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18 pages, 4219 KiB

Open AccessArticle

Synthesis, Neuroprotection, and Antioxidant Activity of 1,1′-Biphenylnitrones as α-Phenyl-N-tert-butylnitrone Analogues in In Vitro Ischemia Models

by Beatriz Chamorro, David García-Vieira, Daniel Diez-Iriepa, Estíbaliz Garagarza, Mourad Chioua, Dimitra Hadjipavlou-Litina, Francisco López-Muñoz, José Marco-Contelles and María Jesús Oset-Gasque

Molecules 2021, 26(4), 1127; https://doi.org/10.3390/molecules26041127 - 20 Feb 2021

Cited by 4 | Viewed by 2116

Abstract

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs1-5 has been measured against oligomycin [...] Read more.

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs1-5 has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC₅₀ = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC₅₀ = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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16 pages, 3992 KiB

Open AccessArticle

PROTACs and Building Blocks: The 2D Chemical Space in Very Early Drug Discovery

by Giuseppe Ermondi, Diego Garcia-Jimenez and Giulia Caron

Molecules 2021, 26(3), 672; https://doi.org/10.3390/molecules26030672 - 28 Jan 2021

Cited by 29 | Viewed by 7893

Abstract

Targeted protein degradation by PROTACs has emerged as a new modality for the knockdown of a range of proteins, and, more recently, it has become increasingly clear that the PROTAC chemical space requires characterization through a pool of ad hoc physicochemical descriptors. In [...] Read more.

Targeted protein degradation by PROTACs has emerged as a new modality for the knockdown of a range of proteins, and, more recently, it has become increasingly clear that the PROTAC chemical space requires characterization through a pool of ad hoc physicochemical descriptors. In this study, a new database named PROTAC-DB that provides extensive information about PROTACs and building blocks was used to obtain the 2D chemical structures of about 1600 PROTACs, 60 E3 ligands, 800 linkers, and 202 warheads. For every structure, we calculated a pool of seven 2D descriptors carefully identified as informative for large and flexible structures. For comparison purposes, the same procedure was applied to a dataset of about 50 bRo5 approved drugs reported in the literature. Correlation matrices, PCAs, box plots, and other graphical tools were used to define and understand the chemical space covered by PROTACs and building blocks in relation to other compounds. Results show that linkers have different properties than E3 ligands and warheads. Polar descriptors additivity is not respected when passing from building blocks to degraders. Moreover, a very preliminary analysis based on three PROTACs with high, intermediate, and low permeability showed how the most permeable compounds seem to occupy a region closer to bRo5 drugs and, thus, exhibit different properties than impermeable compounds. Finally, a second database, PROTACpedia, was used to discuss the relevance of physicochemical descriptors on degradation activity. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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17 pages, 3523 KiB

Open AccessFeature PaperArticle

First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer’s Disease

by Benjamin Guieu, Cedric Lecoutey, Rémi Legay, Audrey Davis, Jana Sopkova de Oliveira Santos, Cosimo Damiano Altomare, Marco Catto, Christophe Rochais and Patrick Dallemagne

Molecules 2021, 26(1), 80; https://doi.org/10.3390/molecules26010080 - 27 Dec 2020

Cited by 15 | Viewed by 3281

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially [...] Read more.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC₅₀ = 0.4 µM) and (h)MAO-B (IC₅₀ = 6.4 µM). Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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15 pages, 2371 KiB

Open AccessArticle

An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit

by Kwok-Fong Chan, Chinh Tran-To Su, Alexander Krah, Ser-Xian Phua, Joshua Yi Yeo, Wei-Li Ling, Peter J. Bond and Samuel Ken-En Gan

Molecules 2020, 25(24), 5902; https://doi.org/10.3390/molecules25245902 - 13 Dec 2020

Cited by 6 | Viewed by 4380

Abstract

The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle—a rational target that [...] Read more.

The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle—a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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16 pages, 17546 KiB

Open AccessArticle

Synthesis of Benzimidazole–Based Analogs as Anti Alzheimer’s Disease Compounds and Their Molecular Docking Studies

by Bushra Adalat, Fazal Rahim, Muhammad Taha, Foziah J. Alshamrani, El Hassane Anouar, Nizam Uddin, Syed Adnan Ali Shah, Zarshad Ali and Zainul Amiruddin Zakaria

Molecules 2020, 25(20), 4828; https://doi.org/10.3390/molecules25204828 - 20 Oct 2020

Cited by 32 | Viewed by 4009

Abstract

We synthesized 10 analogs of benzimidazole-based thiosemicarbazide 1 (a–j) and 13 benzimidazole-based Schiff bases 2 (a–m), and characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) inhibition activities. All [...] Read more.

We synthesized 10 analogs of benzimidazole-based thiosemicarbazide 1 (a–j) and 13 benzimidazole-based Schiff bases 2 (a–m), and characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) inhibition activities. All the synthesized analogs showed varying degrees of acetylcholinesterase and butyrylcholinesterase inhibitory potentials in comparison to the standard drug (IC₅₀ = 0.016 and 4.5 µM. Amongst these analogs 1 (a–j), compounds 1b, 1c, and 1g having IC₅₀ values 1.30, 0.60, and 2.40 µM, respectively, showed good acetylcholinesterase inhibition when compared with the standard. These compounds also showed moderate butyrylcholinesterase inhibition having IC₅₀ values of 2.40, 1.50, and 2.40 µM, respectively. The rest of the compounds of this series also showed moderate to weak inhibition. While amongst the second series of analogs 2 (a–m), compounds 2c, 2e, and 2h having IC₅₀ values of 1.50, 0.60, and 0.90 µM, respectively, showed moderate acetylcholinesterase inhibition when compared to donepezil. Structure Aactivity Relation of both synthesized series has been carried out. The binding interactions between the synthesized analogs and the enzymes were identified through molecular docking simulations. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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21 pages, 4238 KiB

Open AccessArticle

Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

by Vaiyapuri Subbarayan Periasamy, Anvarbatcha Riyasdeen, Venugopal Rajendiran, Mallayan Palaniandavar, Hanumanthappa Krishnamurthy, Ali Abdullah Alshatwi and Mohammad Abdulkader Akbarsha

Molecules 2020, 25(19), 4504; https://doi.org/10.3390/molecules25194504 - 1 Oct 2020

Cited by 13 | Viewed by 3171

Abstract

This research was aimed at finding the cytotoxic potential of the mixed ligand copper(II) complex [Cu(tdp)(phen)](ClO₄)—where H(tdp) is the tetradentate ligand 2-[(2-(2-hydroxyethylamino)-ethylimino)methyl]phenol, and phen is 1,10-phenanthroline—to two genotypically different breast cancer cells, MCF-7 (p53⁺ and ER⁺) and MDA-MB-231 [...] Read more.

This research was aimed at finding the cytotoxic potential of the mixed ligand copper(II) complex [Cu(tdp)(phen)](ClO₄)—where H(tdp) is the tetradentate ligand 2-[(2-(2-hydroxyethylamino)-ethylimino)methyl]phenol, and phen is 1,10-phenanthroline—to two genotypically different breast cancer cells, MCF-7 (p53⁺ and ER⁺) and MDA-MB-231 (p53^- and ER^-). The complex has been already shown to be cytotoxic to ME180 cervical carcinoma cells. The special focus in this study was the induction of cell death by apoptosis and necrosis, and its link with ROS. The treatment brought about nuclear fragmentation, phosphatidylserine externalization, disruption of mitochondrial trans-membrane potential, DNA damage, cell cycle arrest at sub-G1 phase, and increase of ROS generation, followed by apoptotic death of cells during early hours and a late onset of necrosis in the cells surviving the apoptosis. The efficacy of the complex against genotypically different breast cancer cells is attributed to a strong association through p53-mitochondrial redox—cell cycle junction. The ADMET properties and docking of the complex at the active site of Top1 are desirable attributes of a lead molecule for development into a therapeutic. Thus, it is shown that the copper(II)–phenolate complex[Cu(tdp)(phen)]⁺ offers potential to be developed into a therapeutic for breast cancers in general and ER-negative ones in particular. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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23 pages, 3884 KiB

Open AccessArticle

Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei

by Jih Ru Hwu, Avijit Panja, Srinivasan Jayakumar, Shwu-Chen Tsay, Kui-Thong Tan, Wen-Chieh Huang, Yu-Chen Hu, Pieter Leyssen and Johan Neyts

Molecules 2020, 25(17), 3821; https://doi.org/10.3390/molecules25173821 - 22 Aug 2020

Cited by 1 | Viewed by 4020

Abstract

The modern world has no available drugs for the treatment of enteroviruses (EV), which affect millions of people worldwide each year. The EV71 is a major causative disease for hand, foot, and mouth disease; sometimes it is associated with severe central nervous system [...] Read more.

The modern world has no available drugs for the treatment of enteroviruses (EV), which affect millions of people worldwide each year. The EV71 is a major causative disease for hand, foot, and mouth disease; sometimes it is associated with severe central nervous system diseases. Treatment for enteroviral infection is mainly supportive; treatment for aseptic meningitis caused by enteroviruses is also generally symptomatic. Upon the urgent request of new anti-enterovirus drugs, a series of hinged aromatic compounds with polynulei were synthesized through two different chemical pathways. Among these morpholine–furan/thiophene/pyrrole–benzene–pyrazole conjugates, three new agents exhibited inhibitory activity with EC₅₀ = 2.29–6.16 μM toward EV71 strain BrCr in RD cells. Their selectivity index values were reached as high as 33.4. Their structure–activity relationship was deduced that a thiophene derivative with morpholine and trifluorobenzene rings showed the greatest antiviral activity, with EC₅₀ = 2.29 μM. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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20 pages, 4054 KiB

Open AccessFeature PaperArticle

Antimicrobial O-Alkyl Derivatives of Naringenin and Their Oximes Against Multidrug-Resistant Bacteria

by Anna Duda-Madej, Joanna Kozłowska, Paweł Krzyżek, Mirosław Anioł, Alicja Seniuk, Katarzyna Jermakow and Ewa Dworniczek

Molecules 2020, 25(16), 3642; https://doi.org/10.3390/molecules25163642 - 10 Aug 2020

Cited by 17 | Viewed by 4091

Abstract

New antimicrobial agents are needed to address infections caused by multidrug-resistant bacteria. Here, we are reporting novel O-alkyl derivatives of naringenin and their oximes, including novel compounds with a naringenin core and O-hexyl chains, showing activity against clinical strains of clarithromycin-resistant [...] Read more.

New antimicrobial agents are needed to address infections caused by multidrug-resistant bacteria. Here, we are reporting novel O-alkyl derivatives of naringenin and their oximes, including novel compounds with a naringenin core and O-hexyl chains, showing activity against clinical strains of clarithromycin-resistant Helicobacter pylori, vancomycin-resistant Enterococcus faecalis, methicillin-resistant Staphylococcus aureus, and beta-lactam-resistant Acinetobacter baumannii and Klebsiella pneumoniae. The minimum inhibitory concentrations (MICs), which provide a quantitative measure of antimicrobial activity, were in the low microgram range for the selected compounds. Checkerboard assays for the most active compounds in combination with antibiotics revealed interactions that varied from synergistic to neutral. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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11 pages, 1713 KiB

Open AccessArticle

Synergistic Effect of a Pleuromutilin Derivative with Tetracycline against Streptococcus suis In Vitro and in the Neutropenic Thigh Infection Model

by Fang Chen, Meng-Chao Wei, Yi-Dan Luo, Zhen Jin and You-Zhi Tang

Molecules 2020, 25(15), 3522; https://doi.org/10.3390/molecules25153522 - 1 Aug 2020

Cited by 4 | Viewed by 3475

Abstract

Tetracycline (TET) has been widely used in the treatment of Streptococcus suis (S. suis) infection. However, it was found that the efficacy of many antibiotics in S. suis decreased significantly, especially tetracycline. In this study, GML-12 (a novel pleuromutilin derivative) was [...] Read more.

Tetracycline (TET) has been widely used in the treatment of Streptococcus suis (S. suis) infection. However, it was found that the efficacy of many antibiotics in S. suis decreased significantly, especially tetracycline. In this study, GML-12 (a novel pleuromutilin derivative) was used in combination with TET against 12 S. suis isolates. In the checkerboard assay, the TET/GML-12 combination exhibited synergistic and additive effects against S. suis isolates (n = 12). In vitro time-killing assays and in vivo therapeutic experiments were used to confirm the synergistic effect of the TET/GML-12 combination against S. suis strains screened based on an FICI ≤ 0.5. In time-killing assays, the TET/GML-12 combination showed a synergistic effect or an additive effect against three isolates with a bacterial reduction of over 2.4-log₁₀ CFU/mL compared with the most active monotherapy. Additionally, the TET/GML-12 combination displayed potent antimicrobial activity against four isolates in a mouse thigh infection model. These results suggest that the TET/GML-12 combination may be a potential therapeutic strategy for S. suis infection. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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22 pages, 4419 KiB

Open AccessArticle

Structure-Based Virtual Screening, Synthesis and Biological Evaluation of Potential FAK-FAT Domain Inhibitors for Treatment of Metastatic Cancer

by Sahar B. Kandil, Samuel R. Jones, Sonia Smith, Stephen E. Hiscox and Andrew D. Westwell

Molecules 2020, 25(15), 3488; https://doi.org/10.3390/molecules25153488 - 31 Jul 2020

Cited by 7 | Viewed by 5831

Abstract

Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more [...] Read more.

Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC₅₀ values in the range of 4.59–5.28 μM in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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25 pages, 2953 KiB

Open AccessArticle

Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells

by Victor Carramiñana, Ana M. Ochoa de Retana, Francisco Palacios and Jesús M. de los Santos

Molecules 2020, 25(15), 3332; https://doi.org/10.3390/molecules25153332 - 22 Jul 2020

Cited by 12 | Viewed by 3605

Abstract

This work reports a straightforward regioselective synthetic methodology to prepare α-aminophosphine oxides and phosphonates through the addition of oxygen and sulfur nucleophiles to the C–N double bond of 2H-azirine derivatives. Determined by the nature of the nucleophile, different α-aminophosphorus compounds may [...] Read more.

This work reports a straightforward regioselective synthetic methodology to prepare α-aminophosphine oxides and phosphonates through the addition of oxygen and sulfur nucleophiles to the C–N double bond of 2H-azirine derivatives. Determined by the nature of the nucleophile, different α-aminophosphorus compounds may be obtained. For instance, aliphatic alcohols such as methanol or ethanol afford α-aminophosphine oxide and phosphonate acetals after N–C3 ring opening of the intermediate aziridine. However, addition of 2,2,2-trifluoroethanol, phenols, substituted benzenthiols or ethanethiol to 2H-azirine phosphine oxides or phosphonates yields allylic α-aminophosphine oxides and phosphonates in good to high general yields. In some cases, the intermediate aziridine attained by the nucleophilic addition of O- or S-nucleophiles to the starting 2H-azirine may be isolated and characterized before ring opening. Additionally, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and non-malignant cells (MCR-5) was also screened. Some α-aminophosphorus derivatives exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over non-malignant cells (MCR-5) has been detected in almost all compounds tested. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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16 pages, 1073 KiB

Open AccessArticle

Design, Facile Synthesis and Characterization of Dichloro Substituted Chalcones and Dihydropyrazole Derivatives for Their Antifungal, Antitubercular and Antiproliferative Activities

by Afzal B. Shaik, Richie R. Bhandare, Srinath Nissankararao, Zehra Edis, N. Ravikiran Tangirala, Shaik Shahanaaz and M. Mukhlesur Rahman

Molecules 2020, 25(14), 3188; https://doi.org/10.3390/molecules25143188 - 13 Jul 2020

Cited by 34 | Viewed by 4820

Abstract

Infectious diseases caused by fungi and mycobacteria pose an important problem for humankind. Similarly, cancer is one of the leading causes of death globally. Therefore, there is an urgent need for the development of novel agents to combat the deadly problems of cancer, [...] Read more.

Infectious diseases caused by fungi and mycobacteria pose an important problem for humankind. Similarly, cancer is one of the leading causes of death globally. Therefore, there is an urgent need for the development of novel agents to combat the deadly problems of cancer, tuberculosis, and also fungal infections. Hence, in the present study, we designed, synthesized, and characterized 30 compounds including 15 chalcones (2–16) and 15 dihydropyrazoles (17–31) containing dichlorophenyl moiety and also screened these compounds for their antifungal, antitubercular, and antiproliferative activities. Among these compounds, the dihydropyrazoles showed excellent antifungal and antitubercular activities whereas the chalcones exhibited promising antiproliferative activity. Among the dihydropyrazoles, compound 31 containing 2-thienyl moiety showed promising antifungal activity (MIC 5.35 µM), whereas compounds 22 and 24 containing 2,4-difluorophenyl and 4-trifluoromethyl scaffolds revealed significant antitubercular activity with the MICs of 3.96 and 3.67 µM, respectively. Compound 16 containing 2-thienyl moiety in the chalcone series showed the highest anti-proliferative activity with an IC₅₀ value of 17 ± 1 µM. The most active compounds identified through this study could be considered as starting points in the development of drugs with potential antifungal, antitubercular, and antiproliferative activities. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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15 pages, 1862 KiB

Open AccessArticle

DOTA-ZOL: A Promising Tool in Diagnosis and Palliative Therapy of Bone Metastasis—Challenges and Critical Points in Implementation into Clinical Routine

by Michael Meisenheimer, Stefan Kürpig, Markus Essler and Elisabeth Eppard

Molecules 2020, 25(13), 2988; https://doi.org/10.3390/molecules25132988 - 30 Jun 2020

Cited by 10 | Viewed by 3531

Abstract

The novel compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-ZOL (DOTA-conjugated zoledronic acid) is a promising candidate for the diagnosis and therapy of bone metastasis. The combination of the published methodology for this bisphosphonate with pharmaceutical and regulatory requirements turned out to be unexpectedly challenging. The scope [...] Read more.

The novel compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-ZOL (DOTA-conjugated zoledronic acid) is a promising candidate for the diagnosis and therapy of bone metastasis. The combination of the published methodology for this bisphosphonate with pharmaceutical and regulatory requirements turned out to be unexpectedly challenging. The scope of this work is the presentation and discussion of problems encountered during this process. Briefly, the radiolabelling process and purification, as well as the quality control published, did not meet the expectations. The constant effort setting up an automated radiolabelling procedure resulted in (a) an enhanced manual method using coated glass reactors, (b) a combination of three different reliable radio thin-layer chromatography (TLC) methods instead of the published and (c) a preliminary radio high-pressure liquid chromatography (HPLC) method for identification of the compound. Additionally, an automated radiolabelling process was developed, but it requires further improvement, e.g., in terms of a reactor vessel or purification of the crude product. The published purification method was found to be unsuitable for clinical routine, and an intense screening did not lead to a satisfactory result; here, more research is necessary. To sum up, implementation of DOTA-ZOL was possible but revealed a lot of critical points, of which not all could be resolved completely yet. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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12 pages, 1782 KiB

Open AccessArticle

Screening Antibody Libraries with Colony Assay Using scFv-Alkaline Phosphatase Fusion Proteins

by Yoshiro Hanyu and Mieko Kato

Molecules 2020, 25(12), 2905; https://doi.org/10.3390/molecules25122905 - 24 Jun 2020

Cited by 4 | Viewed by 3610

Abstract

Screening antibody libraries is an important step in establishing recombinant monoclonal antibodies. The colony assay can identify positive clones without almost any false-positives; however, its antibody library is smaller than those used in other recombinant screening methods such as phage display. Thus, to [...] Read more.

Screening antibody libraries is an important step in establishing recombinant monoclonal antibodies. The colony assay can identify positive clones without almost any false-positives; however, its antibody library is smaller than those used in other recombinant screening methods such as phage display. Thus, to improve the efficiency of colony assays, it is necessary to increase library size per screening. Here, we report developing a colony assay with single-chain variable fragment (scFv) fused to the N-terminus of bacterial alkaline phosphatase (scFv-PhoA). The scFv-PhoA library was constructed in an expression vector specifically designed for this study. Use of this library allowed the successful and direct detection of positive clones exhibiting PhoA activity, without the need for a secondary antibody. Colony assay screening with scFv-PhoA is simple, rapid, offers a higher success rate than previous methods based on scFv libraries, and—most importantly—it enables high-throughput procedures. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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20 pages, 1726 KiB

Open AccessArticle

Pharmacokinetic Properties of ⁶⁸Ga-labelled Folic Acid Conjugates: Improvement Using HEHE Tag

by Anton Larenkov, Marat Rakhimov, Kristina Lunyova, Olga Klementyeva, Alesya Maruk and Aleksei Machulkin

Molecules 2020, 25(11), 2712; https://doi.org/10.3390/molecules25112712 - 11 Jun 2020

Cited by 5 | Viewed by 4292

Abstract

The folate receptor (FR) is a promising cell membrane-associated target for molecular imaging and radionuclide therapy of cancer (FR-α) and potentially also inflammatory diseases (FR-β) through use of folic acid-based radioconjugate. FR is often overexpressed by cells of epithelial tumors, including tumors of [...] Read more.

The folate receptor (FR) is a promising cell membrane-associated target for molecular imaging and radionuclide therapy of cancer (FR-α) and potentially also inflammatory diseases (FR-β) through use of folic acid-based radioconjugate. FR is often overexpressed by cells of epithelial tumors, including tumors of ovary, cervix, endometrium, lungs, kidneys, etc. In healthy tissues, FR can be found in small numbers by the epithelial cells, mainly in the kidneys. Extremely high undesired accumulation of the folate radioconjugates in the renal tissue is a main drawback of FR-targeting concept. In the course of this work, we aimed to reduce the undesirable accumulation of folate radioconjugates in the kidneys by introducing a histidine/glutamic acid tag into their structure. Two folic acid based compounds were synthesized: NODAGA-1,4-butanediamine-folic acid (FA-I, as control) and NODAGA-[Lys-(HE)₂]-folic acid (FA-II) which contains a (His-Glu)₂ fragment. In vitro studies with FR (+) cells (KB and others) showed that both compounds have specificity for FR. Introduction of (HE)₂-tag does not affect FR binding ability of the conjugates. In vivo biodistribution studies with normal laboratory animals, as well as with KB tumor bearing animals, were carried out. The results showed that introduction of the (HE)₂ tag into the structure of folate radioconjugates can significantly reduce the accumulation of these compounds in non-target tissues and important organs (the accumulation in the kidneys is reduced 2–4 times), leaving the accumulation in tumor at least at the same level, and even increasing it. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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22 pages, 3607 KiB

Open AccessArticle

Synthetic (E)-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1

by Danilo Sousa-Pereira, Thais Silva de Oliveira, Rojane O. Paiva, Otávio Augusto Chaves, José C. Netto-Ferreira, Juliana Echevarria-Lima and Aurea Echevarria

Molecules 2020, 25(11), 2537; https://doi.org/10.3390/molecules25112537 - 29 May 2020

Cited by 5 | Viewed by 3117

Abstract

Synthesis of four compounds belonging to mesoionic class, (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (5a–d) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and [...] Read more.

Synthesis of four compounds belonging to mesoionic class, (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (5a–d) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and non-infected cell lines (Jurkat) are reported. The compounds were obtained by convergent synthesis under microwave irradiation and the cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Results showed IC₅₀ values of all compounds in the range of 1.51–7.70 μM in HTLV-1-infected and non-infected cells. Furthermore, it was observed that 5b could induce necrosis after 24 h for Jurkat and MT2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action for 5b could be related to its capacity to intercalate into DNA. Moreover, the preliminary pharmacokinetic profile of the studied compounds (5a–d) was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential and molecular docking calculations. The interaction HSA:5a–d is spontaneous and moderate (K_a ~ 10⁴ M⁻¹) via a ground-state association, without significantly perturbing both the secondary and surface structures of the albumin in the subdomain IIA (site I), indicating feasible biodistribution in the human bloodstream. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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21 pages, 3406 KiB

Open AccessArticle

Development of Resistance to Endoplasmic Reticulum Stress-Inducing Agents in Mouse Leukemic L1210 Cells

by Martin Cagala, Lucia Pavlikova, Mario Seres, Karolina Kadlecikova, Albert Breier and Zdena Sulova

Molecules 2020, 25(11), 2517; https://doi.org/10.3390/molecules25112517 - 28 May 2020

Cited by 6 | Viewed by 3252

Abstract

Four new variants of L1210 cells resistant to endoplasmic reticulum (ER) stressors, tunicamycin (S_Tun), thapsigargin (S_Thap), bortezomib (S_Bor), and MG-132 (S_MG-132), were developed via an 18-month periodic cultivation in culture medium with a gradual increase [...] Read more.

Four new variants of L1210 cells resistant to endoplasmic reticulum (ER) stressors, tunicamycin (S_Tun), thapsigargin (S_Thap), bortezomib (S_Bor), and MG-132 (S_MG-132), were developed via an 18-month periodic cultivation in culture medium with a gradual increase in substance concentration. Multidrug resistance was generated for S_Tun (to tunicamycin, bortezomib and MG-132), S_Thap (to tunicamycin, thapsigargin and MG-132), S_Bor (to bortezomib and MG-132), and S_MG-132 (to bortezomib and MG-132). These cells were compared to the original L1210 cells and another two variants, which expressed P-gp due to induction with vincristine or transfection with the gene encoding P-gp, in terms of the following properties: sensitivity to either vincristine or the ER stressors listed above, proliferative activity, expression of resistance markers and proteins involved in the ER stress response, and proteasome activity. The resistance of the new cell variants to ER stressors was accompanied by a decreased proliferation rate and increased proteasome activity. The most consistent change in protein expression was the elevation of GRP78/BiP at the mRNA and protein levels in all resistant variants of L1210 cells. In conclusion, the mechanisms of resistance to these stressors have certain common features, but there are also specific differences. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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15 pages, 1351 KiB

Open AccessArticle

Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity

by Su Bin Kim, Taeho Lee, Hong Seop Moon, Sung Hwan Ki, Yoon Sin Oh, Joo-Youn Lee, Sang-Bum Kim, Jeong-Eun Park, Yongseok Kwon, Sanghee Kim, Dong Jae Baek and Eun-Young Park

Molecules 2020, 25(11), 2484; https://doi.org/10.3390/molecules25112484 - 27 May 2020

Cited by 6 | Viewed by 4238

Abstract

PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore, the [...] Read more.

PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore, the purpose of this study was to investigate changes in SK inhibitory and anticancer activities and to explore the role of the tolyl group structure of PF-543 through various modifications. We transformed the methyl group of PF-543 into hydrogen, fluorine, and hydroxy. PF-543 derivatives in which the methyl group was substituted by hydrogen and fluorine (compound 5) demonstrated SK1 inhibitory and anticancer activities similar to PF-543. Moreover, we performed molecular modeling studies of PF-543 and compound 5. To assess the metabolic stability of PF-543 and compound 5, we determined their degree of degradation using the liver microsomes of four different animal species (human, dog, rat, and mouse). However, both PF-543 and compound 5 showed poor microsomal stability. Therefore, for the medical applications of PF-543, the structural modifications of its other parts may be necessary. Our results provide important information for the design of additional PF-543 analogs. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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22 pages, 5282 KiB

Open AccessArticle

Identification of Substituted Amino Acid Hydrazides as Novel Anti-Tubercular Agents, Using a Scaffold Hopping Approach

by Alistair K. Brown, Ahmed K. B. Aljohani, Fatimah M. A. Alsalem, Joseph L. Broadhead, Jason H. Gill, Yucheng Lu and Jonathan D. Sellars

Molecules 2020, 25(10), 2387; https://doi.org/10.3390/molecules25102387 - 21 May 2020

Cited by 5 | Viewed by 4454

Abstract

Discovery and development of new therapeutic options for the treatment of Mycobacterium tuberculosis (Mtb) infection, particularly drug-resistant strains, are urgently required to tackle the global burden of this disease. Herein, we reported the synthesis of a novel series of N-substituted amino [...] Read more.

Discovery and development of new therapeutic options for the treatment of Mycobacterium tuberculosis (Mtb) infection, particularly drug-resistant strains, are urgently required to tackle the global burden of this disease. Herein, we reported the synthesis of a novel series of N-substituted amino acid hydrazides, utilising a scaffold hopping approach within a library of anti-tubercular agents. Efficacy and selectivity were evaluated against three strains of Mtb (wild-type, isoniazid-resistant and rifampicin-resistant), and cytotoxicity against macrophages in vitro. The antibacterial activity and therapeutic index of these molecules were significantly affected by modifications with the N-substituents. Introduction of a 3,5-dinitroaryl moiety demonstrated enhanced antibacterial activity against all three strains of Mtb. In contrast, the inclusion of an imidazo [1,2-a]pyridine-3-carboxy moiety resulted in enhanced activity towards isoniazid mono-resistant Mtb relative to wild-type Mtb. Consequently, this scaffold hopping approach showed significant promise for exemplification of novel molecules with specific activity profiles against drug-resistant tuberculosis. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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17 pages, 5345 KiB

Open AccessArticle

N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity

by Martin Krátký, Zsuzsa Baranyai, Šárka Štěpánková, Katarína Svrčková, Markéta Švarcová, Jiřina Stolaříková, Lilla Horváth, Szilvia Bősze and Jarmila Vinšová

Molecules 2020, 25(10), 2268; https://doi.org/10.3390/molecules25102268 - 12 May 2020

Cited by 12 | Viewed by 3903

Abstract

Based on the isosterism concept, we have designed and synthesized homologous N-alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (from C₁ to C₁₈) as potential antimicrobial agents and enzyme inhibitors. They were obtained from 4-(trifluoromethyl)benzohydrazide by three synthetic approaches and characterized by spectral methods. The derivatives [...] Read more.

Based on the isosterism concept, we have designed and synthesized homologous N-alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (from C₁ to C₁₈) as potential antimicrobial agents and enzyme inhibitors. They were obtained from 4-(trifluoromethyl)benzohydrazide by three synthetic approaches and characterized by spectral methods. The derivatives were screened for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) via Ellman’s method. All the hydrazinecarboxamides revealed a moderate inhibition of both AChE and BuChE, with IC₅₀ values of 27.04–106.75 µM and 58.01–277.48 µM, respectively. Some compounds exhibited lower IC₅₀ for AChE than the clinically used drug rivastigmine. N-Tridecyl/pentadecyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides were identified as the most potent and selective inhibitors of AChE. For inhibition of BuChE, alkyl chain lengths from C₅ to C₇ are optimal substituents. Based on molecular docking study, the compounds may work as non-covalent inhibitors that are placed in a close proximity to the active site triad. The compounds were evaluated against Mycobacterium tuberculosis H₃₇Rv and nontuberculous mycobacteria (M. avium, M. kansasii). Reflecting these results, we prepared additional analogues of the most active carboxamide (n-hexyl derivative 2f). N-Hexyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-amine (4) exhibited the lowest minimum inhibitory concentrations within this study (MIC ≥ 62.5 µM), however, this activity is mild. All the compounds avoided cytostatic properties on two eukaryotic cell lines (HepG2, MonoMac6). Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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9 pages, 973 KiB

Open AccessArticle

Efficient and Divergent Enantioselective Syntheses of DHPVs and Anti-Inflammatory Effect on IEC-6 Cells

by Hyun Su Kim, Sungkyun Chung, Moon-Young Song, Changjin Lim, Hyeyoung Shin, Joonseong Hur, Hyuk Kwon, Young-Ger Suh, Eun-Hee Kim, Dongyun Shin and Seok-Ho Kim

Molecules 2020, 25(9), 2215; https://doi.org/10.3390/molecules25092215 - 8 May 2020

Cited by 7 | Viewed by 2861

Abstract

Despite numerous reports on the beneficial effects of catechin or epicatechin contained in tea and cacao extract on human health, a conclusive and precise molecular mechanism has not been elucidated. Metabolism of chemical compounds in gut microbiota recently gained significant attention, and extensive [...] Read more.

Despite numerous reports on the beneficial effects of catechin or epicatechin contained in tea and cacao extract on human health, a conclusive and precise molecular mechanism has not been elucidated. Metabolism of chemical compounds in gut microbiota recently gained significant attention, and extensive studies have been devoted in this field. In conjunction with these results, our group focused on the anti-inflammatory effects of both enantiomers of DHPV (5-(3′,4′-dihydroxyphenyl)-γ-valerolactone), produced in the intestine by microbiota metabolism, on IEC-6 cells. Divergent and efficient enantioselective synthesis of (S)- and (R)-DHPV was efficiently achieved by cross-metathesis and Sharpless asymmetric dihydroxylation as a key reaction for four steps in 16% and 14% overall yields, respectively. The anti-inflammatory effects of two enantiomers were tested on IEC-6 cells, and we found that (S)-DHPV was more active than (R)-DHPV. This result implicates that the metabolite produced in the gut has beneficial effects on IEC-6 cells of rat intestines, and the chirality of the metabolite is important for its anti-inflammatory activity. This also provided information for the future discovery of novel small molecular therapeutics for the treatment of inflammatory bowel disease. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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19 pages, 3354 KiB

Open AccessArticle

Testing for Ketoprofen Binding to HSA Coated Magnetic Nanoparticles under Normal Conditions and after Oxidative Stress

by Marta Ziegler-Borowska, Kinga Mylkie, Pawel Nowak, Patryk Rybczynski, Adam Sikora, Dorota Chelminiak-Dudkiewicz and Anna Kaczmarek-Kedziera

Molecules 2020, 25(8), 1945; https://doi.org/10.3390/molecules25081945 - 22 Apr 2020

Cited by 5 | Viewed by 3169

Abstract

Binding and transport of ligands is one of the most important functions of human blood serum proteins. Human serum albumin is found in plasma at the highest concentration. Because of this, it is important to study protein–drug interactions for this albumin. Since there [...] Read more.

Binding and transport of ligands is one of the most important functions of human blood serum proteins. Human serum albumin is found in plasma at the highest concentration. Because of this, it is important to study protein–drug interactions for this albumin. Since there is no single model describing this interaction, it is necessary to measure it for each active substance. Drug binding should also be studied in conditions that simulate pathological conditions of the body, i.e., after oxidative stress. Due to this, it is expected that the methods for testing these interactions need to be easy and fast. In this study, albumin immobilized on magnetic nanoparticles was successfully applied in the study of protein–drug binding. Ketoprofen was selected as a model drug and interactions were tested under normal conditions and artificially induced oxidative stress. The quality of obtained results for immobilized protein was confirmed with those for free albumin and literature data. It was shown that the type of magnetic core coverage does not affect the quality of the obtained results. In summary, a new, fast, effective, and universal method for testing protein–drug interactions was proposed, which can be performed in most laboratories. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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21 pages, 1426 KiB

Open AccessArticle

5-Alkylamino-N-phenylpyrazine-2-carboxamides: Design, Preparation, and Antimycobacterial Evaluation

by Weronika Ambrożkiewicz, Marta Kučerová-Chlupáčová, Ondřej Janďourek, Klára Konečná, Pavla Paterová, Pavel Bárta, Jarmila Vinšová, Martin Doležal and Jan Zitko

Molecules 2020, 25(7), 1561; https://doi.org/10.3390/molecules25071561 - 28 Mar 2020

Cited by 8 | Viewed by 2759

Abstract

According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by Mycobacterium tuberculosis against currently used antituberculars is an [...] Read more.

According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by Mycobacterium tuberculosis against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino-N-phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. smegmatis, M. kansasii, M. avium) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against M. tuberculosis H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, N-(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (3c, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)-N-(p-tolyl)pyrazine-2-carboxamide (4e, MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the Candida genus. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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27 pages, 4835 KiB

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Current Updates on Naturally Occurring Compounds Recognizing SARS-CoV-2 Druggable Targets

by Isabella Romeo, Francesco Mesiti, Antonio Lupia and Stefano Alcaro

Molecules 2021, 26(3), 632; https://doi.org/10.3390/molecules26030632 - 26 Jan 2021

Cited by 22 | Viewed by 5956

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified in China as the etiologic agent of the recent COVID-19 pandemic outbreak. Due to its high transmissibility, this virus quickly spread throughout the world, causing considerable health issues. The scientific community exerted [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified in China as the etiologic agent of the recent COVID-19 pandemic outbreak. Due to its high transmissibility, this virus quickly spread throughout the world, causing considerable health issues. The scientific community exerted noteworthy efforts to obtain therapeutic solutions for COVID-19, and new scientific networks were constituted. No certified drugs to efficiently inhibit the virus were identified, and the development of de-novo medicines requires approximately ten years of research. Therefore, the repurposing of natural products could be an effective strategy to handle SARS-CoV-2 infection. This review aims to update on current status of the natural occurring compounds recognizing SARS-CoV-2 druggable targets. Among the clinical trials actually recruited, some natural compounds are ongoing to examine their potential role to prevent and to treat the COVID-19 infection. Many natural scaffolds, including alkaloids, terpenes, flavonoids, and benzoquinones, were investigated by in-silico, in-vitro, and in-vivo approaches. Despite the large data set obtained by a computational approach, experimental evidences in most cases are not available. To fill this gap, further efforts to validate these results are required. We believe that an accurate investigation of naturally occurring compounds may provide insights for the potential treatment of COVID-19 patients. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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42 pages, 3709 KiB

Open AccessReview

A Review of Molecular Imaging of Glutamate Receptors

by Jong-Hoon Kim, János Marton, Simon Mensah Ametamey and Paul Cumming

Molecules 2020, 25(20), 4749; https://doi.org/10.3390/molecules25204749 - 16 Oct 2020

Cited by 44 | Viewed by 7795

Abstract

Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for [...] Read more.

Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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27 pages, 3758 KiB

Open AccessReview

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

by Javier Vázquez, Manel López, Enric Gibert, Enric Herrero and F. Javier Luque

Molecules 2020, 25(20), 4723; https://doi.org/10.3390/molecules25204723 - 15 Oct 2020

Cited by 107 | Viewed by 13191

Abstract

Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of [...] Read more.

Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued efforts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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19 pages, 2187 KiB

Open AccessReview

Radioanalytical Techniques to Quantitatively Assess the Biological Uptake and In Vivo Behavior of Hazardous Substances

by Jae Young Lee, Sajid Mushtaq, Jung Eun Park, Hee Soon Shin, So-Young Lee and Jongho Jeon

Molecules 2020, 25(17), 3985; https://doi.org/10.3390/molecules25173985 - 1 Sep 2020

Cited by 9 | Viewed by 3374

Abstract

Concern about environmental exposure to hazardous substances has grown over the past several decades, because these substances have adverse effects on human health. Methods used to monitor the biological uptake of hazardous substances and their spatiotemporal behavior in vivo must be accurate and [...] Read more.

Concern about environmental exposure to hazardous substances has grown over the past several decades, because these substances have adverse effects on human health. Methods used to monitor the biological uptake of hazardous substances and their spatiotemporal behavior in vivo must be accurate and reliable. Recent advances in radiolabeling chemistry and radioanalytical methodologies have facilitated the quantitative analysis of toxic substances, and whole-body imaging can be achieved using nuclear imaging instruments. Herein, we review recent literature on the radioanalytical methods used to study the biological distribution, changes in the uptake and accumulation of hazardous substances, including industrial chemicals, nanomaterials, and microorganisms. We begin with an overview of the radioisotopes used to prepare radiotracers for in vivo experiments. We then summarize the results of molecular imaging studies involving radiolabeled toxins and their quantitative assessment. We conclude the review with perspectives on the use of radioanalytical methods for future environmental research. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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21 pages, 8997 KiB

Open AccessReview

Research Progress of Small Molecule VEGFR/c-Met Inhibitors as Anticancer Agents (2016–Present)

by Qian Zhang, Pengwu Zheng and Wufu Zhu

Molecules 2020, 25(11), 2666; https://doi.org/10.3390/molecules25112666 - 8 Jun 2020

Cited by 27 | Viewed by 5046

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR-2) binds to VEGFR-A, VEGFR-C and VEGFR-D and participates in the formation of tumor blood vessels, mediates the proliferation of endothelial cells, enhances microvascular permeability, and blocks apoptosis. Blocking or downregulating the signal transduction of VEGFR is [...] Read more.

Vascular endothelial growth factor receptor 2 (VEGFR-2) binds to VEGFR-A, VEGFR-C and VEGFR-D and participates in the formation of tumor blood vessels, mediates the proliferation of endothelial cells, enhances microvascular permeability, and blocks apoptosis. Blocking or downregulating the signal transduction of VEGFR is the main way to discover new drugs for many human angiogenesis-dependent malignancies. Mesenchymal epithelial transfer factor tyrosine kinase (c-Met) is a high affinity receptor for hepatocyte growth factor (HGF). Abnormal c-Met signaling plays an important role in the formation, invasion and metastasis of human tumors. Therefore, the HGF/c-Met signaling pathway has become a significant target for cancer treatment. Related studies have shown that the conduction of the VEGFR and c-Met signaling pathways has a synergistic effect in inducing angiogenesis and inhibiting tumor growth. In recent years, multi-target small molecule inhibitors have become a research hotspot, among which the research of VEGFR and c-Met dual-target small molecule inhibitors has become more and more extensive. In this review, we comprehensively summarize the chemical structures and biological characteristics of novel VEGFR/c-Met dual-target small-molecule inhibitors in the past five years. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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