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11 pages, 11417 KiB

Open AccessArticle

7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries Are Potent and Selective Inhibitors of DNA Methyltransferase 1

by José L. Medina-Franco, Edgar López-López and Liliam P. Martínez-Fernández

Molecules 2022, 27(9), 2892; https://doi.org/10.3390/molecules27092892 - 30 Apr 2022

Cited by 6 | Viewed by 2929

Abstract

Inhibitors of epigenetic writers such as DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug and probe discovery. To advance epigenetic probes and drug discovery, chemical companies are developing focused libraries for epigenetic targets. Based on a knowledge-based approach, herein we report the [...] Read more.

Inhibitors of epigenetic writers such as DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug and probe discovery. To advance epigenetic probes and drug discovery, chemical companies are developing focused libraries for epigenetic targets. Based on a knowledge-based approach, herein we report the identification of two quinazoline-based derivatives identified in focused libraries with sub-micromolar inhibition of DNMT1 (30 and 81 nM), more potent than S-adenosylhomocysteine. Also, both compounds had a low micromolar affinity of DNMT3A and did not inhibit DNMT3B. The enzymatic inhibitory activity of DNMT1 and DNMT3A was rationalized with molecular modeling. The quinazolines reported in this work are known to have low cell toxicity and be potent inhibitors of the epigenetic target G9a. Therefore, the quinazoline-based compounds presented are attractive not only as novel potent inhibitors of DNMTs but also as dual and selective epigenetic agents targeting two families of epigenetic writers. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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17 pages, 7189 KiB

Open AccessArticle

Antibacterial Activity of a Novel Oligosaccharide from Streptomyces californics against Erwinia carotovora subsp. Carotovora

by Maysoon Abdulrahman Al-Zubairy, Khaled Hussein, Salwa H. Alkhyat, Abdullah Yahya Al-Mahdi, Saeed Munassar Alghalibi, Adel Ali Al-Gheethi, Muhanna Mohammed Al-Shaibani, Hesham Ali El Enshasy and Nik Marzuki Sidik

Molecules 2022, 27(8), 2384; https://doi.org/10.3390/molecules27082384 - 7 Apr 2022

Cited by 2 | Viewed by 1909

Abstract

The present study aims to characterize and predict models for antibacterial activity of a novel oligosaccharide from Streptomyces californics against Erwinia carotovora subsp. carotovora using an adaptive neuro-fuzzy inference system and an artificial neural network. The mathematical predication models were used to determine [...] Read more.

The present study aims to characterize and predict models for antibacterial activity of a novel oligosaccharide from Streptomyces californics against Erwinia carotovora subsp. carotovora using an adaptive neuro-fuzzy inference system and an artificial neural network. The mathematical predication models were used to determine the optimal conditions to produce oligosaccharide and determine the relationship between the factors (pH, temperature, and time). The characteristics of the purified antibacterial agent were determined using ultraviolet spectroscopy (UV/Vis), infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (¹H- and ¹³C-NMR), and mass spectrometry (MS). The best performances for the model were 39.45 and 35.16 recorded at epoch 1 for E. carotovora Erw₅ and E. carotovora EMCC 1687, respectively. The coefficient (R²) of the training was more than 0.90. The highest antimicrobial production was recorded after 9 days at 25 °C and a pH of 6.2, at which more than 17 mm of the inhibition zone was obtained. The mass spectrum of antimicrobial agent (peak at R.T. = 3.433 of fraction 6) recorded two molecular ion peaks at m/z = 703.70 and m/z = 338.30, corresponding to molecular weights of 703.70 and 338.30 g/mol, respectively. The two molecular ion peaks matched well with the molecular formulas C₂₉H₅₃NO₁₈ and C₁₄H₂₆O₉, respectively, which were obtained from the elemental analysis result. A novel oligosaccharide from Streptomyces californics with potential activity against E. carotovora EMCC 1687 and E. carotovora Erw₅ was successfully isolated, purified, and characterized. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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10 pages, 1739 KiB

Open AccessArticle

The Effect of Beta Adrenoreceptor Blockers on Viability and Cell Colony Formation of Non-Small Cell Lung Cancer Cell Lines A549 and H1299

by Marina Sidorova and Vilma Petrikaitė

Molecules 2022, 27(6), 1938; https://doi.org/10.3390/molecules27061938 - 17 Mar 2022

Cited by 8 | Viewed by 2952

Abstract

Beta adrenoblockers are a large class of drugs used to treat cardiovascular diseases, migraines, glaucoma and hyperthyroidism. Over the last couple of decades, the anticancer effects of these compounds have been extensively studied. However, the exact mechanism is still not known, and more [...] Read more.

Beta adrenoblockers are a large class of drugs used to treat cardiovascular diseases, migraines, glaucoma and hyperthyroidism. Over the last couple of decades, the anticancer effects of these compounds have been extensively studied. However, the exact mechanism is still not known, and more detailed studies are required. The aim of our study was to evaluate the anticancer activity of beta adrenoblockers in non-small cell lung cancer cell lines A549 and H1299. In order to find the relationship with their selectivity to beta adrenoreceptors, selective (atenolol, betaxolol, esmolol, metoprolol) and non-selective (pindolol, propranolol and timolol) beta blockers were tested. The effect on cell viability was evaluated by MTT assay, and the activity on cell ability to form colonies was tested by clonogenic assay. The type of cell death was evaluated by cell double staining with Hoechst 33342 and Propidium iodide. The most active adrenoblockers against both tested cancer cell lines were propranolol and betaxolol. They completely inhibited lung cancer cell colony formation at 90% of the EC₅₀ (half-maximal effective concentration) value. Most tested compounds induced cell death through apoptosis and necrosis. There was no correlation established between beta adrenoblocker anticancer activity and their selectivity to beta adrenoreceptors. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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14 pages, 3266 KiB

Open AccessArticle

New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells

by Andressa Oliveira, Stefany Moura, Luiz Pimentel, João Neto, Rafael Dantas, Floriano Silva-Jr, Monica Bastos and Nubia Boechat

Molecules 2022, 27(3), 750; https://doi.org/10.3390/molecules27030750 - 24 Jan 2022

Cited by 12 | Viewed by 3214

Abstract

Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are [...] Read more.

Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC₅₀ values of 7.2, 6.4, and 7.3 μM, respectively, and were all more potent than imatinib (IC₅₀ of 65.4 μM). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 µM, showed an IC₅₀ value of 35.8 μM (imatinib, IC₅₀ = 0.08 μM). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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23 pages, 5548 KiB

Open AccessArticle

Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors

by Ali I. M. Ibrahim, Balqis Ikhmais, Elisabet Batlle, Waed K. AbuHarb, Vibhu Jha, Khaled T. Jaradat, Rafael Jiménez, Raquel Pequerul, Xavier Parés, Jaume Farrés and Klaus Pors

Molecules 2021, 26(19), 5770; https://doi.org/10.3390/molecules26195770 - 23 Sep 2021

Cited by 12 | Viewed by 3097

Abstract

Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in [...] Read more.

Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM-15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC₅₀ values of 0.23 and 1.29 µM, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC₅₀ values of 14.0, 13.7 and 13.0 µM, respectively. The computational study supported the experimental results and suggested a good binding for ABMM-15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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17 pages, 2924 KiB

Open AccessArticle

Berberine Inhibits Dengue Virus through Dual Mechanisms

by Thippayawan Ratanakomol, Sittiruk Roytrakul, Nitwara Wikan and Duncan R. Smith

Molecules 2021, 26(18), 5501; https://doi.org/10.3390/molecules26185501 - 10 Sep 2021

Cited by 11 | Viewed by 2778

Abstract

Mosquito transmitted viruses, particularly those of the genus Flavivirus, are a significant healthcare burden worldwide, especially in tropical and sub-tropical areas. However, effective medicines for these viral infections remains lacking. Berberine (BBR) is an alkaloid found in some plants used in traditional [...] Read more.

Mosquito transmitted viruses, particularly those of the genus Flavivirus, are a significant healthcare burden worldwide, especially in tropical and sub-tropical areas. However, effective medicines for these viral infections remains lacking. Berberine (BBR) is an alkaloid found in some plants used in traditional medicines in Southeast Asia and elsewhere, and BBR has been shown to possess anti-viral activities. During a screen for potential application to mosquito transmitted viruses, BBR was shown to have virucidal activity against dengue virus (DENV; IC₅₀ 42.87 µM) as well as against Zika virus (IC₅₀ 11.42 µM) and chikungunya virus (IC₅₀ 14.21 µM). BBR was shown to have cellular effects that lead to an increase in cellular DENV E protein without a concomitant effect on DENV nonstructural proteins, suggesting an effect on viral particle formation or egress. While BBR was shown to have an effect of ERK1/2 activation this did not result in defects in viral egress mechanisms. The primary effect of BBR on viral production was likely to be through BBR acting through AMPK activation and disruption of lipid metabolism. Combined these results suggest that BBR has a dual effect on DENV infection, and BBR may have the potential for development as an anti-DENV antiviral. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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22 pages, 6703 KiB

Open AccessArticle

Potential Anti-Alzheimer Agents from Guanidinyl Tryptophan Derivatives with Activities of Membrane Adhesion and Conformational Transition Inhibitions

by Pathomwat Wongrattanakamon, Jutamas Jiaranaikulwanitch, Opa Vajragupta, Supat Jiranusornkul, Chalermpong Saenjum and Wipawadee Yooin

Molecules 2021, 26(16), 4863; https://doi.org/10.3390/molecules26164863 - 11 Aug 2021

Viewed by 1669

Abstract

Guanidinyl tryptophan derivatives TGN1, TGN2, TGN3, and TGN4 were synthesized, and these compounds were shown to possess in vitro inhibitory activity for amyloid aggregation in a previous study. Nevertheless, the influence of the TGN series of compounds on the binding and permeation behaviors [...] Read more.

Guanidinyl tryptophan derivatives TGN1, TGN2, TGN3, and TGN4 were synthesized, and these compounds were shown to possess in vitro inhibitory activity for amyloid aggregation in a previous study. Nevertheless, the influence of the TGN series of compounds on the binding and permeation behaviors of an Aβ monomer to the cell membranes was not elucidated. In this study, we investigated the effect of compounds in the TGN series on the behavior of an Aβ monomer regarding its toxicity toward the bilayer lipid membrane using molecular dynamics (MD) simulation. MD simulations suggest that TGN4 is a potential agent that can interfere with the movement of the Aβ monomer into the membrane. The MM-GBSA result demonstrated that TGN4 exhibits the highest affinity to the Aβ_1–42 monomer but has the lowest affinity to the bilayer. Moreover, TGN4 also contributes to a decrease in the binding affinity between the Aβ_1–42 monomer and the POPC membrane. Regarding the results of the binding mode and conformational analyses, a high number of amino-acid residues were shown to provide the binding interactions between TGN4 and the Aβ_1–42 monomer. TGN4 also reduces the conformational transition of the Aβ_1–42 monomer by means of interacting with the monomer. The present study presents molecular-level insights into how the TGN series of compounds affect the membrane adsorption and the conformational transition of the Aβ_1–42 monomer, which could be valuable for the further development of new anti-Alzheimer agents. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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13 pages, 3059 KiB

Open AccessArticle

Benzo[f]indole-4,9-dione Derivatives Effectively Inhibit the Growth of Triple-Negative Breast Cancer

by Fabiana Sélos Guerra, Flaviana Rodrigues Fintelman Dias, Anna Claudia Cunha and Patricia Dias Fernandes

Molecules 2021, 26(15), 4414; https://doi.org/10.3390/molecules26154414 - 21 Jul 2021

Cited by 4 | Viewed by 1833

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome, and currently no effective targeted therapies are available. Indole compounds have been shown to have potential antitumor activity against various cancer cells. In the present study, we found that [...] Read more.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome, and currently no effective targeted therapies are available. Indole compounds have been shown to have potential antitumor activity against various cancer cells. In the present study, we found that new four benzo[f]indole-4,9-dione derivatives reduce TNBC cell viability by reactive oxygen species (ROS) accumulation stress in vitro. Further analyses showed that LACBio1, LACBio2, LACBio3 and LACBio4 exert cytotoxic effects on MDA-MB 231 cancer cell line by inducing the intrinsic apoptosis pathway, activating caspase 9 and Bax/Bcl-2 pathway in vitro. These results provide evidence that these new four benzo[f]indole-4,9-dione derivatives could be potential therapeutic agents against TNBC by promoting ROS stress-mediated apoptosis through intrinsic-pathway caspase activation. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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13 pages, 3140 KiB

Open AccessArticle

Characterization of ^βN-Octadecanoyl-5-hydroxytryptamide Anti-Inflammatory Effect

by Thais Biondino Sardella Giorno, Fernanda Alves Lima, Ana Laura Macedo Brand, Camila Martins de Oliveira, Claudia Moraes Rezende and Patricia Dias Fernandes

Molecules 2021, 26(12), 3709; https://doi.org/10.3390/molecules26123709 - 18 Jun 2021

Cited by 6 | Viewed by 2001

Abstract

Background: N-octadecanoyl-5-hydroxytryptamide (C₁₈-5HT) is an amide that can be obtained by the coupling of serotonin and octadecanoic acid. This study aims to characterize the in vivo and in vitro anti-inflammatory activity of C₁₈-5HT. Methods: A subcutaneous air pouch [...] Read more.

Background: N-octadecanoyl-5-hydroxytryptamide (C₁₈-5HT) is an amide that can be obtained by the coupling of serotonin and octadecanoic acid. This study aims to characterize the in vivo and in vitro anti-inflammatory activity of C₁₈-5HT. Methods: A subcutaneous air pouch model (SAP) was used. The exudates were collected from SAP after carrageenan injection to assess cell migration and inflammatory mediators production. RAW 264.7 cells were used for in vitro assays. Results: C₁₈-5HT significantly inhibited leukocyte migration into the SAP as well as nitric oxide (NO) and cytokines production and protein extravasation. We also observed an reduction in some cytokines and an increase in IL-10 production. Assays conducted with RAW 264.7 cells indicated that C₁₈-5HT inhibited NO and cytokine produced. Conclusions: Taken together, our data suggest that C₁₈-5HT presents a significant effect in different cell types (leukocytes collected from exudate, mainly polumorphonuclear leukocytes and cell culture macrophages) and is a promising compound for further studies for the development of a new anti-inflammatory drug. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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15 pages, 2328 KiB

Open AccessArticle

Synthesis and Evaluation of Some Uracil Nucleosides as Promising Anti-Herpes Simplex Virus 1 Agents

by Samir Mohamed Awad, Shima Mahmoud Ali, Yara Essam Mansour and Samar Said Fatahala

Molecules 2021, 26(10), 2988; https://doi.org/10.3390/molecules26102988 - 18 May 2021

Cited by 8 | Viewed by 4324

Abstract

Since herpes simplex virus type 1 (HSV-1) infection is so widespread, several antiviral drugs have been developed to treat it, among which are uracil nucleosides. However, there are major problems with the current medications such as severe side-effects and drug resistance. Here we [...] Read more.

Since herpes simplex virus type 1 (HSV-1) infection is so widespread, several antiviral drugs have been developed to treat it, among which are uracil nucleosides. However, there are major problems with the current medications such as severe side-effects and drug resistance. Here we present some newly synthesized cyclic and acyclic uracil nucleosides that showed very promising activity against HSV-1 compared to acyclovir. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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Review

Jump to: Research

20 pages, 1060 KiB

Open AccessReview

Endometriosis: A Disease with Few Direct Treatment Options

by Patricia Ribeiro de Carvalho França, Anna Carolina Pereira Lontra and Patricia Dias Fernandes

Molecules 2022, 27(13), 4034; https://doi.org/10.3390/molecules27134034 - 23 Jun 2022

Cited by 17 | Viewed by 7792

Abstract

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues inside and outside the pelvic cavity. The evolution of the disease can lead to infertility in addition to high treatment costs. Currently, available medications are only effective in treating endometriosis-related pain; [...] Read more.

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues inside and outside the pelvic cavity. The evolution of the disease can lead to infertility in addition to high treatment costs. Currently, available medications are only effective in treating endometriosis-related pain; however, it is not a targeted treatment. The objective of this work is to review the characteristics of the disease, the diagnostic means and treatments available, as well as to discuss new therapeutic options. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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19 pages, 350 KiB

Open AccessReview

Off-Label Use of Botulinum Toxin in Dermatology—Current State of the Art

by Miłosz Lewandowski, Zuzanna Świerczewska and Wioletta Barańska-Rybak

Molecules 2022, 27(10), 3143; https://doi.org/10.3390/molecules27103143 - 13 May 2022

Cited by 8 | Viewed by 4055

Abstract

Botulinum toxin (BoNT) is a neurotoxin produced by the Clostridium botulinum bacteria. Among seven different isoforms, only BoNT-A and BoNT-B are commercially used. Currently, botulinum toxin has been indicated by the U.S. Food and Drug Administration in several disorders, among others: chronic migraine, [...] Read more.

Botulinum toxin (BoNT) is a neurotoxin produced by the Clostridium botulinum bacteria. Among seven different isoforms, only BoNT-A and BoNT-B are commercially used. Currently, botulinum toxin has been indicated by the U.S. Food and Drug Administration in several disorders, among others: chronic migraine, hyperhidrosis, urinary incontinence from detrusor overactivity, or cosmetics. However, there are numerous promising reports based on off-label BTX usage, indicating its potential effectiveness in other diseases, which remains unknown to many. Among them, dermatological conditions, such as rosacea, annal fissure, Raynaud phenomenon, hypertrophic scars and keloids, and also hidradenitis suppurativa, are currently being investigated. This article aims to provide a comprehensive update on the off-label use of botulinum toxin in dermatology, based on an analysis and summary of the published literature. Full article

(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)

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