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Development and Synthesis of Biologically Active Compounds

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 (30 January 2024) | Viewed by 18273

Special Issue Editors


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Guest Editor
Laboratory of Nitrogen-Containing Compounds, N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Moscow 119991, Russia
Interests: anti-cancer activity; biologically active compounds; heterocyclic chemistry; cycloaddition reactions; rearrangements

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Guest Editor
Department of Drug Science and Technology, Università degli Studi di Torino, 10125 Turin, Italy
Interests: structural and pharmacological design; synthesis and characterization of new multitarget molecules

Special Issue Information

Dear Colleagues,

Biologically active compounds capable of affecting a living organism, tissue, or cell play an important role in treating and preventing various diseases. They can, therefore, promote a significant improvement in the quality of life and increase life expectancy. These compounds represent synthetically produced substances and/or naturally occurring ones in plants, animals, or other types of living organisms.

The Special Issue entitled "Development and Synthesis of Biologically Active Compounds" will present new advances in the design, synthesis, and in vitro and in vivo biological evaluation of bioactive compounds that can lead to the development of natural or synthetic active molecules looking for promising drugs.

This Special Issue welcomes papers addressing different synthetic strategies, isolation from natural sources, biological screening of compound libraries, or in silico approaches.

Dr. Galina A. Gazieva
Prof. Dr. Konstantin Chegaev
Guest Editors

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. 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

  • organic synthesis
  • heterocyclic moieties
  • nature-derived molecules
  • biological activity
  • structure–activity relationships
  • lead optimization
  • drug design
  • molecular modeling

Published Papers (15 papers)

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Editorial

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5 pages, 203 KiB  
Editorial
Special Issue “Development and Synthesis of Biologically Active Compounds”
by Galina A. Gazieva and Konstantin Chegaev
Int. J. Mol. Sci. 2024, 25(7), 4015; https://doi.org/10.3390/ijms25074015 - 04 Apr 2024
Viewed by 357
Abstract
The intention of this Special Issue is to focus on new achievements in the design, preparation, and in vitro and in vivo biological evaluation of bioactive molecules that can result in the development of natural or artificial potent compounds looking for promising pharmaceuticals [...] Read more.
The intention of this Special Issue is to focus on new achievements in the design, preparation, and in vitro and in vivo biological evaluation of bioactive molecules that can result in the development of natural or artificial potent compounds looking for promising pharmaceuticals and agrochemicals [...] Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)

Research

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26 pages, 5077 KiB  
Article
The Conjugates of Indolo[2,3-b]quinoline as Anti-Pancreatic Cancer Agents: Design, Synthesis, Molecular Docking and Biological Evaluations
by Marcin Cybulski, Katarzyna Sidoryk, Magdalena Zaremba-Czogalla, Bartosz Trzaskowski, Marek Kubiszewski, Joanna Tobiasz, Anna Jaromin and Olga Michalak
Int. J. Mol. Sci. 2024, 25(5), 2573; https://doi.org/10.3390/ijms25052573 - 22 Feb 2024
Cited by 1 | Viewed by 814
Abstract
New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5H-indolo[2,3-b]quinoline (2), [...] Read more.
New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5H-indolo[2,3-b]quinoline (2), which contains the ortho-coumaric acid fragment, demonstrated dose-dependent effectiveness against both normal BxPC-3 and metastatic AsPC-1 pancreatic cancer cells. The IC50 values for AsPC-1 and BxPC-3 were 336.5 nM and 347.5 nM, respectively, with a selectivity index of approximately 5 for both pancreatic cancer cells compared to normal dermal fibroblasts. Conjugate 2 did not exhibit any hemolytic activity against human erythrocytes at the tested concentration. Computational studies were performed to predict the pharmacokinetic profile and potential mechanism of action of the synthesized conjugates. These studies focused on the ADME properties of the conjugates and their interactions with DNA, as well as DNA–topoisomerase alpha and beta complexes. All of the conjugates studied showed approximately one order of magnitude stronger binding to DNA compared to the reference DiMIQ, and approximately two orders of magnitude stronger binding to the topoisomerase II–DNA complex compared to DiMIQ. Conjugate 2 was predicted to have the strongest binding to the enzyme–DNA complex, with a Ki value of 2.8 nM. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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19 pages, 2681 KiB  
Article
New Derivatives of 1-(3-Methyl-1-Benzofuran-2-yl)Ethan-1-one: Synthesis and Preliminary Studies of Biological Activity
by Mariola Napiórkowska, Pratheeba Kumaravel, Mithulya Amboo Mahentheran, Ewelina Kiernozek-Kalińska and Emilia Grosicka-Maciąg
Int. J. Mol. Sci. 2024, 25(4), 1999; https://doi.org/10.3390/ijms25041999 - 07 Feb 2024
Cited by 1 | Viewed by 693
Abstract
A set of nine derivatives, including five brominated compounds, was synthesized and the structures of these novel compounds were confirmed using 1H and 13C NMR as well as ESI MS spectra. These compounds were tested on four different cancer cell lines, [...] Read more.
A set of nine derivatives, including five brominated compounds, was synthesized and the structures of these novel compounds were confirmed using 1H and 13C NMR as well as ESI MS spectra. These compounds were tested on four different cancer cell lines, chronic myelogenous leukemia (K562), prostate cancer (PC3), colon cancer (SW620), human kidney cancer (Caki 1), and on healthy human keratocytes (HaCaT). MTT results reveal that two newly developed derivatives (6 and 8) exhibit selective action towards K562 cells and no toxic effect in HaCat cells. The biological activity of these two most promising compounds was evaluated by trypan blue assay, reactive oxygen species generation, and IL-6 secretion. To investigate the proapoptotic activity of selected compounds, the two following types of tests were performed: Annexin V Apoptosis Detection Kit I and Caspase-Glo 3/7 assay. The studies of the mechanism showed that both compounds have pro-oxidative effects and increase reactive oxygen species in cancer cells, especially at 12 h incubation. Through the Caspase-Glo 3/7 assay, the proapoptotic properties of both compounds were confirmed. The Annexin V-FITC test revealed that compounds 6 and 8 induce apoptosis in K562 cells. Both compounds inhibit the release of proinflammatory interleukin 6 (IL-6) in K562 cells. Additionally, all compounds were screened for their antibacterial activities using standard and clinical strains. Within the studied group, compound 7 showed moderate activity towards Gram-positive strains in antimicrobial studies, with MIC values ranging from 16 to 64 µg/mL. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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23 pages, 4911 KiB  
Article
Anticancer and Antiphytopathogenic Activity of Fluorinated Isatins and Their Water-Soluble Hydrazone Derivatives
by Andrei V. Bogdanov, Margarita Neganova, Alexandra Voloshina, Anna Lyubina, Syumbelya Amerhanova, Igor A. Litvinov, Olga Tsivileva, Nurgali Akylbekov, Rakhmetulla Zhapparbergenov, Zulfiia Valiullina, Alexandr V. Samorodov and Igor Alabugin
Int. J. Mol. Sci. 2023, 24(20), 15119; https://doi.org/10.3390/ijms242015119 - 12 Oct 2023
Cited by 1 | Viewed by 1074
Abstract
A series of new fluorinated 1-benzylisatins was synthesized in high yields via a simple one-pot procedure in order to explore the possible effect of ortho-fluoro (3a), chloro (3b), or bis-fluoro (3d) substitution on the biological activity of [...] Read more.
A series of new fluorinated 1-benzylisatins was synthesized in high yields via a simple one-pot procedure in order to explore the possible effect of ortho-fluoro (3a), chloro (3b), or bis-fluoro (3d) substitution on the biological activity of this pharmacophore. Furthermore, the new isatins could be converted into water-soluble isatin-3-hydrazones using their acid-catalyzed reaction with Girard’s reagent P and its dimethyl analog. The cytotoxic action of these substances is associated with the induction of apoptosis caused by mitochondrial membrane dissipation and stimulated reactive oxygen species production in tumor cells. In addition, compounds 3a and 3b exhibit platelet antiaggregation activity at the level of acetylsalicylic acid, and the whole series of fluorine-containing isatins does not adversely affect the hemostasis system as a whole. Among the new water-soluble pyridinium isatin-3-acylhydrazones, compounds 7c and 5c,e exhibit the highest antagonistic effect against phytopathogens of bacterial and fungal origin and can be considered useful leads for combating plant diseases. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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15 pages, 4388 KiB  
Article
Application of Pluronics for Enhancing Aqueous Solubility of Lipophilic Microtubule Destabilizing Compounds on the Sea Urchin Embryo Model
by Marina N. Semenova, Nikolay S. Melik-Nubarov and Victor V. Semenov
Int. J. Mol. Sci. 2023, 24(19), 14695; https://doi.org/10.3390/ijms241914695 - 28 Sep 2023
Cited by 2 | Viewed by 784
Abstract
In screening, the dilution of DMSO stock solution of a lipophilic molecule with an assay medium often causes compound precipitation. To overcome the issue, the application of Pluronics as cosolvents was examined using a phenotypic sea urchin embryo assay that allows for the [...] Read more.
In screening, the dilution of DMSO stock solution of a lipophilic molecule with an assay medium often causes compound precipitation. To overcome the issue, the application of Pluronics as cosolvents was examined using a phenotypic sea urchin embryo assay that allows for the quick and facile evaluation of the antiproliferative effect together with systemic toxicity. Maximum tolerated concentration values for Pluronics L121, P123, and F127 were 1.4 μM, 8.6 μM, and 39.7 μM, respectively, and correlated directly with their hydrophilicity. Pluronics L121 and P123 suppressed cleavage and blastomeres retained the round shape, unlike hydrophilic Pluronic F127, which induced fertilization envelope creasing and embryo deformation that could be associated with the interaction of hydrophilic PEO units with mucopolysaccharides at the surface of sea urchin embryos. The toxicity of P123, but not of L121 and F127, was temperature-dependent and markedly increased at lower temperatures. CMC values obtained at different temperatures confirmed that the toxic effect of P123 was associated with both unimers and micelles, whereas F127 toxicity was related mainly to micelles. Evaluation using phenotypic sea urchin embryo assay revealed that potent microtubule destabilizers, namely albendazole, diarylisoxazole, and two chalcones, retained antimitotic activity after the dilution of their DMSO or 2-pyrrolidone stock solutions with 1.25% w/v Pluronic P123 or 5% w/v Pluronic F127. It was suggested that Pluronic P123 and Pluronic F127 could be used as cosolvents to improve the solubility of lipophilic molecules in aqueous medium. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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14 pages, 2050 KiB  
Article
The Effect of Xanthohumol Derivatives on Apoptosis Induction in Canine Lymphoma and Leukemia Cell Lines
by Małgorzata Grudzień, Aleksandra Pawlak, Tomasz Tronina, Justyna Kutkowska, Angelika Kruszyńska, Jarosław Popłoński, Ewa Huszcza and Andrzej Rapak
Int. J. Mol. Sci. 2023, 24(14), 11724; https://doi.org/10.3390/ijms241411724 - 21 Jul 2023
Cited by 1 | Viewed by 1287
Abstract
Xanthohumol is a cancer chemopreventive agent that can interfere with the initiation, promotion, and progression phase of carcinogenesis via a variety of inhibitory mechanisms. Xanthohumol was reported as an effective agent against leukemia/lymphoma cells. In the present study, we investigated the effect of [...] Read more.
Xanthohumol is a cancer chemopreventive agent that can interfere with the initiation, promotion, and progression phase of carcinogenesis via a variety of inhibitory mechanisms. Xanthohumol was reported as an effective agent against leukemia/lymphoma cells. In the present study, we investigated the effect of xanthohumol and its natural and semisynthetic derivatives against various canine leukemia/lymphoma cell lines. Xanthohumol, three hops minor prenylflavonoids (xanthohumol C, xanthohumol D, α,β-dihydroxanthohumol) and four derivatives obtained by biotransformation (xanthohumol 4′-O-β-D-(4‴-O-methyl)-glucopyranoside) as well as by chemical modification (1″,2″-dihydroxanthohumol K, 2,3-dehydroisoxanthohumol, (Z)-6,4′-dihydroxy-4-methoxy-7-prenylaurone) were tested for their antiproliferative and pro-apoptotic activities against the following canine leukemia/lymphoma cell lines: CLBL-1 (B-cell lymphoma), CLB70 (B-cell leukemia), and GL-1 (B-cell leukemia). The compounds were tested at a final concentration range of 0.1–30 µM for 48 h. All eight of the tested flavonoids exerted concentration-dependent cytotoxicity in the selected canine lymphoma/leukemia cell lines. Three compounds markedly decreased the viability of all cell lines with IC50 in the range of 0.5 to 8 μM. Double-staining of the treated cells with AnnexinV and propidium iodide revealed that the dying cells were mostly in the late apoptosis stage. ROS production and changes in mitochondrial potential were detected. Western blot analysis showed a decreased expression of Bcl-2. Canine lymphoma and leukemia cell lines are sensitive to xanthohumol derivatives, and the compounds acted through an apoptotic cell-death mechanism. These compounds, either used alone or in combination with other therapies, may be useful for the treatment of canine leukemia/lymphoma. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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20 pages, 3992 KiB  
Article
Use of Enzymatically Activated Carbon Monoxide Donors for Sensitizing Drug-Resistant Tumor Cells
by Federica Sodano, Barbara Rolando, Loretta Lazzarato, Costanzo Costamagna, Mariacristina Failla, Chiara Riganti and Konstantin Chegaev
Int. J. Mol. Sci. 2023, 24(14), 11258; https://doi.org/10.3390/ijms241411258 - 09 Jul 2023
Cited by 1 | Viewed by 1030
Abstract
The application of gaseous signaling molecules like NO, H2S or CO to overcome the multidrug resistance in cancer treatment has proven to be a viable therapeutic strategy. The development of CO-releasing molecules (CORMs) in a controlled manner and in targeted tissues [...] Read more.
The application of gaseous signaling molecules like NO, H2S or CO to overcome the multidrug resistance in cancer treatment has proven to be a viable therapeutic strategy. The development of CO-releasing molecules (CORMs) in a controlled manner and in targeted tissues remains a challenge in medicinal chemistry. In this paper, we describe the design, synthesis and chemical and enzymatic stability of a novel non-metal CORM (1) able to release intracellularly CO and, simultaneously, facilitate fluorescent degradation of products under the action of esterase. The toxicity of 1 against different human cancer cell lines and their drug-resistant counterparts, as well as the putative mechanism of toxicity were investigated. The drug-resistant cancer cell lines efficiently absorbed 1 and 1 was able to restore their sensitivity vs. chemotherapeutic drugs by causing a CO-dependent mitochondrial oxidative stress that culminated in mitochondrial-dependent apoptosis. These results demonstrate the importance of CORMs in cases where conventional chemotherapy fails and thus open the horizons towards new combinatorial strategies to overcome multidrug resistance. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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9 pages, 3290 KiB  
Article
Synthetic Study of Natural Metabolites Containing a Benzo[c]oxepine Skeleton: Heterocornol C and D
by Ján Gettler, Tomáš Čarný, Martin Markovič, Peter Koóš, Erika Samoľová, Ján Moncoľ and Tibor Gracza
Int. J. Mol. Sci. 2023, 24(12), 10331; https://doi.org/10.3390/ijms241210331 - 19 Jun 2023
Cited by 1 | Viewed by 741
Abstract
A versatile strategy for the enantioselective synthesis of a benzo[c]oxepine structural core containing natural secondary metabolites was developed. The key steps of the synthetic approach include ring-closing alkene metathesis for seven-member ring construction, the Suzuki–Miyaura cross-coupling reaction for the installation of [...] Read more.
A versatile strategy for the enantioselective synthesis of a benzo[c]oxepine structural core containing natural secondary metabolites was developed. The key steps of the synthetic approach include ring-closing alkene metathesis for seven-member ring construction, the Suzuki–Miyaura cross-coupling reaction for the installation of the double bond and Katsuki–Sharpless asymmetric epoxidation for the introduction of chiral centers. The first total synthesis and absolute configuration assignment of heterocornol D (3a) were achieved. Four stereoisomers, 3a, ent-3a, 3b and ent-3b, of this natural polyketide were prepared, starting with 2,6-dihydroxy benzoic acid and divinyl carbinol. The absolute and relative configuration of heterocornol D was assigned via single-crystal X-ray analysis. The extension of the described synthetic approach is further presented with the synthesis of heterocornol C by applying the ether group reduction method to the lactone. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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16 pages, 3021 KiB  
Article
A New, Convenient Way to Fully Substituted α,β-Unsaturated γ-Hydroxy Butyrolactams
by Alexander V. Aksenov, Dmitrii A. Aksenov, Igor A. Kurenkov, Alexander V. Leontiev and Nicolai A. Aksenov
Int. J. Mol. Sci. 2023, 24(12), 10213; https://doi.org/10.3390/ijms241210213 - 16 Jun 2023
Cited by 1 | Viewed by 731
Abstract
The synthesis of novel, highly functionalized 5-hydroxy 3-pyrrolin-2-ones via a two-step procedure involving an addition reaction between KCN and corresponding chalcones, followed by ring condensation of the obtained β-cyano ketones with het(aryl)aldehydes under basic conditions is described. This protocol enables the preparation of [...] Read more.
The synthesis of novel, highly functionalized 5-hydroxy 3-pyrrolin-2-ones via a two-step procedure involving an addition reaction between KCN and corresponding chalcones, followed by ring condensation of the obtained β-cyano ketones with het(aryl)aldehydes under basic conditions is described. This protocol enables the preparation of various 3,5-di-aryl/heteroaryl-4-benzyl substituted α,β-unsaturated γ-hydroxy butyrolactams, which are subjects of significant interest to synthetic organic and medicinal chemistry. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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30 pages, 2735 KiB  
Article
Synthesis and hLDH Inhibitory Activity of Analogues to Natural Products with 2,8-Dioxabicyclo[3.3.1]nonane Scaffold
by Sofía Salido, Alfonso Alejo-Armijo and Joaquín Altarejos
Int. J. Mol. Sci. 2023, 24(12), 9925; https://doi.org/10.3390/ijms24129925 - 08 Jun 2023
Cited by 1 | Viewed by 1102
Abstract
Human lactate dehydrogenase (hLDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, hLDHA and hLDHB are the predominant ones. In the last few years, hLDHA has emerged as a therapeutic target for [...] Read more.
Human lactate dehydrogenase (hLDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, hLDHA and hLDHB are the predominant ones. In the last few years, hLDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. hLDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new hLDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives (4270) by reaction between flavylium salts (2735) and several nucleophiles (3641). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC50 values lower than 10 µM against hLDHA and better activity than our previously reported compound 2. In order to know the selectivity of the synthesized compounds against hLDHA, their hLDHB inhibitory activities were also measured. In particular, compounds 58, 62a, 65b, and 68a have shown the lowest IC50 values against hLDHA (3.6–12.0 µM) and the highest selectivity rate (>25). Structure–activity relationships have been deduced. Kinetic studies using a Lineweaver–Burk double-reciprocal plot have indicated that both enantiomers of 68a and 68b behave as noncompetitive inhibitors on hLDHA enzyme. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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15 pages, 2106 KiB  
Article
Synthesis and Evaluation on the Fungicidal Activity of S-Alkyl Substituted Thioglycolurils
by Ekaterina E. Vinogradova, Anna L. Alekseenko, Sergey V. Popkov, Natalya G. Kolotyrkina, Angelina N. Kravchenko and Galina A. Gazieva
Int. J. Mol. Sci. 2023, 24(6), 5756; https://doi.org/10.3390/ijms24065756 - 17 Mar 2023
Cited by 3 | Viewed by 1255
Abstract
A series of S-alkyl substituted thioglycolurils was prepared through the alkylation of corresponding thioglycolurils with halogenoalkanes and tested for their fungicidal activity against six phytopathogenic fungi from different taxonomic classes: Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris [...] Read more.
A series of S-alkyl substituted thioglycolurils was prepared through the alkylation of corresponding thioglycolurils with halogenoalkanes and tested for their fungicidal activity against six phytopathogenic fungi from different taxonomic classes: Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum, and two pathogenic yeasts: Candida albicans and Cryptococcus neoformans var. grubii. A number of S-alkyl substituted thioglycolurils exhibited high activity against Venturia inaequalis and Rhizoctonia solani (85–100% mycelium growth inhibition), and moderate activity against other phytopathogens. S-Ethyl substituted thioglycolurils possessed a high activity against Candida albicans. Additionally, the hemolytic and cytotoxic properties of promising derivatives were determined using human red blood cells and human embryonic kidney cells, respectively. Two S-ethyl derivatives possessed both low cytotoxicity against normal human cells and high fungicidal activity against Candida albicans. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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17 pages, 2248 KiB  
Article
[4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones
by Dmitry E. Shybanov, Maxim E. Kukushkin, Yanislav S. Hrytseniuk, Yuri K. Grishin, Vitaly A. Roznyatovsky, Viktor A. Tafeenko, Dmitry A. Skvortsov, Nikolai V. Zyk and Elena K. Beloglazkina
Int. J. Mol. Sci. 2023, 24(5), 5037; https://doi.org/10.3390/ijms24055037 - 06 Mar 2023
Cited by 3 | Viewed by 1425
Abstract
Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels–Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe [...] Read more.
Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels–Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI2 is an effective catalyst in the Diels–Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH2Cl or Boc2O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH2Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H2O2 or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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19 pages, 4479 KiB  
Article
Obtaining Highly Active Catalytic Antibodies Capable of Enzymatically Cleaving Antigens
by Tamami Nonaka, Hiroaki Taguchi, Taizo Uda and Emi Hifumi
Int. J. Mol. Sci. 2022, 23(22), 14351; https://doi.org/10.3390/ijms232214351 - 18 Nov 2022
Cited by 2 | Viewed by 1326
Abstract
A catalytic antibody has multiple functions compared with a monoclonal antibody because it possesses unique features to digest antigens enzymatically. Therefore, many catalytic antibodies, including their subunits, have been produced since 1989. The catalytic activities often depend on the preparation methods and conditions. [...] Read more.
A catalytic antibody has multiple functions compared with a monoclonal antibody because it possesses unique features to digest antigens enzymatically. Therefore, many catalytic antibodies, including their subunits, have been produced since 1989. The catalytic activities often depend on the preparation methods and conditions. In order to elicit the high catalytic activity of the antibodies, the most preferable methods and conditions, which can be generally applicable, must be explored. Based on this view, systematic experiments using two catalytic antibody light chains, #7TR and H34, were performed by varying the purification methods, pH, and chemical reagents. The experimental results obtained by peptidase activity tests and kinetic analysis, revealed that the light chain’s high catalytic activity was observed when it was prepared under a basic condition. These data imply that a small structural modulation of the catalytic antibody occurs during the purification process to increase the catalytic activity while the antigen recognition ability is kept constant. The presence of NaCl enhanced the catalytic activity. When the catalytic light chain was prepared with these preferable conditions, #7TR and H34 hugely enhanced the degradation ability of Amyloid-beta and PD-1 peptide, respectively. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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37 pages, 3734 KiB  
Article
Synthesis, Anticancer and Antitubercular Properties of New Chalcones and Their Nitrogen-Containing Five-Membered Heterocyclic Hybrids Bearing Sulfonamide Moiety
by Lina Fernanda Castaño, Jairo Quiroga, Rodrigo Abonia, Daniel Insuasty, Oscar M. Vidal, Rosalia Seña, Vivian Rubio, Gloria Puerto, Manuel Nogueras, Justo Cobo, Juan Guzman, Alberto Insuasty and Braulio Insuasty
Int. J. Mol. Sci. 2022, 23(20), 12589; https://doi.org/10.3390/ijms232012589 - 20 Oct 2022
Cited by 9 | Viewed by 2288
Abstract
A new series of sulfonamides, 8a-b, 10, 12, and 14a-b, were synthesized by N-sulfonation reaction with sulfonyl chlorides 6a-b. Five new series of chalcone-sulfonamide hybrids (16-20)a-f were prepared via Claisen–Schmidt condensation of the newly obtained sulfonamides with aromatic aldehydes [...] Read more.
A new series of sulfonamides, 8a-b, 10, 12, and 14a-b, were synthesized by N-sulfonation reaction with sulfonyl chlorides 6a-b. Five new series of chalcone-sulfonamide hybrids (16-20)a-f were prepared via Claisen–Schmidt condensation of the newly obtained sulfonamides with aromatic aldehydes 15a-f in basic medium. Chalcones substituted with chlorine at position 4 of each series were used as precursors for the generation of their five-membered heterocyclic pyrazoline (22-23)a-d, (24-25)a-b and carbothioamide 27a-f derivatives. The synthesized compounds were evaluated for their anticancer and antituberculosis activities. To determine their anticancer activity, compounds were screened against sixty human cancer cell lines at a single dose (10 μM). Compounds 17a-c were highly active against LOX IMVI (melanoma), with IC50 values of 0.34, 0.73 and 0.54 μM, respectively. Chalcone 18e showed remarkable results against the entire panel of leukemia cell lines with IC50 values between 0.99–2.52 μM. Moreover, compounds 20e and 20f displayed growth inhibition of Mycobacterium tuberculosis H37Rv at concentrations below 10 μM. Although they showed low selectivity in cytotoxicity tests against the Vero cell line, further optimization could advance the potential biological activity of the selected compounds. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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Review

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36 pages, 22711 KiB  
Review
Recent Developments in the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors Incorporating Pyridine Moiety
by Alexey M. Starosotnikov and Maxim A. Bastrakov
Int. J. Mol. Sci. 2023, 24(11), 9314; https://doi.org/10.3390/ijms24119314 - 26 May 2023
Cited by 3 | Viewed by 1625
Abstract
Human immunodeficiency virus (HIV) causes one of the most dangerous diseases—acquired immunodeficiency syndrome (AIDS). An estimated about 40 million people are currently living with HIV worldwide, most of whom are already on antiretroviral therapy. This makes the development of effective drugs to combat [...] Read more.
Human immunodeficiency virus (HIV) causes one of the most dangerous diseases—acquired immunodeficiency syndrome (AIDS). An estimated about 40 million people are currently living with HIV worldwide, most of whom are already on antiretroviral therapy. This makes the development of effective drugs to combat this virus very relevant. Currently, one of the dynamically developing areas of organic and medicinal chemistry is the synthesis and identification of new compounds capable of inhibiting HIV-1 integrase—one of the HIV enzymes. A significant number of studies on this topic are published annually. Many compounds inhibiting integrase incorporate pyridine core. Therefore, this review is an analysis of the literature on the methods for the synthesis of pyridine-containing HIV-1 integrase inhibitors since 2003 to the present. Full article
(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)
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