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Special Issue "Heterocycles in Medicinal Chemistry"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 May 2019).

Special Issue Editor

Prof. Dr. Josef Jampilek
Website
Guest Editor
1. Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
2. Regional Centre of Advanced Technologies and Materials, Palacky University, Olomouc, Czech Republic
Interests: medicinal chemistry; drug design; structure-activity relationships; pharmaceutical analysis; polymorphism; drug bioavailability; ADME; nanoparticles; nanoformulations; controlled/targeted delivery
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Special Issue Information

Dear Colleagues,

Heteroatoms constitute a very common fragment of a number of active pharmaceutical ingredients, as well as excipients; from the point of view of significance, it is all the same if these are isosterically/bioisosterically replaced carbons/carbon substructures in aliphatic structures or real heterocycles. Many heterocyclic scaffolds can be considered as privilege structures. Most frequently, nitrogen heterocycles or various positional combinations of nitrogen atoms, sulphur and oxygen in five- or six-membered rings can be found. According to statistics, more than 85% of all biologically-active chemical entities contain a heterocycle. This fact reflects the central role of heterocycles in modern drug design. The application of heterocycles provides a useful tool for modification of solubility, lipophilicity, polarity and hydrogen bonding capacity of biologically active agents, which results in the optimization of the ADME/Tox properties of drugs or drug candidates. The increasing presence of various heterocycles in drugs is related to advances in synthetic methodologies, such as metal-catalysed cross-coupling and hetero-coupling reactions, that allow rapid access to a wide variety of functionalized heterocycles. On the other hand, many heterocyclic lead compounds were isolated from natural resources, and their structures were subsequently simplified and modified by medicinal chemists. Thus, heterocycles have critical importance for medicinal chemists, because using them, it is possible to expand the available drug-like chemical space and drive more effective drug discovery programs. As medicinal chemistry is “a chemistry-based discipline, also involving aspects of biological, medical and pharmaceutical sciences” and “concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure-activity relationships”, this Special Issue of Molecules titled “Heterocycles in Medicinal Chemistry” is devoted to the following research topics focused on heterocycles: (i) synthesis and analysis; (ii) natural compounds; (iii) carbohydrates; (iv) drug design; (v) in silico investigations; (vi) biological screening; (vii) chemical biology and biological chemistry; (vii) biomaterials; and in general, other topics related to heterocycles.

Prof. Dr. Josef Jampilek
Guest Editor

Manuscript Submission Information

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Keywords

  • drugs
  • heterocycles
  • pharmacophore
  • drug design
  • computer study
  • synthesis
  • analysis
  • natural compounds
  • carbohydrates
  • physicochemical properties
  • ADMET
  • biological screening
  • chemical biology
  • biological chemistry
  • biomaterials

Published Papers (20 papers)

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Editorial

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Open AccessEditorial
Heterocycles in Medicinal Chemistry
Molecules 2019, 24(21), 3839; https://doi.org/10.3390/molecules24213839 - 25 Oct 2019
Cited by 1
Abstract
Heteroatoms constitute a very common fragment of a number of active pharmaceutical ingredients as well as excipients; from the point of view of significance, it is all the same if these are isosterically/bioisosterically replaced carbons/carbon substructures in aliphatic structures or real heterocycles [...] [...] Read more.
Heteroatoms constitute a very common fragment of a number of active pharmaceutical ingredients as well as excipients; from the point of view of significance, it is all the same if these are isosterically/bioisosterically replaced carbons/carbon substructures in aliphatic structures or real heterocycles [...] Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)

Research

Jump to: Editorial, Review

Open AccessArticle
Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics
Molecules 2019, 24(17), 3121; https://doi.org/10.3390/molecules24173121 - 28 Aug 2019
Cited by 1
Abstract
Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML [...] Read more.
Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
Open AccessArticle
Fluorimetric Properties of 3-Aminoflavone Biomolecule (3-AF). X-ray Crystal Structure of New Polymorph of 3-AF
Molecules 2019, 24(16), 2927; https://doi.org/10.3390/molecules24162927 - 13 Aug 2019
Cited by 1
Abstract
The crystal structure of the new polymorphic form of 3-aminoflavone (3-AF) has been determined by single crystal X-ray diffraction. This report presents results of fluorimetric studies on 3-AF in methanol and aquatic solvents. Based on 3D fluorescence emission spectra, optimal values for excitation [...] Read more.
The crystal structure of the new polymorphic form of 3-aminoflavone (3-AF) has been determined by single crystal X-ray diffraction. This report presents results of fluorimetric studies on 3-AF in methanol and aquatic solvents. Based on 3D fluorescence emission spectra, optimal values for excitation (λex) and emission/analytical (λem) wavelength, the analytical concentration range as well as the range of concentration quenching for the studied compound were established. Moreover, the limit of detection (LOD) and the limit of quantification (LOQ) were determined. The results were compared with those obtained using the standard UV-Vis absorption spectrophotometric method. The effect of acidity (pH) and the concentration of halide anions (chlorides, bromides, iodides and fluorides) on fluorescence quenching were analysed. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Dihydrogen Bond in the Aminoborane Complex of a Nicergoline Intermediate
Molecules 2019, 24(14), 2548; https://doi.org/10.3390/molecules24142548 - 12 Jul 2019
Cited by 1
Abstract
An aminoborane side product from the nicergoline manufacture process was identified by single-crystal X-ray diffraction. As boranes of pharmaceutical molecules are quite rare, the binding potential of the BH3 group was investigated and compared with similar compounds using Cambridge Structural Database (CSD). [...] Read more.
An aminoborane side product from the nicergoline manufacture process was identified by single-crystal X-ray diffraction. As boranes of pharmaceutical molecules are quite rare, the binding potential of the BH3 group was investigated and compared with similar compounds using Cambridge Structural Database (CSD). Surprisingly, the packing was stabilized by a dihydrogen bond, which triggered a false alert for too-short contact of hydrogen atoms in IUCR checkCIF. As the dihydrogen bond concept is not widely known, such an alert might mislead crystallographers to force –CH3 optimal geometry to –BH3 groups. The B–H distances equal to or less than 1.0 Å (17% of the CSD structures) are substantially biased when analyzing the structures of aminoborane complexes in CSD. To conduct proper searching, B–H bond length normalization should be applied in the CSD search. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Synthesis and AChE Inhibitory Activity of Novel Thiazolylhydrazone Derivatives
Molecules 2019, 24(13), 2392; https://doi.org/10.3390/molecules24132392 - 28 Jun 2019
Cited by 3
Abstract
Alzheimer’s disease (AD) is the most common of the degenerative brain diseases and is described together with the impairment of cognitive function. Patients with AD lose the capability to code new memories, and life conditions are extremely difficult. The development of new drugs [...] Read more.
Alzheimer’s disease (AD) is the most common of the degenerative brain diseases and is described together with the impairment of cognitive function. Patients with AD lose the capability to code new memories, and life conditions are extremely difficult. The development of new drugs in this area continues at a great pace. A novel series of thiazole-piperazine hybrids, aimed against Alzheimer’s disease (AD), have been synthesized. The structure identification of synthesized compounds was elucidated by 1HNMR, 13C-NMR, and LCMSMS spectroscopic methods. The inhibitory potential of the synthesized compounds on cholinesterase enzymes was investigated. The compounds 3a, 3c and 3i showed significant inhibitory activity on the acetylcholinesterase (AChE) enzyme. On the other hand, none of the compounds showed significant inhibitory activity on the butyrylcholinesterase (BChE) enzyme. In addition to enzyme inhibition studies, enzyme kinetic studies were performed to observe the effects of the most active inhibitor compounds on the substrate–enzyme relationship. In addition to in vitro tests, docking studies also indicated that compound 3c potentially acts as a dual binding site AChE inhibitor. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Screening of Phenanthroquinolizidine Alkaloid Derivatives for Inducing Cell Death of L1210 Leukemia Cells with Negative and Positive P-glycoprotein Expression
Molecules 2019, 24(11), 2127; https://doi.org/10.3390/molecules24112127 - 05 Jun 2019
Cited by 2
Abstract
We describe the screening of a set of cryptopleurine derivatives, namely thienoquinolizidine derivatives and (epi-)benzo analogs with bioactive phenanthroquinolizidine alkaloids that induce cytotoxic effects in the mouse lymphocytic leukemia cell line L1210. We used three variants of L1210 cells: i) parental cells (S) [...] Read more.
We describe the screening of a set of cryptopleurine derivatives, namely thienoquinolizidine derivatives and (epi-)benzo analogs with bioactive phenanthroquinolizidine alkaloids that induce cytotoxic effects in the mouse lymphocytic leukemia cell line L1210. We used three variants of L1210 cells: i) parental cells (S) negative for P-glycoprotein (P-gp) expression; ii) P-glycoprotein positive cells (R), obtained by selection with vincristine; iii) P-glycoprotein positive cells (T), obtained by stable transfection with a human gene encoding P-glycoprotein. We identified the most effective derivative 11 with a median lethal concentration of ≈13 μM in all three L1210 cell variants. The analysis of the apoptosis/necrosis induced by derivative 11 revealed that cell death was the result of apoptosis with late apoptosis characteristics. Derivative 11 did not induce a strong alteration in the proportion of cells in the G1, S or G2/M phase of the cell cycle, but a strong increase in the number of S, R and T cells in the subG1 phase was detected. These findings indicated that we identified the most effective inducer of cell death, derivative 11, and this derivative effectively induced cell death in S, R and T cells at similar inhibitory concentrations independent of P-gp expression. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
A Study of 5-Fluorouracil Desorption from Mesoporous Silica by RP-UHPLC
Molecules 2019, 24(7), 1317; https://doi.org/10.3390/molecules24071317 - 03 Apr 2019
Cited by 2
Abstract
In cancer treatment, the safe delivery of the drug to the target tissue is an important task. 5-fluorouracil (5-FU), the well-known anticancer drug, was encapsulated into the pores of unmodified mesoporous silica SBA-15, as well as silica modified with 3-aminopropyl and cyclohexyl groups. [...] Read more.
In cancer treatment, the safe delivery of the drug to the target tissue is an important task. 5-fluorouracil (5-FU), the well-known anticancer drug, was encapsulated into the pores of unmodified mesoporous silica SBA-15, as well as silica modified with 3-aminopropyl and cyclohexyl groups. The drug release studies were performed in two different media, in a simulated gastric fluid (pH = 2) and in a simulated body fluid (pH = 7) by RP-UHPLC. The simple and rapid RP-UHPLC method for quantitative determination of 5-fluorouracil released from unmodified and modified mesoporous silica SBA-15 was established on ODS Hypersil C18 column (150 × 4.6 mm, 5 µm) eluted with mobile phase consisted of methanol: phosphate buffer in volume ratio of 3:97 (v/v). Separation was achieved by isocratic elution. The flow rate was kept at 1 mL/min, the injection volume was set at 20 µL and the column oven temperature was maintained at 25 °C. The effluent was monitored at 268 nm. This paper provides information about the quantitative determination of the released 5-FU from silica. It was found out that larger amount of the drug was released in neutral pH in comparison with the acidic medium. In addition, surface functionalisation of silica SBA-15 influences the release properties of the drug. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Design, Synthesis, and Biological Evaluation of Novel Nitrogen Heterocycle-Containing Ursolic Acid Analogs as Antitumor Agents
Molecules 2019, 24(5), 877; https://doi.org/10.3390/molecules24050877 - 01 Mar 2019
Cited by 1
Abstract
Nineteen ursolic acid analogues were designed, synthesized, and evaluated for their antiproliferative activity against the Hela and MKN45 cell lines. Some compounds containing a piperazine moiety displayed moderate to high levels of antitumor activities against the tested cancer cell lines. The most potent [...] Read more.
Nineteen ursolic acid analogues were designed, synthesized, and evaluated for their antiproliferative activity against the Hela and MKN45 cell lines. Some compounds containing a piperazine moiety displayed moderate to high levels of antitumor activities against the tested cancer cell lines. The most potent compound shares the IC50 value of 2.1 µM and 2.6 µM for the Hela and MKN45 cell lines, respectively. Further mechanism studies and in vivo antitumor studies have shown that it decreased the apoptosis regulator (BCL2/BAX) ratio, disrupted mitochondrial potential and induced apoptosis, and suppressed the growth of Hela xenografts in nude mice. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Synthesis and Biological Evaluation of Novel Thiazolyl-Coumarin Derivatives as Potent Histone Deacetylase Inhibitors with Antifibrotic Activity
Molecules 2019, 24(4), 739; https://doi.org/10.3390/molecules24040739 - 19 Feb 2019
Cited by 1
Abstract
New histone deacetylases (HDAC) inhibitors with low toxicity to non-cancerous cells, are a prevalent issue at present because these enzymes are actively involved in fibrotic diseases. We designed and synthesized a novel series of thiazolyl-coumarins, substituted at position 6 (R = H, Br, [...] Read more.
New histone deacetylases (HDAC) inhibitors with low toxicity to non-cancerous cells, are a prevalent issue at present because these enzymes are actively involved in fibrotic diseases. We designed and synthesized a novel series of thiazolyl-coumarins, substituted at position 6 (R = H, Br, OCH3), linked to classic zinc binding groups, such as hydroxamic and carboxylic acid moieties and alternative zinc binding groups such as disulfide and catechol. Their in vitro inhibitory activities against HDACs were evaluated. Disulfide and hydroxamic acid derivatives were the most potent ones. Assays with neonatal rat cardiac fibroblasts demonstrated low cytotoxic effects for all compounds. Regarding the parameters associated to cardiac fibrosis development, the compounds showed antiproliferative effects, and triggered a strong decrease on the expression levels of both α-SMA and procollagen I. In conclusion, the new thiazolyl-coumarin derivatives inhibit HDAC activity and decrease profibrotic effects on cardiac fibroblasts. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Position-Selective Synthesis and Biological Evaluation of Four Isomeric A-Ring Amino Derivatives of the Alkaloid Luotonin A
Molecules 2019, 24(4), 716; https://doi.org/10.3390/molecules24040716 - 16 Feb 2019
Cited by 6
Abstract
Following two orthogonal synthetic routes, a series of all four possible A-ring amino derivatives of the natural product Luotonin A (a known Topoisomerase I inhibitor) was synthesized. In both strategies, intramolecular cycloaddition reactions are the key step. The target compounds were obtained in [...] Read more.
Following two orthogonal synthetic routes, a series of all four possible A-ring amino derivatives of the natural product Luotonin A (a known Topoisomerase I inhibitor) was synthesized. In both strategies, intramolecular cycloaddition reactions are the key step. The target compounds were obtained in good yields by mild catalytic transfer hydrogenation of the corresponding nitro precursors. In-vitro evaluation of the antiproliferative activity towards human tumor cell lines revealed the 4-amino compound (5b) to be the most effective agent, showing an interesting profile of cytotoxic activity. Among other effects, a significant G2/M cell cycle arrest was observed for this compound, suggesting that either Topoisomerase I is not the only biological target, or that some atypical mechanism is responsible for inhibition of this enzyme. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Investigation of Permeation of Theophylline through Skin Using Selected Piperazine-2,5-Diones
Molecules 2019, 24(3), 566; https://doi.org/10.3390/molecules24030566 - 04 Feb 2019
Cited by 3
Abstract
Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical [...] Read more.
Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 °C and using full-thickness pig (Sus scrofa f. domestica) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (w/w) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3S,6S)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Synthesis, In Silico, and In Vitro Evaluation of Long Chain Alkyl Amides from 2-Amino-4-Quinolone Derivatives as Biofilm Inhibitors
Molecules 2019, 24(2), 327; https://doi.org/10.3390/molecules24020327 - 17 Jan 2019
Cited by 3
Abstract
Infection from multidrug resistant bacteria has become a growing health concern worldwide, increasing the need for developing new antibacterial agents. Among the strategies that have been studied, biofilm inhibitors have acquired relevance as a potential source of drugs that could act as a [...] Read more.
Infection from multidrug resistant bacteria has become a growing health concern worldwide, increasing the need for developing new antibacterial agents. Among the strategies that have been studied, biofilm inhibitors have acquired relevance as a potential source of drugs that could act as a complement for current and new antibacterial therapies. Based on the structure of 2-alkyl-3-hydroxy-4-quinolone and N-acylhomoserine lactone, molecules that act as mediators of quorum sensing and biofilm formation in Pseudomonas aeruginosa, we designed, prepared, and evaluated the biofilm inhibition properties of long chain amide derivatives of 2-amino-4-quinolone in Staphylococcus aureus and P. aeruginosa. All compounds had higher biofilm inhibition activity in P. aeruginosa than in S. aureus. Particularly, compounds with an alkyl chain of 12 carbons exhibited the highest inhibition of biofilm formation. Docking scores and molecular dynamics simulations of the complexes of the tested compounds within the active sites of proteins related to quorum sensing had good correlation with the experimental results, suggesting the diminution of biofilm formation induced by these compounds could be related to the inhibition of these proteins. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents
Molecules 2018, 23(11), 2913; https://doi.org/10.3390/molecules23112913 - 08 Nov 2018
Cited by 5
Abstract
Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-n-propyl-2-thiouracil (PTU). The previously solved X-ray crystal structure of the PTU bound to mammalian lactoperoxidase (LPO) reveals that the LPO-PTU binding site [...] Read more.
Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-n-propyl-2-thiouracil (PTU). The previously solved X-ray crystal structure of the PTU bound to mammalian lactoperoxidase (LPO) reveals that the LPO-PTU binding site is basically a hydrophobic channel. There are two hydrophobic side chains directed towards the oxygen atom in the C-4 position of the thiouracil ring. In the current study, the structural activity relationship (SAR) was performed on the thiouracil nucleus of PTU to target these hydrophobic side chains and gain more favorable interactions and, in return, more antithyroid activity. Most of the designed compounds show superiority over PTU in reducing the mean serum T4 levels of hyperthyroid rats by 3% to 60%. In addition, the effect of these compounds on the levels of serum T3 was found to be comparable to the effect of PTU treatment. The designed compounds in this study showed a promising activity profile in reducing levels of thyroid hormones and follow up experiments will be needed to confirm the use of the designed compounds as new potential antithyroid agents. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Synthesis of New Furothiazolo Pyrimido Quinazolinones from Visnagenone or Khellinone and Antimicrobial Activity
Molecules 2018, 23(11), 2793; https://doi.org/10.3390/molecules23112793 - 27 Oct 2018
Cited by 5
Abstract
Substituted-6-methyl-1-thioxo-1,2-dihydro-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-ones (5a,b) were synthesized from condensation of visnagenone (2a) or khellinone (2b) with 6-amino-thiouracil (3) in dimethylformamide or refluxing of (4a) or (4b) in dimethylformamide. Hence, compounds [...] Read more.
Substituted-6-methyl-1-thioxo-1,2-dihydro-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-ones (5a,b) were synthesized from condensation of visnagenone (2a) or khellinone (2b) with 6-amino-thiouracil (3) in dimethylformamide or refluxing of (4a) or (4b) in dimethylformamide. Hence, compounds (5a,b) were used as the starting materials for preparing many new heterocyclic compounds such as; furo[3,2-g]pyrimido[1,6-a]quinazoline (6a,b), furo[3,2-g]thiazolo[2′,3′:2,3]pyrimido[1,6-a]quinazolinone (7a,b), substituted-benzylidene-furo[3,2-g]thiazolo[2′,3′:2,3]pyrimido[1,6-a]quinazoline-3,5-dione (8af), 3-oxo-furo[3,2-g]pyrimido[1,6-a]quinazoline-pentane-2,4-dione (9a,b), 1-(pyrazole)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (10a,b), 2-(oxo or thioxo)-pyrimidine-furo[3,2-g]pyrimido[1,6-a]quinazolinone (11ad), 1-(methylthio)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (12a,b), 1-(methyl-sulfonyl)-furo[3,2-g]pyrimido[1,6-a]quinazolinone (13a,b) and 6-methyl-1-((piperazine) or morpholino)-3H-furo[3,2-g]pyrimido[1,6-a]quinazolin-3-one (14ad). The structures of the prepared compounds were elucidated on the basis of spectral data (IR, 1H-NMR, 13C-NMR, MS) and elemental analysis. Antimicrobial activity was evaluated for the synthesized compounds against Gram-positive, Gram-negative bacteria and fungi. The new compounds, furothiazolo pyrimido quinazolines 8af and 11ad displayed results excellent for growth inhibition of bacteria and fungi. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
New Nitrogen Compounds Coupled to Phenolic Units with Antioxidant and Antifungal Activities: Synthesis and Structure–Activity Relationship
Molecules 2018, 23(10), 2530; https://doi.org/10.3390/molecules23102530 - 03 Oct 2018
Cited by 3
Abstract
A selection of 1-amino-2-arylidenamine-1,2-(dicyano)ethenes 3 was synthesized and cyclized to 2-aryl-4,5-dicyano-1H-imidazoles 4 upon reflux in ethyl acetate/acetonitrile, in the presence of manganese dioxide. These compounds were tested for their antioxidant capacity by cyclic voltammetry, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and deoxyribose degradation assays. [...] Read more.
A selection of 1-amino-2-arylidenamine-1,2-(dicyano)ethenes 3 was synthesized and cyclized to 2-aryl-4,5-dicyano-1H-imidazoles 4 upon reflux in ethyl acetate/acetonitrile, in the presence of manganese dioxide. These compounds were tested for their antioxidant capacity by cyclic voltammetry, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and deoxyribose degradation assays. The minimum inhibitory concentration of all compounds was evaluated against two yeast species, Saccharomyces cerevisiae and Candida albicans. Their toxicity was tested in mammal fibroblasts. Among the synthesised compounds, two presented dual antioxidant/antifungal activity without toxic effects in fibroblasts. The new compounds synthesized in this work are potential biochemical tools and/or therapeutic drugs. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Dibasic Derivatives of Phenylcarbamic Acid against Mycobacterial Strains: Old Drugs and New Tricks?
Molecules 2018, 23(10), 2493; https://doi.org/10.3390/molecules23102493 - 28 Sep 2018
Cited by 3
Abstract
In order to provide a more detailed view on the structure–antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1ad)/dichlorides (1eh) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates ( [...] Read more.
In order to provide a more detailed view on the structure–antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1ad)/dichlorides (1eh) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1il)/dichlorides (1mp; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube’s stalagmometric method), electronic features (log ε; UV/Vis spectrophotometry) and lipophilic properties (log kw; isocratic RP-HPLC) as well. The experimental log kw dataset was studied together with computational logarithms of partition coefficients (log P) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and in silico lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The in vitro activity of compounds 1ap was inspected against Mycobacterium tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794, respectively), M. tuberculosis H37Ra ATCC 25177, M. kansasii CNCTC My 235/80 (identical with ATCC 12478), the M. kansasii 6509/96 clinical isolate, M. kansasii DSM 44162, M. avium CNCTC My 330/80 (identical with ATCC 25291), M. smegmatis ATCC 700084 and M. marinum CAMP 5644, respectively. In vitro susceptibility of the mycobacteria to reference drugs isoniazid, ethambutol, ofloxacin or ciprofloxacin was tested as well. A very unique aspect of the research was that many compounds from the set 1ap were highly efficient almost against all tested mycobacteria. The most promising derivatives showed MIC values varied from 1.9 μM to 8 μM, which were lower compared to those of used standards, especially if concerning ability to fight M. tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 or M. avium CNCTC My 330/80. Current in vitro biological assays and systematic SAR studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds 1ap represented a very promising molecular framework for development of ‘non-traditional’ but effective antimycobacterial agents. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Synthesis, Bacteriostatic and Anticancer Activity of Novel Phenanthridines Structurally Similar to Benzo[c]phenanthridine Alkaloids
Molecules 2018, 23(9), 2155; https://doi.org/10.3390/molecules23092155 - 27 Aug 2018
Cited by 3
Abstract
In this study, we report the synthesis, antibacterial and anticancer evaluation of 38 novel phenanthridines that were designed as analogs of the benzo[c]phenanthridine alkaloids. The prepared phenanthridines differ from the benzo[c]phenanthridines in the absence of a benzene A-ring. All [...] Read more.
In this study, we report the synthesis, antibacterial and anticancer evaluation of 38 novel phenanthridines that were designed as analogs of the benzo[c]phenanthridine alkaloids. The prepared phenanthridines differ from the benzo[c]phenanthridines in the absence of a benzene A-ring. All novel compounds were prepared from 6-bromo-2-hydroxy-3-methoxybenzaldehyde in several synthetic steps through reduction of Schiff bases and accomplished by radical cyclization. Twelve derivatives showed high antibacterial activity against Bacillus subtilis, Micrococcus luteus and/or Mycobacterium vaccae at single digit micromolar concentrations. Some compounds also displayed cytotoxicity against the K-562 and MCF-7 cancer cell lines at as low as single digit micromolar concentrations and were more potent than chelerythrine and sanguinarine. The active compounds caused cell-cycle arrest in cancer cells, increased levels of p53 protein and caused apoptosis-specific fragmentation of PARP-1. Biological activity was connected especially with the presence of the N-methyl quaternary nitrogen and 7-benzyloxy substitution (compounds 7i, 7j, 7k, and 7l) of phenanthridine. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessArticle
Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells
Molecules 2018, 23(8), 1996; https://doi.org/10.3390/molecules23081996 - 10 Aug 2018
Cited by 4
Abstract
Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 [...] Read more.
Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 13 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 13 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Review

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Open AccessReview
Bridged Nucleic Acids Reloaded
Molecules 2019, 24(12), 2297; https://doi.org/10.3390/molecules24122297 - 21 Jun 2019
Cited by 4
Abstract
Oligonucleotides are key compounds widely used for research, diagnostics, and therapeutics. The rapid increase in oligonucleotide-based applications, together with the progress in nucleic acids research, has led to the design of nucleotide analogs that, when part of these oligomers, enhance their efficiency, bioavailability, [...] Read more.
Oligonucleotides are key compounds widely used for research, diagnostics, and therapeutics. The rapid increase in oligonucleotide-based applications, together with the progress in nucleic acids research, has led to the design of nucleotide analogs that, when part of these oligomers, enhance their efficiency, bioavailability, or stability. One of the most useful nucleotide analogs is the first-generation bridged nucleic acids (BNA), also known as locked nucleic acids (LNA), which were used in combination with ribonucleotides, deoxyribonucleotides, or other analogs to construct oligomers with diverse applications. However, there is still room to improve their efficiency, bioavailability, stability, and, importantly, toxicity. A second-generation BNA, BNANC (2′-O,4′-aminoethylene bridged nucleic acid), has been recently made available. Oligomers containing these analogs not only showed less toxicity when compared to LNA-containing compounds but, in some cases, also exhibited higher specificity. Although there are still few applications where BNANC-containing compounds have been researched, the promising results warrant more effort in incorporating these analogs for other applications. Furthermore, newer BNA compounds will be introduced in the near future, offering great hope to oligonucleotide-based fields of research and applications. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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Open AccessReview
Cinnoline Scaffold—A Molecular Heart of Medicinal Chemistry?
Molecules 2019, 24(12), 2271; https://doi.org/10.3390/molecules24122271 - 18 Jun 2019
Cited by 2
Abstract
The cinnoline nucleus is a very important bicyclic heterocycle that is used as the structural subunit of many compounds with interesting pharmaceutical properties. Cinnoline derivatives exhibit broad spectrum of pharmacological activities such as antibacterial, antifungal, antimalarial, anti-inflammatory, analgesic, anxiolytic and antitumor activities. Some [...] Read more.
The cinnoline nucleus is a very important bicyclic heterocycle that is used as the structural subunit of many compounds with interesting pharmaceutical properties. Cinnoline derivatives exhibit broad spectrum of pharmacological activities such as antibacterial, antifungal, antimalarial, anti-inflammatory, analgesic, anxiolytic and antitumor activities. Some of them are under evaluation in clinical trials. In the present review, we have compiled studies focused on the biological properties of cinnoline derivatives conducted by many research groups worldwide between 2005 and 2019. Comprehensive and target oriented information clearly indicate that the development of cinnoline based molecules constitute a significant contribution to the identification of lead compounds with optimized pharmacodynamic and pharmacokinetic properties. Full article
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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