Design, Synthesis and Biological Evaluation of Novel Small Molecules as Multi-target Enzyme Inhibitors

Topic Information

Dear Colleagues,

We are delighted to announce the initiation of a Topic, "Design, Synthesis and Biological Evaluation of Novel Small Molecules as Multi-target Enzyme Inhibitors", dedicated to exploring the dynamic intersection of synthetic organic chemistry and biology, with profound implications for diverse medical applications.

Within this specialized topic, our focus is on the synthesis and biological assessment of novel small molecules designed to inhibit multiple enzymes concurrently. Multi-target enzyme inhibitors offer a comprehensive treatment approach by simultaneously targeting multiple disease-related pathways, enhancing therapeutic efficacy. Their ability to mitigate drug resistance, improve selectivity, and potentially provide synergistic effects makes them promising candidates for treating complex diseases. Additionally, the versatility of these inhibitors allows for a more personalized treatment strategy, addressing the multifactorial origins of various medical conditions.

The synthesis process involves optimizing for favorable pharmacokinetic properties and target specificity, leading to a varied library of compounds. The potential applications of the target inhibitors extend into critical areas of medical research, including neurological disorders, the antimicrobial field, antidiabetic therapies, and so on.

We also welcome investigations into novel synthetic methodologies, recognizing their importance in developing innovative strategies to access multi-target inhibitors. Contributions in the form of reviews and original research papers are encouraged for publication. We invite your participation in creating a comprehensive collection of articles, promoting a deeper understanding of the synthesis and evaluation of small molecules with multi-target enzyme-inhibitory properties and the development of novel synthetic routes.

We eagerly anticipate and welcome your valuable contributions to advancing the discourse surrounding this exciting and rapidly evolving field.

Dr. Davide Moi
Prof. Dr. Daniele Passarella
Dr. Andrea Citarella
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
BioChem biochem	-	-	2021	21.7 Days	CHF 1000	Submit
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700	Submit
Current Issues in Molecular Biology cimb	2.8	2.9	1999	15.8 Days	CHF 2200	Submit
Molecules molecules	4.2	7.4	1996	15.1 Days	CHF 2700	Submit
Pharmaceutics pharmaceutics	4.9	7.9	2009	15.5 Days	CHF 2900	Submit
Scientia Pharmaceutica scipharm	2.3	4.6	1930	26.1 Days	CHF 1000	Submit

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Published Papers (3 papers)

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All BioChem Biomolecules CIMB Molecules Pharmaceutics Sci. Pharm.

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Supplementary material:
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Open AccessArticle

Concomitant Inhibition and Collaring of Dual-Species Biofilms Formed by Candida auris and Staphylococcus aureus by Triazole Based Small Molecule Inhibitors

by Humaira Parveen, Sayeed Mukhtar, Mona O. Albalawi, Syed Khasim, Aijaz Ahmad and Mohmmad Younus Wani

Pharmaceutics 2024, 16(12), 1570; https://doi.org/10.3390/pharmaceutics16121570 - 8 Dec 2024

Cited by 1 | Viewed by 1194

Abstract

Background/Objectives: Biofilm-associated infections, particularly those involving Candida auris and Staphylococcus aureus, pose significant challenges in clinical settings due to their resilience and resistance to conventional treatments. This study aimed to synthesize novel triazole derivatives containing a piperazine ring via click chemistry and evaluate [...] Read more.

Background/Objectives: Biofilm-associated infections, particularly those involving Candida auris and Staphylococcus aureus, pose significant challenges in clinical settings due to their resilience and resistance to conventional treatments. This study aimed to synthesize novel triazole derivatives containing a piperazine ring via click chemistry and evaluate their efficacy in disrupting biofilms formed by these pathogens. Methods: Triazole derivatives were synthesized using click chemistry techniques. The antimicrobial activity of the compounds was tested against planktonic cells of C. auris and S. aureus in single and dual-species culture conditions. Biofilm disruption efficacy was assessed, alongside the evaluation of physicochemical properties, oral bioavailability potential, and toxicity profiles. Results: The compound T3 demonstrated potent antimicrobial activity against planktonic cells of C. auris and S. aureus in both single and dual-species cultures. T3 exhibited significant efficacy in reducing microbial viability within biofilms formed by these pathogens. Physicochemical analyses revealed favorable solubility and permeability profiles, supporting its potential for oral bioavailability. Toxicity assessments showed a non-toxic profile, highlighting a promising safety margin for further development. Conclusions: This study underscores the anti-biofilm properties of novel triazole-piperazine derivatives, particularly T3, against single and dual-species biofilms of C. auris and S. aureus. These findings position T3 as a promising candidate for developing therapies targeting polymicrobial infections and provide a foundation for future research into alternative strategies for combating biofilm-associated infections. Full article

(This article belongs to the Topic Design, Synthesis and Biological Evaluation of Novel Small Molecules as Multi-target Enzyme Inhibitors)

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26 pages, 5799 KiB  

Open AccessReview

Exploring the Benzazoles Derivatives as Pharmacophores for AChE, BACE1, and as Anti-Aβ Aggregation to Find Multitarget Compounds against Alzheimer’s Disease

by Martha Cecilia Rosales Hernández, Marycruz Olvera-Valdez, Jazziel Velazquez Toledano, Jessica Elena Mendieta Wejebe, Leticia Guadalupe Fragoso Morales and Alejandro Cruz

Molecules 2024, 29(19), 4780; https://doi.org/10.3390/molecules29194780 - 9 Oct 2024

Cited by 1 | Viewed by 1925

Abstract

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer’s disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and [...] Read more.

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer’s disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified—some are involved with amyloid beta (Aβ) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aβ. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π–π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC₅₀ value in the μM range. Also, benzimidazoles and benzothiazoles can inhibit Aβ aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC₅₀ value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles’ activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets. Full article

(This article belongs to the Topic Design, Synthesis and Biological Evaluation of Novel Small Molecules as Multi-target Enzyme Inhibitors)

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Supplementary File 1 (ZIP, 1745 KiB)

18 pages, 2383 KiB  

Open AccessArticle

The Effects of the Steroids 5-Androstenediol and Dehydroepiandrosterone and Their Synthetic Derivatives on the Viability of K562, HeLa, and Wi-38 Cells and the Luminol-Stimulated Chemiluminescence of Peripheral Blood Mononuclear Cells from Healthy Volunteers

by Mikhail N. Sokolov, Vladimir V. Rozhkov, Maria E. Uspenskaya, Darya N. Ulchenko, Vladimir I. Shmygarev, Vladimir M. Trukhan, Andrei V. Churakov, Nikolay L. Shimanovsky and Tatiana A. Fedotcheva

Biomolecules 2024, 14(3), 373; https://doi.org/10.3390/biom14030373 - 19 Mar 2024

Cited by 2 | Viewed by 2086

Abstract

In order to evaluate the role of substituents at 3-C and 17-C in the cytotoxic and cytoprotective actions of DHEA and 5-AED molecules, their derivatives were synthesized by esterification using the corresponding acid anhydrides or acid chlorides. As a result, seven compounds were [...] Read more.

In order to evaluate the role of substituents at 3-C and 17-C in the cytotoxic and cytoprotective actions of DHEA and 5-AED molecules, their derivatives were synthesized by esterification using the corresponding acid anhydrides or acid chlorides. As a result, seven compounds were obtained: four DHEA derivatives (DHEA 3-propionate, DHEA 3-butanoate, DHEA 3-acetate, DHEA 3-methylsulfonate) and three 5-AED derivatives (5-AED 3-butanoate, 5-AED 3,17-dipropionate, 5-AED 3,17-dibutanoate). All of these compounds showed micromolar cytotoxic activity toward HeLa and K562 human cancer cells. The maximum cytostatic effect during long-term incubation for five days with HeLa and K562 cells was demonstrated by the propionic esters of the steroids: DHEA 3-propionate and 5-AED 3,17-dipropionate. These compounds stimulated the growth of normal Wi-38 cells by 30–50%, which indicates their cytoprotective properties toward noncancerous cells. The synthesized steroid derivatives exhibited antioxidant activity by reducing the production of reactive oxygen species (ROS) by peripheral blood mononuclear cells from healthy volunteers, as demonstrated in a luminol-stimulated chemiluminescence assay. The highest antioxidant effects were shown for the propionate ester of the steroid DHEA. DHEA 3-propionate inhibited luminol-stimulated chemiluminescence by 73% compared to the control, DHEA, which inhibited it only by 15%. These data show the promise of propionic substituents at 3-C and 17-C in steroid molecules for the creation of immunostimulatory and cytoprotective substances with antioxidant properties. Full article

(This article belongs to the Topic Design, Synthesis and Biological Evaluation of Novel Small Molecules as Multi-target Enzyme Inhibitors)

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