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Rational Design and Synthesis of Bioactive Molecules
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Rational Design and Synthesis of Bioactive Molecules

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (25 April 2024) | Viewed by 6645

Special Issue Editors

Prof. Dr. Irena Kostova

E-Mail Website
Guest Editor
Department of Chemistry, Faculty of Pharmacy, Medical University, 2 Dunav St., Sofia 1000, Bulgaria
Interests: bioinorganic chemistry; medicinal chemistry; coordination chemistry; theoretical chemistry; vibrational spectroscopy; drug discovery; pharmacological investigations; biologically active compounds
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Santiago Gómez-Ruiz

E-Mail Website
Guest Editor
COMET-NANO Group, Department of Biology and Geology, Physics and Inorganic Chemistry, ESCET, Universidad Rey Juan Carlos, Calle Tulipán s/n, E-28933 Móstoles, Madrid, Spain
Interests: bioinorganic chemistry; medicinal chemistry; coordination chemistry; nanomaterials; drug discovery; pharmacological investigations; catalysis; photocatalysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development and application of bioorganic, bioinorganic, coordination chemistry and nanostructured materials to medicine is an emerging field, and novel therapeutic and diagnostic compounds are now having an impact on medical practice. Much attention has focused on designing new structures with the desired composition and improved pharmacological properties and a broader range of activity. The application of new synthetic, analytical, spectral methodologies, theoretical and drug delivery approaches, widely used in drug discovery, is beneficial for the development of bioactive substances as therapeutics and diagnostics due to mutual efforts of chemists, biologists and experts in pharmacology, photophysics, bioimaging, etc.

The Special Issue entitled “Rational Design and Synthesis of Bioactive Molecules” focuses on recent advances in this multidisciplinary field. Special emphasis is put on the rational design and synthesis, structure determination, bonding, theoretical, analytical and physicochemical drug discovery strategies, together with the design of novel drug delivery systems related to the biologically relevant applications of a variety of compounds with improved efficiency. The scope of this issue is to review, critically discuss the current developments and to provide the reader with up-to-date information on various aspects of this fascinating research area. Original research articles, short communications and reviews, highlighting the latest advances in the field, will be considered for publication.

Prof. Dr. Irena Kostova
Prof. Dr. Santiago Gómez-Ruiz
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • synthesis
  • structure
  • bonding
  • reactivity
  • chemical properties
  • physical properties
  • pharmacological activity
  • structure-activity relationship
  • applications

Published Papers (7 papers)

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Research

13 pages, 5791 KiB  
Article
Design and Synthesis of Pleuromutilin Derivatives as Antibacterial Agents Using Quantitative Structure–Activity Relationship Model
by Jiaming Zhang, Qinqin Liu, Haoxia Zhao, Guiyu Li, Yunpeng Yi and Ruofeng Shang
Int. J. Mol. Sci. 2024, 25(4), 2256; https://doi.org/10.3390/ijms25042256 - 13 Feb 2024
Viewed by 609
Abstract
The quantitative structure–activity relationship (QSAR) is one of the most popular methods for the virtual screening of new drug leads and optimization. Herein, we collected a dataset of 955 MIC values of pleuromutilin derivatives to construct a 2D-QSAR model with an accuracy of [...] Read more.
The quantitative structure–activity relationship (QSAR) is one of the most popular methods for the virtual screening of new drug leads and optimization. Herein, we collected a dataset of 955 MIC values of pleuromutilin derivatives to construct a 2D-QSAR model with an accuracy of 80% and a 3D-QSAR model with a non-cross-validated correlation coefficient (r2) of 0.9836 and a cross-validated correlation coefficient (q2) of 0.7986. Based on the obtained QSAR models, we designed and synthesized pleuromutilin compounds 1 and 2 with thiol-functionalized side chains. Compound 1 displayed the highest antimicrobial activity against both Staphylococcus aureus ATCC 29213 (S. aureus) and Methicillin-resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentrations (MICs) < 0.0625 μg/mL. These experimental results confirmed that the 2D and 3D-QSAR models displayed a high accuracy of the prediction function for the discovery of lead compounds from pleuromutilin derivatives. Full article
(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules)
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22 pages, 2834 KiB  
Article
Cyclobutanone Inhibitors of Diaminopimelate Desuccinylase (DapE) as Potential New Antibiotics
by Thahani S. Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl, Katherine Konczak, Megan Beulke, Janielle Javier, Kenneth W. Olsen and Daniel P. Becker
Int. J. Mol. Sci. 2024, 25(2), 1339; https://doi.org/10.3390/ijms25021339 - 22 Jan 2024
Viewed by 693
Abstract
Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified [...] Read more.
Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor (3y, IC50 = 23.1 µM) enabled determination of a Ki value of 10.2 +/− 0.26 µM and observed two separate Tm values for H. influenzae DapE (HiDapE). Full article
(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules)
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16 pages, 4835 KiB  
Article
Identification of a Pentasaccharide Lead Compound with High Affinity to the SARS-CoV-2 Spike Protein via In Silico Screening
by Binjie Li, Tianji Zhang, Hui Cao, Vito Ferro, Jinping Li and Mingjia Yu
Int. J. Mol. Sci. 2023, 24(22), 16115; https://doi.org/10.3390/ijms242216115 - 09 Nov 2023
Viewed by 928
Abstract
The spike (S) protein on the surface of the SARS-CoV-2 virus is critical to mediate fusion with the host cell membrane through interaction with angiotensin-converting enzyme 2 (ACE2). Additionally, heparan sulfate (HS) on the host cell surface acts as an attachment factor to [...] Read more.
The spike (S) protein on the surface of the SARS-CoV-2 virus is critical to mediate fusion with the host cell membrane through interaction with angiotensin-converting enzyme 2 (ACE2). Additionally, heparan sulfate (HS) on the host cell surface acts as an attachment factor to facilitate the binding of the S receptor binding domain (RBD) to the ACE2 receptor. Aiming at interfering with the HS-RBD interaction to protect against SARS-CoV-2 infection, we have established a pentasaccharide library composed of 14,112 compounds covering the possible sulfate substitutions on the three sugar units (GlcA, IdoA, and GlcN) of HS. The library was used for virtual screening against RBD domains of SARS-CoV-2. Molecular modeling was carried out to evaluate the potential antiviral properties of the top-hit pentasaccharide focusing on the interactive regions around the interface of RBD-HS-ACE2. The lead pentasaccharide with the highest affinity for RBD was analyzed via drug-likeness calculations, showing better predicted druggable profiles than those currently reported for RBD-binding HS mimetics. The results provide significant information for the development of HS-mimetics as anti-SARS-CoV-2 agents. Full article
(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules)
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17 pages, 5235 KiB  
Article
The Effect of Polymer Blends on the In Vitro Release/Degradation and Pharmacokinetics of Moxidectin-Loaded PLGA Microspheres
by Hongjuan Zhang, Zhen Yang, Di Wu, Baocheng Hao, Yu Liu, Xuehong Wang, Wanxia Pu, Yunpeng Yi, Ruofeng Shang and Shengyi Wang
Int. J. Mol. Sci. 2023, 24(19), 14729; https://doi.org/10.3390/ijms241914729 - 29 Sep 2023
Viewed by 769
Abstract
To investigate the effect of polymer blends on the in vitro release/degradation and pharmacokinetics of moxidectin-loaded PLGA microspheres (MOX-MS), four formulations (F1, F2, F3 and F4) were prepared using the O/W emulsion solvent evaporation method by blending high (75/25, 75 kDa) and low [...] Read more.
To investigate the effect of polymer blends on the in vitro release/degradation and pharmacokinetics of moxidectin-loaded PLGA microspheres (MOX-MS), four formulations (F1, F2, F3 and F4) were prepared using the O/W emulsion solvent evaporation method by blending high (75/25, 75 kDa) and low (50/50, 23 kDa) molecular weight PLGA with different ratios. The addition of low-molecular-weight PLGA did not change the release mechanism of microspheres, but sped up the drug release of microspheres and drastically shortened the lag phase. The in vitro degradation results show that the release of microspheres consisted of a combination of pore diffusion and erosion, and especially autocatalysis played an important role in this process. Furthermore, an accelerated release method was also developed to reduce the period for drug release testing within one month. The pharmacokinetic results demonstrated that MOX-MS could be released for at least 60 days with only a slight blood drug concentration fluctuation. In particular, F3 displayed the highest AUC and plasma concentration (AUC0–t = 596.53 ng/mL·d, Cave (day 30-day 60) = 8.84 ng/mL), making it the optimal formulation. Overall, these results indicate that using polymer blends could easily adjust hydrophobic drug release from microspheres and notably reduce the lag phase of microspheres. Full article
(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules)
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23 pages, 37842 KiB  
Article
Peculiarities of the Spatial and Electronic Structure of 2-Aryl-1,2,3-Triazol-5-Carboxylic Acids and Their Salts on the Basis of Spectral Studies and DFT Calculations
by Mauricio Alcolea Palafox, Nataliya P. Belskaya and Irena P. Kostova
Int. J. Mol. Sci. 2023, 24(18), 14001; https://doi.org/10.3390/ijms241814001 - 12 Sep 2023
Cited by 2 | Viewed by 650
Abstract
The molecular structure and vibrational spectra of six 1,2,3-triazoles-containing molecules with possible anticancer activity were investigated. For two of them, the optimized geometry was determined in the monomer, cyclic dimer and stacking forms using the B3LYP, M06-2X and MP2 methods implemented in the [...] Read more.
The molecular structure and vibrational spectra of six 1,2,3-triazoles-containing molecules with possible anticancer activity were investigated. For two of them, the optimized geometry was determined in the monomer, cyclic dimer and stacking forms using the B3LYP, M06-2X and MP2 methods implemented in the GAUSSIAN-16 program package. The effect of the para-substitution on the aryl ring was evaluated based on changes in the molecular structure and atomic charge distribution of the triazole ring. An increment in the positive N4 charge was linearly related to a decrease in both the aryl ring and the carboxylic group rotation, with respect to the triazole ring, and by contrast, to an increment in the pyrrolidine ring rotation. Anionic formation had a larger effect on the triazole ring structure than the electronic nature of the different substituents on the aryl ring. Several relationships were obtained that could facilitate the selection of substituents on the triazole ring for their further synthesis. The observed IR and Raman bands in the solid state of two of these compounds were accurately assigned according to monomer and dimer form calculations, together with the polynomic scaling equation procedure (PSE). The large red-shift of the C=O stretching mode indicates that strong H-bonds in the dimer form appear in the solid state through this group. Full article
(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules)
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14 pages, 1683 KiB  
Article
Antioxidant Properties of Selected Flavonoids in Binary Mixtures—Considerations on Myricetin, Kaempferol and Quercetin
by Małgorzata Olszowy-Tomczyk and Dorota Wianowska
Int. J. Mol. Sci. 2023, 24(12), 10070; https://doi.org/10.3390/ijms241210070 - 13 Jun 2023
Cited by 4 | Viewed by 1092
Abstract
Flavonoids, secondary plant metabolites with many health-promoting properties, including antioxidant, are a valuable component of food products, especially functional foods. In the latter, plant extracts are commonly used, the properties of which are attributed to the characteristic main ingredients. However, in a mixture [...] Read more.
Flavonoids, secondary plant metabolites with many health-promoting properties, including antioxidant, are a valuable component of food products, especially functional foods. In the latter, plant extracts are commonly used, the properties of which are attributed to the characteristic main ingredients. However, in a mixture the antioxidant properties of the individual ingredients do not always show an additive effect. This paper presents and discusses the antioxidant properties of naturally occurring flavonoid aglycones and their binary mixtures. In the experiments, model systems were used that differed in the volume of the alcoholic antioxidant solution in the measuring system and its concentration in the range in which it occurs in nature. Antioxidant properties were determined by ABTS and DPPH methods. The presented data proved that the dominant resultant effect in the mixtures is antioxidant antagonism. The magnitude of the observed antagonism depends on the mutual relations of individual components, their concentrations and the method used to assess antioxidant properties. It was shown that the observed non-additive antioxidant effect of the mixture results from the formation of intramolecular hydrogen bonds between phenolic groups of the antioxidant molecule. The presented results may be useful in the context of proper design of functional foods. Full article
(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules)
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19 pages, 6298 KiB  
Article
Combined NMR Spectroscopy and Quantum-Chemical Calculations in Fluorescent 1,2,3-Triazole-4-carboxylic Acids Fine Structures Analysis
by Nikita E. Safronov, Irena P. Kostova, Mauricio Alcolea Palafox and Nataliya P. Belskaya
Int. J. Mol. Sci. 2023, 24(10), 8947; https://doi.org/10.3390/ijms24108947 - 18 May 2023
Cited by 4 | Viewed by 1166
Abstract
The peculiarities of the optical properties of 2-aryl-1,2,3-triazole acids and their sodium salts were investigated in different solvents (1,4-dioxane, dimethyl sulfoxide DMSO, methanol MeOH) and in mixtures with water. The results were discussed in terms of the molecular structure formed by inter- and [...] Read more.
The peculiarities of the optical properties of 2-aryl-1,2,3-triazole acids and their sodium salts were investigated in different solvents (1,4-dioxane, dimethyl sulfoxide DMSO, methanol MeOH) and in mixtures with water. The results were discussed in terms of the molecular structure formed by inter- and intramolecular noncovalent interactions (NCIs) and their ability to ionize in anions. Theoretical calculations using the Time-Dependent Density Functional Theory (TDDFT) were carried out in different solvents to support the results. In polar and nonpolar solvents (DMSO, 1,4-dioxane), fluorescence was provided by strong neutral associates. Protic MeOH can weaken the acid molecules’ association, forming other fluorescent species. The fluorescent species in water exhibited similar optical characteristics to those of triazole salts; therefore, their anionic character can be assumed. Experimental 1H and 13C-NMR spectra were compared to their corresponding calculated spectra using the Gauge-Independent Atomic Orbital (GIAO) method and several relationships were established. All these findings showed that the obtained photophysical properties of the 2-aryl-1,2,3-triazole acids noticeably depend on the environment and, therefore, are good candidates as sensors for the identification of analytes with labile protons. Full article
(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules)
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