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Molecules (Basel, Switzerland) Jun 2024Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome...
Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of -hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC values in the low μM range (1.1-7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure-activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents.
Topics: Hepatitis B virus; Virus Replication; Antiviral Agents; Ribonuclease H; Humans; Structure-Activity Relationship; Molecular Docking Simulation; Catalytic Domain; Oximes; Molecular Structure; Hep G2 Cells; Enzyme Inhibitors
PubMed: 38931006
DOI: 10.3390/molecules29122942 -
Molecules (Basel, Switzerland) Jun 2024The crystal structures of two newly synthesized nitrilotriacetate oxidovanadium(IV) salts, namely [QH][VO(nta)(HO)](HO) () and [(acr)H][VO(nta)(HO)](HO) (), were...
The crystal structures of two newly synthesized nitrilotriacetate oxidovanadium(IV) salts, namely [QH][VO(nta)(HO)](HO) () and [(acr)H][VO(nta)(HO)](HO) (), were determined. Additionally, the cytotoxic effects of four N-heterocyclic nitrilotriacetate oxidovanadium(IV) salts-1,10-phenanthrolinium, [(phen)H][VO(nta)(HO)](HO) (), 2,2'-bipyridinium [(bpy)H][VO(nta)(HO)](HO) (), and two newly synthesized compounds () and ()-were evaluated against prostate cancer (PC3) and breast cancer (MCF-7) cells. All the compounds exhibited strong cytotoxic effects on cancer cells and normal cells (HaCaT human keratinocytes). The structure-activity relationship analysis revealed that the number and arrangement of conjugated aromatic rings in the counterion had an impact on the antitumor effect. The compound (III), the 1,10-phenanthrolinium analogue, exhibited the greatest activity, whereas the acridinium salt (II), with a different arrangement of three conjugated aromatic rings, showed the lowest toxicity. The increased concentrations of the compounds resulted in alterations to the cell cycle distribution with different effects in MCF-7 and PC3 cells. In MCF-7 cells, compounds and were observed to block the G/M phase, while compounds and were found to arrest the cell cycle in the G/G phase. In PC3 cells, all compounds increased the rates of cells in the G/G phase.
Topics: Humans; Antineoplastic Agents; Breast Neoplasms; Male; Female; MCF-7 Cells; Prostatic Neoplasms; Nitrilotriacetic Acid; Structure-Activity Relationship; Cell Line, Tumor; Cell Proliferation; Heterocyclic Compounds; Vanadium; PC-3 Cells; Cell Cycle; Molecular Structure; Salts; Cell Survival; Apoptosis
PubMed: 38930989
DOI: 10.3390/molecules29122924 -
Molecules (Basel, Switzerland) Jun 2024Sulforaphane is a chiral phytochemical with chemopreventive properties. The presence of a stereogenic sulfur atom is responsible for the chirality of the natural...
Green HPLC Enantioseparation of Chemopreventive Chiral Isothiocyanates Homologs on an Immobilized Chiral Stationary Phase Based on Amylose tris-[()-α-Methylbenzylcarbamate].
Sulforaphane is a chiral phytochemical with chemopreventive properties. The presence of a stereogenic sulfur atom is responsible for the chirality of the natural isothiocyanate. The key role of sulfur chirality in biological activity is underscored by studies of the efficacy of individual enantiomers as chemoprotective agents. The predominant native () enantiomer is active, whereas the () antipode is inactive or has little or no biological activity. Here we provide an enantioselective high-performance liquid chromatography (HPLC) protocol for the direct and complete resolution of sulforaphane and its chiral natural homologs with different aliphatic chain lengths between the sulfinyl sulfur and isothiocyanate group, namely iberin, alyssin, and hesperin. The chromatographic separations were carried out on the immobilized-type CHIRALPAK IH-3 chiral stationary phase with amylose tris-[()-methylbenzylcarbamate] as a chiral selector. The effects of different mobile phases consisting of pure alcoholic solvents and hydroalcoholic mixtures on enantiomer retention and enantioselectivity were carefully investigated. Simple and environmentally friendly enantioselective conditions for the resolution of all chiral ITCs were found. In particular, pure ethanol and highly aqueous mobile phases gave excellent enantioseparations. The retention factors of the enantiomers were recorded as the water content in the aqueous-organic modifier (methanol, ethanol, or acetonitrile) mobile phases progressively varied. U-shaped retention maps were generated, indicating a dual and competitive hydrophilic interaction liquid chromatography (HILIC) and reversed-phase liquid chromatography retention mechanism on the CHIRALPAK IH-3 chiral stationary phase. Finally, experimental chiroptical studies performed in ethanol solution showed that the () enantiomers were eluted before the () counterpart under all eluent conditions investigated.
Topics: Isothiocyanates; Chromatography, High Pressure Liquid; Stereoisomerism; Amylose; Green Chemistry Technology
PubMed: 38930960
DOI: 10.3390/molecules29122895 -
Molecules (Basel, Switzerland) Jun 2024Based on the fact that substances with a β-phenyl-α,β-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity,...
Based on the fact that substances with a β-phenyl-α,β-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs - were prepared as potential tyrosinase inhibitors. Four analogs (- and ) inhibited mushroom tyrosinase strongly. Especially, analog showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs and competitively inhibited tyrosinase, whereas analogs and inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs and could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs , , and effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs , , and inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs and exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders.
Topics: Monophenol Monooxygenase; Agaricales; Animals; Antioxidants; Mice; Enzyme Inhibitors; Molecular Docking Simulation; Melanins; Thiazolidines; Cell Line, Tumor; Kinetics; Melanoma, Experimental; Benzylidene Compounds; Pyrones
PubMed: 38930952
DOI: 10.3390/molecules29122887 -
Molecules (Basel, Switzerland) Jun 2024Fluconazole (2-(2,4-difluorophenyl)-1,3-bis(1-1,2,4-triazol-1-yl)propan-2-ol), which was patented in 1981 and introduced for commercial use in 1988, is a widely utilized... (Review)
Review
Fluconazole (2-(2,4-difluorophenyl)-1,3-bis(1-1,2,4-triazol-1-yl)propan-2-ol), which was patented in 1981 and introduced for commercial use in 1988, is a widely utilized antifungal drug whose mechanism of action involves inhibition of the activity of 14-α lanosterol demethylase. Its safety and effectiveness have established it as one of the most frequently employed antifungal agents. Resistance to azole antifungal drugs is becoming more common. It may be related to a mutation of the gene encoding the enzyme. To address this issue, molecules with modifications in three main regions of fluconazole, namely the hydroxyl group, the aromatic ring, and the 1,2,4-triazole rings, have been synthesized in an attempt to create more potent antifungal drugs. These modifications aim at enhancing the effectiveness against microorganisms and improving pharmacokinetic parameters and safety profiles of the synthesized compounds. The present review explores the synthesis of fluconazole derivatives, accompanied by insights into the results of biological studies evaluating the therapeutic effects of these compounds.
Topics: Fluconazole; Antifungal Agents; Humans; Structure-Activity Relationship; Microbial Sensitivity Tests; Animals; Drug Resistance, Fungal; Molecular Structure
PubMed: 38930921
DOI: 10.3390/molecules29122855 -
Molecules (Basel, Switzerland) Jun 2024The geometric structure and bonding features of dinuclear vanadium-group transition metal carbonyl cation complexes in the form of VM(CO) ( = 9-11, M = V, Nb, and Ta)...
The geometric structure and bonding features of dinuclear vanadium-group transition metal carbonyl cation complexes in the form of VM(CO) ( = 9-11, M = V, Nb, and Ta) are studied by infrared photodissociation spectroscopy in conjunction with density functional calculations. The homodinuclear V(CO) is characterized as a quartet structure with C symmetry, featuring two side-on bridging carbonyls and an end-on semi-bridging carbonyl. In contrast, for the heterodinuclear VNb(CO) and VTa(CO), a C sextet isomer with a linear bridging carbonyl is determined to coexist with the lower-lying C structure analogous to V(CO). Bonding analyses manifest that the detected VM(CO) complexes featuring an (OC)M-V(CO) pattern can be regarded as the reaction products of two stable metal carbonyl fragments, and indicate the presence of the M-V covalent interaction in the C structure of VM(CO). In addition, it is demonstrated that the significant activation of the bridging carbonyls in the VM(CO) complexes is due in large part to the diatomic cooperation of M-V, where the strong oxophilicity of vanadium is crucial to facilitate its binding to the oxygen end of the carbonyl groups. The results offer important insight into the structure and bonding of dinuclear vanadium-containing transition metal carbonyl cluster cations and provide inspiration for the design of active vanadium-based diatomic catalysts.
PubMed: 38930895
DOI: 10.3390/molecules29122831 -
Molecules (Basel, Switzerland) Jun 2024Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril...
Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics.
Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer's. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau-amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer's drug design.
Topics: tau Proteins; Molecular Dynamics Simulation; Machine Learning; Molecular Docking Simulation; Humans; Protein Binding; Antioxidants; Amyloid; Catechin; Protein Aggregates
PubMed: 38930883
DOI: 10.3390/molecules29122818 -
Molecules (Basel, Switzerland) Jun 2024Aurones, particular polyphenolic compounds belonging to the class of minor flavonoids and overlooked for a long time, have gained significative attention in medicinal... (Review)
Review
Aurones, particular polyphenolic compounds belonging to the class of minor flavonoids and overlooked for a long time, have gained significative attention in medicinal chemistry in recent years. Indeed, considering their unique and outstanding biological properties, they stand out as an intriguing reservoir of new potential lead compounds in the drug discovery context. Nevertheless, several physicochemical, pharmacokinetic, and pharmacodynamic (P3) issues hinder their progression in more advanced phases of the drug discovery pipeline, making lead optimization campaigns necessary. In this context, scaffold hopping has proven to be a valuable approach in the optimization of natural products. This review provides a comprehensive and updated picture of the scaffold-hopping approaches directed at the optimization of natural and synthetic aurones. In the literature analysis, a particular focus is given to nitrogen and sulfur analogues. For each class presented, general synthetic procedures are summarized, highlighting the key advantages and potential issues. Furthermore, the biological activities of the most representative scaffold-hopped compounds are presented, emphasizing the improvements achieved and the potential for further optimization compared to the aurone class.
Topics: Nitrogen; Humans; Sulfur; Benzofurans; Biological Products; Structure-Activity Relationship; Drug Discovery; Animals; Molecular Structure
PubMed: 38930878
DOI: 10.3390/molecules29122813 -
Molecules (Basel, Switzerland) Jun 2024The diketopyrrolopyrrole (DPP) unit represents one of the building blocks more widely employed in the field of organic electronics; in most of the reported DPP-based...
The diketopyrrolopyrrole (DPP) unit represents one of the building blocks more widely employed in the field of organic electronics; in most of the reported DPP-based small molecules, this unit represents the electron acceptor core symmetrically coupled to donor moieties, and the solubility is guaranteed by functionalizing lactamic nitrogens with long and branched alkyl tails. In this paper, we explored the possibility of modulating the solubility by realizing asymmetric DPP derivatives, where the molecular structure is extended in just one direction. Four novel derivatives have been prepared, characterized by a common dithyenil-DPP fragment and functionalized on one side by a thiophene unit linked to different auxiliary electron acceptor groups. As compared to previously reported symmetric analogs, the novel dyes showed an increased solubility in chloroform and proved to be soluble in THF as well. The novel dyes underwent a thorough optical and electrochemical characterization. Electronic properties were studied at the DFT levels. All the dyes were used as active layers in organic field effect transistors, showing balanced charge transport properties.
PubMed: 38930874
DOI: 10.3390/molecules29122805 -
Molecules (Basel, Switzerland) Jun 2024Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised...
Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A () and echinosulfonic acids A-D (-). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid (), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3'-indolyl) acids and acetates (-) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3'-indolyl) and α-methine bis(3'-indolyl) analogues (, , and ) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3'-indolyl) alkaloids (, , , and ) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant . Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3'-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3'-indolyl) alkaloids.
Topics: Anti-Bacterial Agents; Indole Alkaloids; Cheminformatics; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship; Biological Products
PubMed: 38930871
DOI: 10.3390/molecules29122806