounds were optimized through a hybrid functional method B3LYP using the 6-31G(d,p) basis set, and various structural parameters were studied. The experimental and theoretical parameters (bond angle and bond length) of the compounds were compared with each other and are in close agreement. The in vitro esterase potential of the synthesized compounds was checked using a spectrophotometric model, while in silico molecular docking studies were performed with AutoDock against two enzymes of the esterase family. The docking studies and the in vitro assessment predicted that such molecules could be used as enzyme inhibitors against the tested enzymes: acetylcholine esterase (AChE) and butyrylcholine esterase (BChE). Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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17 pages, 3987 KiB

Open AccessArticle

Dual Anta-Inhibitors Targeting Protein Kinase CK1δ and A_2A Adenosine Receptor Useful in Neurodegenerative Disorders

by Beatrice Francucci, Simone Angeloni, Diego Dal Ben, Catia Lambertucci, Massimo Ricciutelli, Andrea Spinaci, Aleksei Smirnov, Rosaria Volpini, Michela Buccioni and Gabriella Marucci

Molecules 2023, 28(12), 4762; https://doi.org/10.3390/molecules28124762 - 14 Jun 2023

Viewed by 962

Abstract

Currently, the number of patients with neurodegenerative pathologies is estimated at over one million, with consequences also on the economic level. Several factors contribute to their development, including overexpression of A_2A adenosine receptors (A_2AAR) in microglial cells and up-regulation and post-translational alterations of some casein kinases (CK), among them, CK-1δ. The aim of the work was to study the activity of A_2AAR and CK1δ in neurodegeneration using in-house synthesized A_2A/CK1δ dual anta-inhibitors and to evaluate their intestinal absorption. Experiments were performed on N13 microglial cells, which were treated with a proinflammatory CK cocktail to simulate an inflammatory state typical of neurodegenerative diseases. Results showed that the dual anta-inhibitors have the ability to counteract the inflammatory state, even if compound 2 is more active than compound 1. In addition, compound 2 displayed an important antioxidant effect similar to the reference compound ZM241385. Since many known kinase inhibitors are very often unable to cross lipid bilayer membranes, the ability of A_2A/CK1δ double anta-inhibitors to cross the intestinal barrier was investigated by an everted gut sac assay. HPLC analysis revealed that both compounds are able to cross the intestinal barrier, making them promising candidates for oral therapy. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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0 pages, 6920 KiB

Open AccessArticle

One-Pot Synthesis and Evaluation of Antioxidative Stress and Anticancer Properties of an Active Chromone Derivative

by Chirattikan Maicheen, Chokchaloemwat Churnthammakarn, Nichapat Pongsroypech, Thitiphong Khamkhenshorngphanuch, Jiraporn Ungwitayatorn, Kanin Rungsardthong, Rathapon Asasutjarit and Sewan Theeramunkong

Molecules 2023, 28(7), 3129; https://doi.org/10.3390/molecules28073129 - 31 Mar 2023

Viewed by 1281

Abstract

Chromones are the structural building blocks of several natural flavonoids. The synthesis of chromones, which contain a hydroxy group on the ring, presents some challenges. We used the one-pot method to synthesize ten chromone derivatives and two related compounds using modified Baker-Venkataraman reactions. The structures were confirmed using FT-IR, ¹H NMR, ¹³C NMR, and HRMS. The in vitro antioxidant assay revealed that compounds 2e, 2f, 2j, and 3i had potent antioxidant activity and that all these synthesized compounds, except those containing nitro groups, were harmless to normal cells. In addition, compounds 2b, 2d, 2e, 2f, 2g, 2i, and 2j had anticancer activity. Compounds 2f and 2j were used to investigate the mechanism of anticancer activity. Both 2f and 2j induced a slightly early apoptotic effect but significantly impacted the S phase in the cell cycle. The effect on cell invasion indicates that both compounds significantly inhibited the growth of cervical cancer cells. A chromone scaffold possesses effective chemoprotective and antioxidant properties, making it a promising candidate for antioxidant and future cancer treatments. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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19 pages, 6327 KiB

Open AccessArticle

Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA

by Jiajia Chang, Shi Hou, Xinlin Yan, Wei Li and Junhai Xiao

Molecules 2023, 28(7), 2906; https://doi.org/10.3390/molecules28072906 - 23 Mar 2023

Cited by 6 | Viewed by 2389

Abstract

The stimulator-of-interferon-gene (STING) protein is involved in innate immunity. The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) proved to be a potent murine-STING (mSTING) agonist but had little effect on human-STING (hSTING). In this paper, we draw upon the comparison of different crystal structures and protein-ligand interaction relationships analysis to venture the hypothesis that the drug design of DMXAA variants has the potential to convert STING agonists to inhibitors. Based on our previous discovery of two DMXAA analogs, 3 and 4 (both could bind to STING), we structurally optimized them and synthesized new derivatives, respectively. In binding assays, we found compounds 11 and 27 to represent STING binders that were superior to the original structures and discussed the structure-activity relationships. All target compounds were inactive in cellular assays for the screening of STING agonistic activity. Gratifyingly, we identified 11 and 27 as STING inhibitors with micromolar activity in both hSTING and mSTING pathways. In addition, 11 and 27 inhibited the induction of interferon and inflammatory cytokines activated by 2′3′-cGAMP without apparent cytotoxicity. These findings break the rigid thinking that DMXAA provides the structural basis specifically for STING agonists and open up more possibilities for developing novel STING agonists or inhibitors. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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18 pages, 4562 KiB

Open AccessArticle

Cytotoxic and Luminescent Properties of Novel Organotin Complexes with Chelating Antioxidant Ligand

by Evgeny Nikitin, Ekaterina Mironova, Dmitry Shpakovsky, Yulia Gracheva, Daniil Koshelev, Valentina Utochnikova, Konstantin Lyssenko, Yury Oprunenko, Dmitry Yakovlev, Roman Litvinov, Mariya Seryogina, Alexander Spasov and Elena Milaeva

Molecules 2022, 27(23), 8359; https://doi.org/10.3390/molecules27238359 - 30 Nov 2022

Cited by 5 | Viewed by 1455

Abstract

A novel polydentate chelating antioxidant ligand and series of organotin complexes on its base were synthesized and characterized by NMR ¹H, ¹³C, ¹¹⁹Sn, IR spectroscopy, X-ray, and elemental analysis. Their antioxidant activity was evaluated in DPPH and NBT-tests, and as lipoxygenase inhibitory activity. It was shown that ligand alone is a radical scavenger, while introducing tin in the structure of the compound significantly decreases its activity. For the ligand alone the ability to strongly suppress the formation of advanced glycation end products (AGEs) was shown, which may be associated with the established antiradical activity. All synthesized compounds appeared to be moderate lipoxygenase inhibitors. The stability of compounds to hydrolysis under different pH was estimated. The ligand undergoes decomposition after about an hour, while organotin complexes on its base demonstrate vast stability, showing signs of decomposition only after 5 h of experimentation. Cytotoxicity of compounds was studied by standard MTT-test, which showed unorthodox results: the ligand itself demonstrated noticeable cytotoxicity while the introduction of organotin moiety either did not affect the toxicity levels or reduced them instead of increasing. Organotin complexes possess luminescence both as powders and DMSO solutions, its quantum yields reaching 67% in DMSO. The combination of luminescence with unique cytotoxic properties allows us to propose the synthesized compounds as perspective theranostic agents. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Novel Small Molecules Inhibitors)

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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Marine bioactive molecules may treat Rheumatoid Arthritis: virtual screening-based molecular analysis
Author: Ahmed
Highlights: We provided a detailed analysis for the amino acid residues at JAK proteins to which the currently proposed set of bioactive molecules are interacting. Our reference or reliable pharmacophore was the comparative analysis to the FDA approved inhibitors tofacitinib and baricitinib besides the interaction with the ATP binding sites.

Title: First highly inhibiting anti-NDM-1 nanobodies as alternative to tackle antibiotic resistance
Author: Ben Abderrazek
Highlights: - No commercially metallo-β-lactamase inhibitors are available for serious infections. -The use of small inhibitors based on the antigen-binding single domain fragements called nanobodies derived drom dromedary constitutes an attractive issue. -Selected nanobody inhibitor binders by biopannig phage display from VHH immune Library behaved as competitive inhibitors against NDM-1 enzyme

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