Discovery of novel human acrosin inhibitors by virtual screening

Human acrosin is an attractive target for the discovery of male contraceptive drugs. For the first time, structure-based drug design was applied to discover structurally diverse human acrosin inhibitors. A parallel virtual screening strategy in combination with pharmacophore-based and docking-based techniques was used to screen the SPECS database. From 16 compounds selected by virtual screening, a total of 10 compounds were found to be human acrosin inhibitors. Compound 2 was found to be the most potent hit (IC₅₀ = 14 μM) and its binding mode was investigated by molecular dynamics simulations. The hit interacted with human acrosin mainly through hydrophobic and hydrogen-bonding interactions, which provided a good starting structure for further optimization studies.     

Structure-guided fragment-based<Emphasis Type="Italic"> in silico</Emphasis> drug design of dengue protease inhibitors

An in silico fragment-based drug design approach was devised and applied towards the identification of small molecule inhibitors of the dengue virus (DENV) NS2B-NS3 protease. Currently, no DENV protease co-crystal structure with bound inhibitor and fully formed substrate binding site is available. Therefore a homology model of DENV NS2B-NS3 protease was generated employing a multiple template spatial restraints method and used for structure-based design. A library of molecular fragments was derived from the ZINC screening database with help of the retrosynthetic combinatorial analysis procedure (RECAP). 150,000 molecular fragments were docked to the DENV protease homology model and the docking poses were rescored using a target-specific scoring function. High scoring fragments were assembled to small molecule candidates by an implicit linking cascade. The cascade included substructure searching and structural filters focusing on interactions with the S1 and S2 pockets of the protease. The chemical space adjacent to the promising candidates was further explored by neighborhood searching. A total of 23 compounds were tested experimentally and two compounds were discovered to inhibit dengue protease (IC₅₀ = 7.7 μM and 37.9 μM, respectively) and the related West Nile virus protease (IC₅₀ = 6.3 μM and 39.0 μM, respectively). This study demonstrates the successful application of a structure-guided fragment-based in silico drug design approach for dengue protease inhibitors providing straightforward hit generation using a combination of homology modeling, fragment docking, chemical similarity and structural filters.     

Synthesis,characterization and biological activity studies of octahedral nickel(II) complexes

Abstract  

Three nickel(II) complexes, namely [Ni(BH)₃](H₂O)(NO₃)(ClO₄) 1, [Ni(BH)₂(NO₃)₂] 2 and [Ni(BH)(Tren)](ClO₄)₂ 3 (BH = Benzoylhydrazine, Tren = Tris(2-aminoethyl)amine) have been synthesized and characterized by physico-chemical techniques. X-ray crystallographic analysis shows the nickel to be six-coordinated in these complexes. The complexes are efficient catalysts for the dismutation of superoxide in alkaline DMSO-NBT assays. The IC₅₀ values are 74,108 and 105 μM for 1, 2 and 3, respectively.     

Synthesis,characterization, and urease inhibitory activity of two copper(II) complexes of cyclohexanecarboxylate

The crystal structures of two copper(II) complexes of the cyclohexanecarboxylate ligand, namely [Cu(C₆H₁₁CO₂)₂(H₂O)₂]·H₂O (1) and [Cu(dpyam)₂(C₆H₁₁CO₂)](NO₃)·H₂O (2) (C₆H₁₁CO₂H = cyclohexanecarboxylic acid; dpyam = di-2-pyridylamine), have been determined by single-crystal X-ray analysis. Complex 1 contains the square-planar trans-CuO₄ chromophore, while 2 shows the square pyramidal cis-distorted octahedral CuN₄OO′ chromophore. Both complexes were found to show strong inhibitory activity against jack bean urease (IC₅₀ = 1.75 and 8.57 μM for 1 and 2, respectively), when compared with acetohydroxamic acid (IC₅₀ = 63.12 μM).     

Discovery of a New Drug-like Series of OGT Inhibitors by Virtual Screening

O-GlcNAcylation is an essential post-translational modification installed by the enzyme O-β-N-acetyl-d-glucosaminyl transferase (OGT). Modulating this enzyme would be extremely valuable to better understand its role in the development of serious human pathologies, such as diabetes and cancer. However, the limited availability of potent and selective inhibitors hinders the validation of this potential therapeutic target. To explore new chemotypes that target the active site of OGT, we performed virtual screening of a large library of commercially available compounds with drug-like properties. We purchased samples of the most promising virtual hits and used enzyme assays to identify authentic leads. Structure-activity relationships of the best identified OGT inhibitor were explored by generating a small library of derivatives. Our best hit displays a novel uridine mimetic scaffold and inhibited the recombinant enzyme with an IC₅₀ value of 7 µM. The current hit represents an excellent starting point for designing and developing a new set of OGT inhibitors that may prove useful for exploring the biology of OGT.     

Virtual and experimental high-throughput screening (HTS) in search of novel inosine 5′-monophosphate dehydrogenase II (IMPDH II) inhibitors

IMPDH (Inosine 5??-monophosphate dehydrogenase) catalyzes a rate-limiting step in the de novo biosynthesis of guanine nucleotides. IMPDH inhibition in sensitive cell types (e.g., lymphocytes) blocks proliferation (by blocking RNA and DNA synthesis as a result of decreased cellular levels of guanine nucleotides). This makes it an interesting target for cancer and autoimmune disorders. Currently available IMPDH inhibitors such as mycophenolic acid (MPA, uncompetitive inhibitor) and nucleoside analogs (e.g., ribavirin, competitive inhibitor after intracellular activation by phosphorylation) have unfavorable tolerability profiles which limit their use. Hence, the quest for novel IMPDH inhibitors continues. In the present study, a ligand-based virtual screening using IMPDH inhibitor pharmacophore models was performed on in-house compound collection. A total of 50,000 virtual hits were selected for primary screen using in vitro IMPDH II inhibition up to 10???M. The list of 2,500 hits (with >70?% inhibition) was further subjected to hit confirmation for the determination of IC₅₀ values. The hits obtained were further clustered using maximum common substructure based formalism resulting in 90 classes and 7 singletons. A thorough inspection of these yielded 7 interesting classes in terms of mini-SAR with IC₅₀ values ranging from 0.163???M to little over 25???M. The average ligand efficiency was found to be 0.3 for the best class. The classes thus discovered represent structurally novel chemotypes which can be taken up for further development.     

Synthesis,Characterization and Crystal Structures of New Difurylphosphido-bridged Dinuclear Ruthenium Carbonyl Complexes Derived from Ferrocenylacetylene Ligands

The difurylphosphido-bridged dinuclear complex [Ru₂(CO)₆(μ-PFu₂)(μ-η¹,η²-Fu)] (Fu = 2-furyl) 1 readily reacts with two equivalents of each of the terminal alkynes HC≡CR (R = Fc, p-C₆H₄Fc, p-C₆H₄NO₂, Fc = Fe(η⁵-C₅H₅)(η⁵-C₅H₄)) by an interesting head-to-tail ynyl coupling with a furan group to form a series of phosphido-bridged diruthenium compounds containing a novel furyl-substituted C₄ hydrocarbyl chain of stoichiometry [Ru₂(CO)₄(μ-PFu₂){μ-η¹,η¹,η²,η³-RCC(H)C(R)C(H)Fu}] (R = Fc 2, p-C₆H₄Fc 3, p-C₆H₄NO₂ 4) in moderate to good yields. Reaction of 1 with an equimolar amount of HC≡CFc and HC≡C(p-C₆H₄NO₂) afforded a pair of isomers of [Ru₂(CO)₄(μ-PFu₂){μ-η¹,η¹,η²,η³-R¹CC(H)C(R²)C(H)Fu}] (R¹ = Fc, R² = p-C₆H₄NO₂ 5a; R¹ = p-C₆H₄NO₂, R² = Fc 5b) together with a small mixture of 4. X-ray crystal structures of 2, 3, 5a and 5b are reported. All of these new alkyne-derived dinuclear complexes are electron precise with 34 cluster valence electrons in which the μ-η¹,η²-furyl ligand acts as a three-electron donor and the μ-phosphido Ru₂ framework is retained in the products upon alkyne coupling reactions. The resulting organic fragment of each complex is coordinated to the Ru atoms via a π, a π-allyl and two σ bonds, and donates seven electrons to the metal core. Dedicated to the memory of Professor F. Albert Cotton.     

Synthesis and Anticancer Activity of Long-Chain Isonicotinic Ester Ligand-Containing Arene Ruthenium Complexes and Nanoparticles

Arene ruthenium complexes containing long-chain N-ligands L¹ = NC₅H₄–4-COO–C₆H₄–4-O–(CH₂)₉–CH₃ or L² = NC₅H₄–4-COO–(CH₂)₁₀–O–C₆H₄–4-COO–C₆H₄–4-C₆H₄–4-CN derived from isonicotinic acid, of the type [(arene)Ru(L)Cl₂] (arene = C₆H₆, L = L¹: 1; arene = p-MeC₆H₄Pr ⁱ , L = L¹: 2; arene = C₆Me₆, L = L¹: 3; arene = C₆H₆, L = L²: 4; arene = p-MeC₆H₄Pr ⁱ , L = L²: 5; arene = C₆Me₆, L = L²: 6) have been synthesized from the corresponding [(arene)RuCl₂]₂ precursor with the long-chain N-ligand L in dichloromethane. Ruthenium nanoparticles stabilized by L¹ have been prepared by the solvent-free reduction of 1 with hydrogen or by reducing [(arene)Ru(H₂O)₃]SO₄ in ethanol in the presence of L¹ with hydrogen. These complexes and nanoparticles show a high anticancer activity towards human ovarian cell lines, the highest cytotoxicity being obtained for complex 2 (IC₅₀ = 2 μM for A2780 and 7 μM for A2780cisR).     

Synthesis, crystal and molecular structures of an isomorphic N, S-bridged [Cu2(μ2-I)2(PPh3)2(μ2-N, S-pymSH)] dimer and S-bonded [CuX(η1-S-pymSH)(PPh3)2] monomers (X = Cl, Br)

Abstract  Monoclinic crystals of [Cu₂(μ-I)₂(PPh₃)₂(μ-N, S-pymSH)] · CH₃CN) (1), were obtained by equimolar reaction of copper(I) iodide with pyrimidine-2-thione (pymSH), followed by the addition of triphenylphosphine (PPh₃) in acetonitrile. Crystal data for 1: space group P2₁, Z = 2, a = 9.896, b = 18.378, c = 11.703 ?, β = 101.73°. It has an iodo-bridged Cu(μ-I)₂Cu core and the pyrimdine-2-thione binds to both Cu centers via N, S-bridging across the Cu(μ-I)₂Cu core. This N, S-bridging, a rare coordination mode for pyrimidine-2-thione, leads to a short Cu···Cu separation of 2.675(2) ? (sum of van der Waals radius of Cu atoms, 2.80 ?). The geometry around each Cu center is distorted tetrahedral with angles varying in the range, ca. 102–119°. Copper(I) chloride and bromide also yielded monoclinic crystals of S-bonded tetrahedral monomers, [CuBr(pymSH)(PPh₃)₂] 2 and [CuCl(pymSH)(PPh₃)₂] 3. Crystal data for 2: space group P2₁/n, Z = 8, a = 12.825, b = 43.122, c = 13.396 ?, β = 90.79°. Crystal data for 3: space group P2₁/c, Z = 4, a = 14.340, b = 10.111, c = 24.200 ?, β = 94.36°. Compound 2 has two crystallographically independent molecules in crystal lattice. The ³¹P NMR spectrum of 1 showed two signals for PPh₃ ligands bonded to two Cu centers with different coordination cores: CuI₂PN and CuI₂PS. Both 2 and 3 showed one signal each for PPh₃ in their ³¹P NMR spectra. Graphical abstract  Reaction of copper(I) iodide with pyrimidine-2-thione and triphenylphosphine formed monoclinic crystals of dimer 1 with unusual N, S-bridging across Cu(μ₂-I)₂Cu core.      

Optimization of pyrazolo[1,5-a]pyrimidine based compounds with pyridine scaffold: Synthesis,biological evaluation and molecular modeling study

BackgroundPyrazolopyrimidine heterocycle and its isosteres represent the main scaffold for many pharmacologically active drugs including anti-inflammatory agents. The COX-2 inhibitors are the principal gate for the design of new safe and potent anti-inflammatory agents.MethodsNovel derivatives of pyrazolo[1,5-a] pyrimidines were synthesized and screened in vivo and in vitro for their anti-inflammatory potential.ResultsWithin the constructed compounds, compound 11 was the most active compound on IL-6 and TNF-α (percentage inhibition = 80 and 89%, respectively). In addition, compound 12 displayed the most inhibitory effect towards COX-2 (IC₅₀ = 1.11 µM), whereas compound 11 recorded the highest COX-2 selectivity (S.I = 8.97). The target derivatives 11–14 displayed good edema inhibitory potential (46–68%) and compound 11 was the most potent candidate (ED₅₀ = 35 mg/kg). Additionally, the most potent sPLA2-V inhibitors were compounds 11 and 13 (IC₅₀ = 1 and 1.7 µM respectively). Regarding activity towards 15-LOX, derivative 12 was the most active compound with IC₅₀ = 5.6 µM revealing higher inhibitory activity than nor-dihydroguaiaretic acid (IC₅₀ = 8.5 µM). To confirm the anti-inflammatory potential of the target derivatives, molecular modeling was performed inside COX-2 and 15-LOX active sites.ConclusionDisplay discoveries increment the plausibility that these pyrazolo[1,5-a]pyrimidines might act as a beginning point for the improvement of anti-inflammatory agents.     

A Series of 1-D Lanthanide Coordination Polymers Based on [Ln4(μ3-OH)4] (Ln = Er, Tb, Gd) Cluster Units

Abstract  

A series of 1-D lanthanide coordination polymers [Ln(μ₃-OH)(pybz)(pa)] _n (Ln = Er (1), Tb (2), Gd (3), Hpybz = 4-pyridin-4-yl-benzoic acid, Hpa = 2-picolinic acid) based on [Ln₄(μ₃-OH)₄] cluster units have been hydrothermally synthesized and characterized by single crystal X-ray diffraction, IR, elemental analysis, and thermogravimetric analysis. X-ray crystal structure analyses reveal that 1–3 are isomorphous with tetragonal space group P [`4] \overline{4} 2₁c and comprise tetranuclear Ln–O clusters, in which four Ln³⁺ centers are joined together by four μ₃-bridging hydroxyl groups to form cubane-like [Ln₄(μ₃-OH)₄]⁸⁺ cores that are further linked by four μ₃-pa⁻ ligands to produce 1-D chains along the c-axis.     

Antioxidant activityofaromatic alkaloids from the marine sponges <Emphasis Type="Italic">Aaptos aaptos</Emphasis> and <Emphasis Type="Italic">Hyrtios</Emphasis> SP.

Aaptamine (1) and isoaaptamine (2) were isolated from the marine sponge Aaptos aaptos; 6-bromo-2′-de-N-methylaplysinopsin (3) from the marine sponge Hyrtios sp. Alkaloids 1–3 were tested for the ability to trap 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, to reduce Folin–Ciocalteau reagent (FCR), and to inhibit oxidation of linoleic acid (LA) induced by peroxide radicals. Compounds 1 (IC₅₀ 18 μM), 2 (IC₅₀ 16 μM), and 3 (IC₅₀ 18 μM) reacted strongly with DPPH, comparable with trolox (IC₅₀ 16 μM) and showed high reducing ability for FCR. The inhibition of LA oxidation by 1–3 was comparable with that of ionol (BHT). It was shown that the antioxidant activity of 1–3 was related to their ability to release both electrons and H atoms.     

Evaluation of the synergetic radio-chemotherapy effects of the radio labelled cisplatin for the treatment of glioma

The proposal of this work was to investigate the effect of the radioactive (NH₃)₂PtCl₂, cis-diamminedichloroplatinum (II) or CDDP* on malignant glioma cells and verify if the low-dose continuous internal radio-chemotherapy would be able to produce additive effects. The antitumoral activity of CDDP* and the non labeled cisplatin, CDDP, were evaluated in glioblastoma. Cisplatin was cytotoxic for glioblastoma cells in a dose dependent manner. Treatment with CDDP*, (IC₅₀ = 1.75 ± 0.07 μM), proved to be more potent than using just CDDP, (IC₅₀ = 4.96 ± 0.40 μM). These results suggest that cisplatin is a very potent radiosensitizer evoking a supra additive effect. Internal radio-chemotherapy treatment based on CDDP* may be useful alternative to reduce the drug concentration required for effective inhibition of glioblastoma growth.     

Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling,molecular docking, 3D-QSAR model and binding free energy calculation studies

B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔG_bind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC₅₀ < 50 μM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs.     

Synthesis, structure, and properties of a binuclear Fe(III) complex with N-(1-propanol)-N,N-bis(3-tert-butyl-5-methyl-2-hydroxybenxyl)amine

Mannich reaction of 2-Amino propanol, 2-tert-butyl-4-methylphenol, and formaldehyde in the ratio of 1:2:2 provides a new compound, N-(1-propanol)-N,N-bis(3-tert-butyl-5-methyl-2-hydroxybenxyl)amine (H₃L), which has been characterized by X-ray crystallography and elemental analysis. In the presence of Et₃N, the reaction of H₃L and FeCl₃·6H₂O gives a dinuclear Fe(III) complex [Fe₂L₂] 1, which has been characterized by X-ray crystallography, magnetic measurement, and cyclic voltammetry. The value of μ_eff at room temperature (5.97 μ_B) is much less than the expected spin-only value (8.37 μ_B) of two high spin (hs) Fe³⁺ (S = 5/2) ions [μ = g[∑ZS(S + 1)]^1/2], indicating there are strong coupling interactions between Fe³⁺ ions. The magnetic behavior of 1 denotes the occurrence of intramolecular antiferromagnetic interactions (J = −13.35 cm⁻¹ ). CV of 1 reveals two reversible waves at 0.433 and 1.227 V versus AgCl/Ag, which can be ascribed to the successive redox coupling of Fe^IIFe^II/Fe^IIIFe^II and Fe^IIIFe^II/Fe^IIIFe^III, respectively.     

Lanthanide-Organic Frameworks Based on {Ln<Subscript>4</Subscript>(μ<Subscript>3</Subscript>-OH)<Subscript>4</Subscript>(μ<Subscript>2</Subscript>-OH)<Subscript>2</Subscript>} Cluster Units

Abstract  

Three novel lanthanide-organic frameworks: [Ln₂(pyba)₃(μ₃-OH)₂(μ₂-OH)(H₂O)] _n (Ln = Er (1), Y (2), Dy (3) Hpyba = 4-pyridin-4-yl-benzoic acid) have been hydrothermally synthesized and structurally characterized by single crystal X-ray diffraction. Structure analysis shows that each {Ln₄(μ₃-OH)₄(μ₂-OH)₂} cluster units interconnect to form 1-D chains, which are further linked by π–π interactions to make a 3-D supramolecular network structure. Furthermore, the IR, PXRD and TGA of compounds 1–3 were also studied.     

Virtual screening of dipeptidyl peptidase-4 inhibitors using quantitative structure–activity relationship-based artificial intelligence and molecular docking of hit compounds

Dipeptidyl peptidase-4 (DPP-4) inhibitors are becoming an essential drug in the treatment of type 2 diabetes mellitus; however, some classes of these drugs exert side effects, including joint pain and pancreatitis. Studies suggest that these side effects might be related to secondary inhibition of DPP-8 and DPP-9. In this study, we identified DPP-4-inhibitor hit compounds selective against DPP-8 and DPP-9. We built a virtual screening workflow using a quantitative structure–activity relationship (QSAR) strategy based on artificial intelligence to allow faster screening of millions of molecules for the DPP-4 target relative to other screening methods. Five regression machine learning algorithms and four classification machine learning algorithms were applied to build virtual screening workflows, with the QSAR model applied using support vector regression (R²_pred 0.78) and the classification QSAR model using the random forest algorithm with 92.2% accuracy. Virtual screening results of > 10 million molecules obtained 2 716 hits compounds with a pIC₅₀ value of > 7.5. Additionally, molecular docking results of several potential hit compounds for DPP-4, DPP-8, and DPP-9 identified CH0002 as showing high inhibitory potential against DPP-4 and low inhibitory potential for DPP-8 and DPP-9 enzymes. These results demonstrated the effectiveness of this technique for identifying DPP-4-inhibitor hit compounds selective for DPP-4 and against DPP-8 and DPP-9 and suggest its potential efficacy for applications to discover hit compounds of other targets.     

Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment‐Based Drug Design Facilitated by Dynamic Combinatorial Chemistry

Fragment‐based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit‐identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X‐ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis‐acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC₅₀ value of 54 nm , which represents a 240‐fold improvement in potency compared to the parent hits. Subsequent X‐ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit‐identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit‐to‐lead optimization.     

Photochemical reactions of M(CO)5THF (M = Cr, Mo, W) with thio Schiff bases

The hitherto unknown complexes, [M₂(CO)₆(μ-CO)(μ-L)], [M = Cr; 1, Mo; 2, W; 3] and [M₂(CO)₆(μ-CO)(μ-L′)], [M = Cr; 4, Mo; 5, W; 6] have been synthesized by the photochemical reactions of photogenerated intermediate, M(CO)₅THF (M = Cr, Mo, W) with thio Schiff base ligands, N,N′-bis(2-aminothiophenol)-1,4-bis(2-carboxaldehydephenoxy)butane (H ₂ L) and N,N′-bis(2-aminothiophenol)-1,7-bis(2-formylphenyl)-1,4,7-trioxaheptane (H ₂ L′). The complexes have been characterized by elemental analysis, LC-mass spectrometry, magnetic studies, FT-IR and ¹H NMR spectroscopy. The spectroscopic studies show that H ₂ L and H ₂ L′ ligands are converted to benzothiazole derivatives, L and L′ after UV irradiation and coordinated to the central metal as bridging ligands via the central azomethine nitrogen and sulphur atoms in 1–6.     

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.

Fragment-based screening of a shape-diverse collection yielded four hits against three proteins. Up to 14 analogues of each hit were rapidly generated, enabling four fragment growth vectors to be explored using inexpensive materials and reliable synthetic transformations.