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10 pages, 2484 KiB

Open AccessArticle

Chlorin e6-Biotin Conjugates for Tumor-Targeting Photodynamic Therapy

by Wei Liu, Xingqun Ma, Yingying Jin, Jie Zhang, Yang Li, Yuxia Tang, Yong Song and Shouju Wang

Molecules 2021, 26(23), 7342; https://doi.org/10.3390/molecules26237342 - 3 Dec 2021

Cited by 16 | Viewed by 2859

Abstract

To improve the tumor-targeting efficacy of photodynamic therapy, biotin was conjugated with chlorin e6 to develop a new tumor-targeting photosensitizer, Ce6-biotin. The Ce6-biotin had good water solubility and low aggregation. The singlet-oxygen generation rate of Ce6-biotin was slightly increased compared to Ce6. Flow [...] Read more.

To improve the tumor-targeting efficacy of photodynamic therapy, biotin was conjugated with chlorin e6 to develop a new tumor-targeting photosensitizer, Ce6-biotin. The Ce6-biotin had good water solubility and low aggregation. The singlet-oxygen generation rate of Ce6-biotin was slightly increased compared to Ce6. Flow cytometry and confocal laser scanning microscopy results confirmed Ce6-biotin had higher binding affinity toward biotin-receptor-positive HeLa human cervical carcinoma cells than its precursor, Ce6. Due to the BR-targeting ability of Ce6-biotin, it exhibited stronger cytotoxicity to HeLa cells upon laser irradiation. The IC50 against HeLa cells of Ce6-biotin and Ce6 were 1.28 µM and 2.31 µM, respectively. Furthermore, both Ce6-biotin and Ce6 showed minimal dark toxicity. The selectively enhanced therapeutic efficacy and low dark toxicity suggest that Ce6-biotin is a promising PS for BR-positive-tumor-targeting photodynamic therapy. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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12 pages, 1211 KiB

Open AccessArticle

Antiviral Potential of Naphthoquinones Derivatives Encapsulated within Liposomes

by Viveca Giongo, Annarita Falanga, Camilly P. Pires De Melo, Gustavo B. da Silva, Rosa Bellavita, Salvatore G. De-Simone, Izabel C. Paixão and Stefania Galdiero

Molecules 2021, 26(21), 6440; https://doi.org/10.3390/molecules26216440 - 25 Oct 2021

Cited by 6 | Viewed by 1844

Abstract

HSV infections, both type 1 and type 2, are among the most widespread viral diseases affecting people of all ages. Their symptoms could be mild, with cold sores up to 10 days of infection, blindness and encephalitis caused by HSV-1 affecting immunocompetent and [...] Read more.

HSV infections, both type 1 and type 2, are among the most widespread viral diseases affecting people of all ages. Their symptoms could be mild, with cold sores up to 10 days of infection, blindness and encephalitis caused by HSV-1 affecting immunocompetent and immunosuppressed individuals. The severe effects derive from co-evolution with the host, resulting in immune evasion mechanisms, including latency and growing resistance to acyclovir and derivatives. An efficient alternative to controlling the spreading of HSV mutations is the exploitation of new drugs, and the possibility of enhancing their delivery through the encapsulation of drugs into nanoparticles, such as liposomes. In this work, liposomes were loaded with a series of 2-aminomethyl- 3-hydroxy-1,4-naphthoquinones derivatives with n-butyl (compound 1), benzyl (compound 2) and nitrobenzene (compound 3) substituents in the primary amine of naphthoquinone. They were previously identified to have significant inhibitory activity against HSV-1. All of the aminomethylnaphthoquinones derivatives encapsulated in the phosphatidylcholine liposomes were able to control the early and late phases of HSV-1 replication, especially those substituted with the benzyl (compound 2) and nitrobenzene (compound 3), which yields selective index values that are almost nine times more efficient than acyclovir. The growing interest of the industry in topical administration against HSV supports our choice of liposome as a drug carrier of aminomethylnaphthoquinones derivatives for formulations of in vivo pre-clinical assays. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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17 pages, 2553 KiB

Open AccessArticle

Design, Synthesis, and Antipoliferative Activities of Novel Substituted Imidazole-Thione Linked Benzotriazole Derivatives

by Ahdab N. Khayyat, Khaled O. Mohamed, Azizah M. Malebari and Afaf El-Malah

Molecules 2021, 26(19), 5983; https://doi.org/10.3390/molecules26195983 - 2 Oct 2021

Cited by 8 | Viewed by 2589

Abstract

A new series of benzotriazole moiety bearing substituted imidazol-2-thiones at N1 has been designed, synthesized and evaluated for in vitro anticancer activity against the different cancer cell lines MCF-7(breast cancer), HL-60 (Human promyelocytic leukemia), and HCT-116 (colon cancer). Most of the benzotriazole analogues [...] Read more.

A new series of benzotriazole moiety bearing substituted imidazol-2-thiones at N1 has been designed, synthesized and evaluated for in vitro anticancer activity against the different cancer cell lines MCF-7(breast cancer), HL-60 (Human promyelocytic leukemia), and HCT-116 (colon cancer). Most of the benzotriazole analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, BI9 showed potent activity against the cancer cell lines such as MCF-7, HL-60 and HCT-116 with IC₅₀ 3.57, 0.40 and 2.63 µM, respectively. Compound BI9 was taken up for elaborate biological studies and the HL-60 cells in the cell cycle were arrested in G₂/M phase. Compound BI9 showed remarkable inhibition of tubulin polymerization with the colchicine binding site of tubulin. In addition, compound BI9 promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2. These results provide guidance for further rational development of potent tubulin polymerization inhibitors for the treatment of cancer. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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18 pages, 3800 KiB

Open AccessArticle

Discovery of Active Ingredients Targeted TREM2 by SPR Biosensor-UPLC/MS Recognition System, and Investigating the Mechanism of Anti-Neuroinflammatory Activity on the Lignin-Amides from Datura metel Seeds

by Si-Yi Wang, Yan Liu, Xiao-Mao Li, Adnan Mohammed Algradi, Hai Jiang, Yan-Ping Sun, Wei Guan, Juan Pan, Hai-Xue Kuang and Bing-You Yang

Molecules 2021, 26(19), 5946; https://doi.org/10.3390/molecules26195946 - 30 Sep 2021

Cited by 5 | Viewed by 2865

Abstract

As a new target protein for Alzheimer’s disease (AD), the triggering receptor expressed on myeloid Cells 2 (TREM2) was expressed on the surface of microglia, which was shown to regulate neuroinflammation, be associated with a variety of neuropathologic, and regarded as a potential [...] Read more.

As a new target protein for Alzheimer’s disease (AD), the triggering receptor expressed on myeloid Cells 2 (TREM2) was expressed on the surface of microglia, which was shown to regulate neuroinflammation, be associated with a variety of neuropathologic, and regarded as a potential indicator for monitoring AD. In this study, a novel recognition system based on surface plasmon resonance (SPR) for the TREM2 target spot was established coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-MS), in order to screen the active ingredients targeting TREM2 from Datura metel seeds. The results showed that four lignan-amides were discovered as candidate compounds by SPR biosensor-UPLC/MS recognition analysis. According to the guidance of the active ingredients discovered by the system, the lignin-amides from Datura metel seeds (LDS) were preliminarily identified as containing 27 lignan-amides, which were enriched compositions by the HP-20 of Datura metel seeds. Meanwhile, the anti-inflammatory activity of LDS was evaluated in BV2 microglia induced by LPS. Our experimental results demonstrated that LDS could reduce NO release in LPS-treated BV2 microglia cells and significantly reduce the expression of the proteins of inducible Nitric Oxide Synthase (iNOS), cyclooxygenase 2 (COX-2), microtubule-associated protein tau (Tau), and ionized calcium-binding adapter molecule 1 (IBA-1). Accordingly, LDS might increase the expression of TREM2/DNAX-activating protein of 12 kDa (DAP12) and suppress the Toll-like receptor SX4 (TLR4) pathway and Recombinant NLR Family, Pyrin Domain Containing Protein 3 (NLRP3)/cysteinyl aspartate specific proteinase-1 (Caspase-1) inflammasome expression by LDS in LPS-induced BV2 microglial cells. Then, the inhibitory release of inflammatory factors Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and Tumor necrosis factor-alpha (TNFα) inflammatory cytokines were detected to inhibit neuroinflammatory responses. The present results propose that LDS has potential as an anti-neuroinflammatory agent against microglia-mediated neuroinflammatory disorders. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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17 pages, 930 KiB

Open AccessFeature PaperArticle

Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency

by Panagiotis Theodosis-Nobelos, Georgios Papagiouvannis, Paraskevi Tziona, Panos N. Kourounakis and Eleni A. Rekka

Molecules 2021, 26(13), 4060; https://doi.org/10.3390/molecules26134060 - 2 Jul 2021

Cited by 11 | Viewed by 2352

Abstract

A series of L-serine amides of antioxidant acids, such as Trolox, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (phenolic derivative of cinnamic acid) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (structurally similar to butylated hydroxytoluene), was synthesized. The hydroxy group of serine was esterified with two [...] Read more.

A series of L-serine amides of antioxidant acids, such as Trolox, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (phenolic derivative of cinnamic acid) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (structurally similar to butylated hydroxytoluene), was synthesized. The hydroxy group of serine was esterified with two classical NSAIDs, ibuprofen and ketoprofen. The Trolox derivatives with ibuprofen (7) and ketoprofen (10) were the most potent inhibitors of lipid peroxidation (IC₅₀ 3.4 μΜ and 2.8 μΜ), several times more potent than the reference Trolox (IC₅₀ 25 μΜ). Most of the compounds decreased carrageenan-induced rat paw edema (37–67% at 150 μmol/kg). They were moderate inhibitors of soybean lipoxygenase, with the exception of ibuprofen derivative 8 (IC₅₀ 13 μΜ). The most active anti-inflammatory compounds exhibited a significant decrease in lipidemic indices in the plasma of Triton-induced hyperlipidemic rats, e.g., the most active compound 9 decreased triglycerides, total cholesterol and low-density lipoprotein cholesterol by 52%, 61% and 70%, respectively, at 150 μmol/kg (i.p.), similar to that of simvastatin, a well-known hypocholesterolemic drug. Since the designed compounds seem to exhibit multiple pharmacological actions, they may be of use for the development of agents against inflammatory and degenerative conditions. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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14 pages, 2151 KiB

Open AccessArticle

5-Phenoxy Primaquine Analogs and the Tetraoxane Hybrid as Antimalarial Agents

by Somruedee Jansongsaeng, Nitipol Srimongkolpithak, Jutharat Pengon, Sumalee Kamchonwongpaisan and Tanatorn Khotavivattana

Molecules 2021, 26(13), 3991; https://doi.org/10.3390/molecules26133991 - 30 Jun 2021

Cited by 6 | Viewed by 3162

Abstract

The rapid emergence of drug resistance to the current antimalarial agents has led to the urgent need for the discovery of new and effective compounds. In this work, a series of 5-phenoxy primaquine analogs with 8-aminoquinoline core (7a–7h) was [...] Read more.

The rapid emergence of drug resistance to the current antimalarial agents has led to the urgent need for the discovery of new and effective compounds. In this work, a series of 5-phenoxy primaquine analogs with 8-aminoquinoline core (7a–7h) was synthesized and investigated for their antimalarial activity against Plasmodium falciparum. Most analogs showed improved blood antimalarial activity compared to the original primaquine. To further explore a drug hybrid strategy, a conjugate compound between tetraoxane and the representative 5-phenoxy-primaquine analog 7a was synthesized. In our work, the hybrid compound 12 exhibited almost a 30-fold increase in the blood antimalarial activity (IC₅₀ = 0.38 ± 0.11 μM) compared to that of primaquine, with relatively low toxicity against mammalian cells (SI = 45.61). Furthermore, we found that these 5-phenoxy primaquine analogs and the hybrid exhibit significant heme polymerization inhibition, an activity similar to that of chloroquine, which could contribute to their improved antimalarial activity. The 5-phenoxy primaquine analogs and the tetraoxane hybrid could serve as promising candidates for the further development of antimalarial agents. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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19 pages, 8015 KiB

Open AccessArticle

Synthesis and Antiviral Evaluation of Nucleoside Analogues Bearing One Pyrimidine Moiety and Two D-Ribofuranosyl Residues

by Olga V. Andreeva, Bulat F. Garifullin, Vladimir V. Zarubaev, Alexander V. Slita, Iana L. Yesaulkova, Alexandrina S. Volobueva, Mayya G. Belenok, Maria A. Man’kova, Liliya F. Saifina, Marina M. Shulaeva, Alexandra D. Voloshina, Anna P. Lyubina, Vyacheslav E. Semenov and Vladimir E. Kataev

Molecules 2021, 26(12), 3678; https://doi.org/10.3390/molecules26123678 - 16 Jun 2021

Cited by 8 | Viewed by 2139

Abstract

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was [...] Read more.

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC₅₀ values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC₅₀ values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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17 pages, 16001 KiB

Open AccessFeature PaperArticle

In Vitro Confirmation of Siramesine as a Novel Antifungal Agent with In Silico Lead Proposals of Structurally Related Antifungals

by Josipa Vlainić, Ozren Jović, Ivan Kosalec, Oliver Vugrek, Rozelindra Čož-Rakovac and Tomislav Šmuc

Molecules 2021, 26(12), 3504; https://doi.org/10.3390/molecules26123504 - 8 Jun 2021

Cited by 5 | Viewed by 2302

Abstract

The limited number of medicinal products available to treat of fungal infections makes control of fungal pathogens problematic, especially since the number of fungal resistance incidents increases. Given the high costs and slow development of new antifungal treatment options, repurposing of already known [...] Read more.

The limited number of medicinal products available to treat of fungal infections makes control of fungal pathogens problematic, especially since the number of fungal resistance incidents increases. Given the high costs and slow development of new antifungal treatment options, repurposing of already known compounds is one of the proposed strategies. The objective of this study was to perform in vitro experimental tests of already identified lead compounds in our previous in silico drug repurposing study, which had been conducted on the known Drugbank database using a seven-step procedure which includes machine learning and molecular docking. This study identifies siramesine as a novel antifungal agent. This novel indication was confirmed through in vitro testing using several yeast species and one mold. The results showed susceptibility of Candida species to siramesine with MIC at concentration 12.5 µg/mL, whereas other candidates had no antifungal activity. Siramesine was also effective against in vitro biofilm formation and already formed biofilm was reduced following 24 h treatment with a MBEC range of 50–62.5 µg/mL. Siramesine is involved in modulation of ergosterol biosynthesis in vitro, which indicates it is a potential target for its antifungal activity. This implicates the possibility of siramesine repurposing, especially since there are already published data about nontoxicity. Following our in vitro results, we provide additional in depth in silico analysis of siramesine and compounds structurally similar to siramesine, providing an extended lead set for further preclinical and clinical investigation, which is needed to clearly define molecular targets and to elucidate its in vivo effectiveness as well. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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25 pages, 2806 KiB

Open AccessArticle

Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein

by Virginia Spanò, Marilia Barreca, Vincenzo Cilibrasi, Michele Genovese, Mario Renda, Alessandra Montalbano, Luis Juan Vicente Galietta and Paola Barraja

Molecules 2021, 26(5), 1275; https://doi.org/10.3390/molecules26051275 - 26 Feb 2021

Cited by 21 | Viewed by 2283

Abstract

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named “correctors”. So [...] Read more.

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named “correctors”. So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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15 pages, 1090 KiB

Open AccessArticle

Possible Participation of Ionotropic Glutamate Receptors and l-Arginine-Nitric Oxide-Cyclic Guanosine Monophosphate-ATP-Sensitive K⁺ Channel Pathway in the Antinociceptive Activity of Cardamonin in Acute Pain Animal Models

by Chung Pui Ping, Muhammad Nadeem Akhtar, Daud Ahmad Israf, Enoch Kumar Perimal and Mohd Roslan Sulaiman

Molecules 2020, 25(22), 5385; https://doi.org/10.3390/molecules25225385 - 18 Nov 2020

Cited by 8 | Viewed by 2273

Abstract

The perception of pain caused by inflammation serves as a warning sign to avoid further injury. The generation and transmission of pain impulses involves various pathways and receptors. Cardamonin isolated from Boesenbergia rotunda (L.) Mansf. has been reported to exert antinociceptive effects in [...] Read more.

The perception of pain caused by inflammation serves as a warning sign to avoid further injury. The generation and transmission of pain impulses involves various pathways and receptors. Cardamonin isolated from Boesenbergia rotunda (L.) Mansf. has been reported to exert antinociceptive effects in thermal and mechanical pain models; however, the precise mechanism has yet to be examined. The present study investigated the possible mechanisms involved in the antinociceptive activity of cardamonin on protein kinase C, N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors, l-arginine/cyclic guanosine monophosphate (cGMP) mechanism, as well as the ATP-sensitive potassium (K⁺) channel. Cardamonin was administered to the animals intra-peritoneally. Present findings showed that cardamonin significantly inhibited pain elicited by intraplantar injection of phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator) with calculated mean ED₅₀ of 2.0 mg/kg (0.9–4.5 mg/kg). The study presented that pre-treatment with MK-801 (NMDA receptor antagonist) and NBQX (non-NMDA receptor antagonist) significantly modulates the antinociceptive activity of cardamonin at 3 mg/kg when tested with glutamate-induced paw licking test. Pre-treatment with l-arginine (a nitric oxide precursor), ODQ (selective inhibitor of soluble guanylyl cyclase) and glibenclamide (ATP-sensitive K⁺ channel inhibitor) significantly enhanced the antinociception produced by cardamonin. In conclusion, the present findings showed that the antinociceptive activity of cardamonin might involve the modulation of PKC activity, NMDA and non-NMDA glutamate receptors, l-arginine/nitric oxide/cGMP pathway and ATP-sensitive K⁺ channel. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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18 pages, 1940 KiB

Open AccessArticle

Acetamidine-Based iNOS Inhibitors as Molecular Tools to Counteract Inflammation in BV2 Microglial Cells

by Silvia Grottelli, Rosa Amoroso, Lara Macchioni, Fiorella D’Onofrio, Katia Fettucciari, Ilaria Bellezza and Cristina Maccallini

Molecules 2020, 25(11), 2646; https://doi.org/10.3390/molecules25112646 - 6 Jun 2020

Cited by 16 | Viewed by 2938

Abstract

Neurodegenerative diseases are associated with increased levels of nitric oxide (NO) mainly produced by microglial cells through inducible nitric oxide synthase (iNOS) whose expression is induced by inflammatory stimuli. NO can both exert cytotoxic functions and induce a metabolic switch by inhibiting oxidative [...] Read more.

Neurodegenerative diseases are associated with increased levels of nitric oxide (NO) mainly produced by microglial cells through inducible nitric oxide synthase (iNOS) whose expression is induced by inflammatory stimuli. NO can both exert cytotoxic functions and induce a metabolic switch by inhibiting oxidative phosphorylation and upregulating glycolytic flux. Here, we investigated whether two newly synthesized acetamidine based iNOS inhibitors, namely CM292 and CM544, could inhibit lipopolysaccharide (LPS)-induced BV2 microglial cell activation, focusing on both inflammatory and metabolic profiles. We found that CM292 and CM544, without affecting iNOS protein expression, reduced NO production and reverted LPS-induced inflammatory and cytotoxic response. Furthermore, in the presence of the inflammatory stimulus, both the inhibitors increased the expression of glycolytic enzymes. In particular, CM292 significantly reduced nuclear accumulation of pyruvate kinase M2, increased mitochondrial membrane potential and oxygen consumption rate, and augmented the expression of pyruvate dehydrogenase, pointing to a metabolic switch toward oxidative phosphorylation. These data confirm the role played by NO in the connection between cell bioenergetics profile and inflammation, and suggest the potential usefulness of iNOS inhibitors in redirecting microglia from detrimental to pro-regenerative phenotype. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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16 pages, 3983 KiB

Open AccessArticle

Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs

by Ting-Ting Li, Christophe Pannecouque, Erik De Clercq, Chun-Lin Zhuang and Fen-Er Chen

Molecules 2020, 25(7), 1581; https://doi.org/10.3390/molecules25071581 - 30 Mar 2020

Cited by 10 | Viewed by 3066

Abstract

Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most [...] Read more.

Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds B4 (EC₅₀ = 6 nM) and B6 (EC₅₀ = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC₅₀ values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC₅₀ = 0.08 μM). The preliminary structure–activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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14 pages, 1344 KiB

Open AccessArticle

Design, Synthesis and Study of Nitrogen Monoxide Donors as Potent Hypolipidaemic and Anti-Inflammatory Agents

by Panagiotis Theodosis-Nobelos, Georgios Papagiouvanis, Maria Pantelidou, Panos N. Kourounakis, Chrysoula Athanasekou and Eleni A. Rekka

Molecules 2020, 25(1), 19; https://doi.org/10.3390/molecules25010019 - 19 Dec 2019

Cited by 10 | Viewed by 2591

Abstract

Inflammation and oxidative stress are involved in cardiovascular diseases. Nitrogen monoxide participates in the regulation of endothelial processes. Thus, derivatives of classic nonsteroidal anti-inflammatory drugs (NSAIDs), trolox or cinnamic acids esterified with 2-(nitrooxy)ethanol were designed and studied. It was found that the nitrogen [...] Read more.

Inflammation and oxidative stress are involved in cardiovascular diseases. Nitrogen monoxide participates in the regulation of endothelial processes. Thus, derivatives of classic nonsteroidal anti-inflammatory drugs (NSAIDs), trolox or cinnamic acids esterified with 2-(nitrooxy)ethanol were designed and studied. It was found that the nitrogen monoxide (NO) releasing activity was comparable to that of S-nitroso-N-acetylpenicillamine. The nitrooxy derivatives decreased potently lipid indices in the plasma of hyperlipidaemic rats (30–85%). All compounds presented increased anti-inflammatory activity in vivo, inhibiting carrageenan-induced rat paw oedema as high as 76%, up to six times higher than that of the parent acids. Lipoxygenase inhibitory activity was significant for most of them, although the parent molecules exerted a minor effect (IC₅₀ > 0.2 mM). Those compounds incorporating an antioxidant structure inhibited rat microsomal membrane lipid peroxidation strongly and possessed radical scavenging activity. These results indicated that the described compounds could act at different targets in multifactorial diseases, further limiting the possible adverse effects of drug combinations. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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14 pages, 3420 KiB

Open AccessArticle

Kinesin Eg5 Targeting Inhibitors as a New Strategy for Gastric Adenocarcinoma Treatment

by Guya Diletta Marconi, Simone Carradori, Alessia Ricci, Paolo Guglielmi, Amelia Cataldi and Susi Zara

Molecules 2019, 24(21), 3948; https://doi.org/10.3390/molecules24213948 - 31 Oct 2019

Cited by 16 | Viewed by 3311

Abstract

The Kinesins are proteins involved in several biological processes such as mitosis, intracellular transport, and microtubule movement. The mitotic process is allowed by the correct formation of the mitotic spindle which consists of microtubules originating from the spindle poles. In recent years, kinesin [...] Read more.

The Kinesins are proteins involved in several biological processes such as mitosis, intracellular transport, and microtubule movement. The mitotic process is allowed by the correct formation of the mitotic spindle which consists of microtubules originating from the spindle poles. In recent years, kinesin Eg5 inhibitors were studied as new chemotherapeutic drugs, due to the lack of side effects and resistance mechanisms. The aim of this work was to investigate the molecular signaling underlying the administration of novel kinesis Eg5 inhibitors in an in vitro model of gastric adenocarcinoma. Data obtained from analogues of K858 led us to select compounds 2 and 41, due to their lower IC₅₀ values. The ability of kinesin inhibitors to induce apoptosis was investigated by evaluating Bax and Caspase-3 protein expression, evidencing that compound 41 and K858 markedly raise Bax expression, while only compounds 2 and 41 co-administrated with K858 trigger Caspase-3 activation. The inhibition of mitotic spindle was measured by β-tubulin immunofluorescence analysis revealing monopolar spindles formation in gastric cancer cells treated with compounds 2, 41, and K858. Nitric Oxide Synthase (NOS-2) and Matrix Metalloproteinase 9 (MMP-9) expression levels were measured finding a NOS-2-mediated downregulation of MMP-9 when compound 41 and K858 are co-administered. However, this is in contrast to what was reported by migration assay in which both novel compounds and K858 in monotherapy markedly reduce cell migration. This work remarks the importance of understanding and exploring the biological effects of different novel Eg5 kinesin inhibitors administered in monotherapy and in combination with K858 as potential strategy to counteract gastric cancer. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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Review

Jump to: Research

23 pages, 24326 KiB

Open AccessReview

Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria

by Sijongesonke Peter, Siphesihle Jama, Sibusiso Alven and Blessing A. Aderibigbe

Molecules 2021, 26(24), 7521; https://doi.org/10.3390/molecules26247521 - 11 Dec 2021

Cited by 17 | Viewed by 3764

Abstract

Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the [...] Read more.

Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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21 pages, 1778 KiB

Open AccessReview

Chalcone Scaffolds, Bioprecursors of Flavonoids: Chemistry, Bioactivities, and Pharmacokinetics

by Mithun Rudrapal, Johra Khan, Abdul Aziz Bin Dukhyil, Randa Mohammed Ibrahim Ismail Alarousy, Emmanuel Ifeanyi Attah, Tripti Sharma, Shubham Jagdish Khairnar and Atul Rupchand Bendale

Molecules 2021, 26(23), 7177; https://doi.org/10.3390/molecules26237177 - 26 Nov 2021

Cited by 70 | Viewed by 6128

Abstract

Chalcones are secondary metabolites belonging to the flavonoid (C₆-C₃-C₆ system) family that are ubiquitous in edible and medicinal plants, and they are bioprecursors of plant flavonoids. Chalcones and their natural derivatives are important intermediates of the flavonoid biosynthetic [...] Read more.

Chalcones are secondary metabolites belonging to the flavonoid (C₆-C₃-C₆ system) family that are ubiquitous in edible and medicinal plants, and they are bioprecursors of plant flavonoids. Chalcones and their natural derivatives are important intermediates of the flavonoid biosynthetic pathway. Plants containing chalcones have been used in traditional medicines since antiquity. Chalcones are basically α,β-unsaturated ketones that exert great diversity in pharmacological activities such as antioxidant, anticancer, antimicrobial, antiviral, antitubercular, antiplasmodial, antileishmanial, immunosuppressive, anti-inflammatory, and so on. This review provides an insight into the chemistry, biosynthesis, and occurrence of chalcones from natural sources, particularly dietary and medicinal plants. Furthermore, the pharmacological, pharmacokinetics, and toxicological aspects of naturally occurring chalcone derivatives are also discussed herein. In view of having tremendous pharmacological potential, chalcone scaffolds/chalcone derivatives and bioflavonoids after subtle chemical modification could serve as a reliable platform for natural products-based drug discovery toward promising drug lead molecules/drug candidates. Full article

(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)

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