Hybrid Pharmacophore Design,Molecular Docking,Synthesis, and Biological Evaluation of Novel Aldimine‐Type Schiff Base Derivatives as Tubulin Polymerization Inhibitor

A series of hybrid aldimine‐type Schiff base derivatives including trimethoxyphenyl ring and 1,2,4‐triazole‐3‐thiol/thione were designed as tubulin inhibitors. The molecular docking simulations on tubulin complex (PDB: 1SA0) revealed that derivatives with nitro and/or chloro or dimethylamino substitutes (4‐nitro, 2‐nitro, 3‐nitro, 4‐Cl‐3‐nitro, and 4‐Me₂N) on the aldehyde ring were the best compounds with remarkable binding energies (?9.09, ?9.07, ?8.63, ?8.11, and ?8.07 kcal mol^?1, respectively) compared to colchicine (?8.12 kcal mol^?1). These compounds were also showed remarkable binding energies from ?10.66 to ?9.79 and ?10.12 to ?8.95 kcal mol^?1 on human (PDB: 1PD8) and Candida albicans (PDB: 3QLS) DHFR, respectively. The obtained results of cytotoxic activities against HT1080, HepG2, HT29, MCF‐7, and A549 cancer cell lines indicated that 4‐nitro and 2‐nitro substituted compounds were the most effective agents by mean IC₅₀ values of 11.84 ± 1.01 and 19.92 ± 1.36 μm , respectively. 4‐Nitro substituted compound (5 μm ) and 2‐nitro substituted compound (30 μm ) were able to strongly inhibit the tubulin polymerization compared to colchicine (5 μm ) and 4‐nitro substituted compound displayed IC₅₀ values of 0.16 ± 0.01 μm compared to that of colchicine (0.19 ± 0.01 μm ). This compound also showed the lowest MIC values on all tested microbial strains including three Gram‐positive, four Gram‐negative, and three yeast pathogens.     

Synthesis and in Vitro Antiviral Activities of [(Dihydrofuran‐2‐yl)oxy]methyl‐phosphonate Nucleosides with 2‐Substituted Adenine as Base

The synthesis of [(2′,5′‐dihydrofuran‐2‐yl)oxy]methyl‐phosphonate nucleosides with a 2‐substituted adenine base moiety starting from 2‐deoxy‐3,5‐bis‐O‐(4‐methylbenzoyl)‐α‐L ‐ribofuranosyl chloride and 2,6‐dichloropurine is described. The key step is the regiospecific and stereoselective introduction of a phosphonate synthon at C(2) of the furan ring. None of the synthesized compounds showed significant in vitro activity against HIV, BVDV, and HBV.     

Synthesis and in vitro antioxidant activity study of some new piperazinyl flavone compounds

Flavones exhibit a variety of beneficial effects and are well known for their medicinal importance in several diseases, including cardiovascular, neurodegenerative and cancer. The inclusion of the piperazine ring to the flavone backbone is an important strategy in drug discovery but only a few studies have synthesized piperazinyl flavone compounds to test their biological activity. While there is a major focus on the antioxidant properties of drugs in therapy of several diseases of inflammatory origin, we synthesized a series of the novel piperazinyl flavone analogues bearing the phenyl ring with different substituents. The analogues were evaluated for in vitro antioxidant activity against superoxide anion radical, hydroxyl radical, 2,2‐diphenyl‐1‐picrylhydrazyl radical, and hydrogen peroxide scavenging properties. The total antioxidant status based on the absorbance of the 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulphonic acid) radical cation (ABTS^+?) and total antioxidant capacity using the Fe(III)‐ferrozine complex were also monitored. The results of the above studies showed that the compounds synthesized were found possessed moderate radical scavenging potential, and that their interaction with reactive oxygen species is complex and depends on their structural conformation and the type of substituent R in the piperazine ring being attached. Best antiradical activity were found for the compounds with methoxy groups on the phenyl ring of substituent R, whereas the presence of methoxy or trifluoromethyl groups in substituent R resulted in higher ABTS^+? and ion Fe(III) reduction. These compounds are promising molecules to be used for their antioxidant properties and may be regarded, after improvement of the antioxidant potential, to control diseases of free radical etiology.     

Synthesis and Characterization of Novel Thiazolo[3,2‐a]pyrimidine Derivatives and Evaluation of Antioxidant and Cytotoxic Activities

A series of novel thiazolo[3,2‐a]pyrimidines were synthesized and characterized by FT‐IR, ¹H, ¹³C‐NMR and mass techniques. Their antioxidant activities were investigated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical scavenging assay and the results showed that all the synthesized compounds exhibit good antioxidant activity. In addition, it was found that any substituent on the aromatic ring of the products plays an important role in their antioxidant activity. In vitro cytotoxicity of compounds 4a – 4j was investigated using MTT cell viability assay. Among these compounds, 6‐ethyl 2,3‐dimethyl 5‐(4‐chlorophenyl)‐7‐methyl‐2,3‐dihydro‐5H‐[1,3]thiazolo[3,2‐a]pyrimidine‐2,3,6‐tricarboxylate ( 4e ) bearing a chlorine substituent displayed the highest cytotoxic effect (IC₅₀=6.26±0.6 μm ) in comparison with doxorubicin (IC₅₀=0.68±0.1 μm ) as a standard after 72 h. Therefore, it is assumed that these compounds could be used as effective antioxidant and cytotoxic agents.     

First Synthesis of Double Headed 1,3,4‐Oxadiazino[6,5‐b]indole Acyclo C‐Nucleosides

Condensation of 1,3‐dihydro‐2,3‐dioxo‐2H‐indoles (1a–c) with galactaric acid bis hydrazide (2) gave the corresponding galactaric acid bis[2‐(1,2‐dihydro‐2‐oxo‐3H‐indol‐3‐ylidene)hydrazides] (3a–c). Acetylation of the latter compounds with acetic anhydride in the presence of pyridine at ambient temperature gave the 2,3,4,5‐tetra‐O‐acetylgalactaric acid bis[2‐(1,2‐dihydro‐2‐oxo‐1‐substituted‐3H‐indol‐3‐ylidene)hydrazides] (4b–d). Heterocyclization of the tetra‐O‐acetates 4b–d by heating with thionyl chloride afforded the double headed acyclo C‐nucleosides: 1,2,3,4‐tetra‐O‐acetyl‐1,4‐bis{9‐substituted‐1,3,4‐oxadiazino[6,5‐b]indol‐2‐yl‐1‐ium}‐galacto‐tetritol dichlorides (5b–d). Structures of the prepared compounds were elucidated from their spectral properties.     

New phthalimide‐appended Schiff bases: Studies of DNA binding,molecular docking and antioxidant activities

Herein, we investigated new phthalimide‐based Schiff base molecules as promising DNA‐binding and free radical scavenging agents. Physicochemical properties of these molecules were demonstrated on the basis of elemental analysis, ultraviolet–visible (UV–Vis), infra‐red (IR), ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy. All spectral data are agreed well with the proposed Schiff base framework. The DNA‐binding potential of synthesized compounds were investigated by means of UV–visible, fluorescence, iodide quenching, circular dichroism, viscosity and thermal denaturation studies. The intrinsic binding constants (K _b) were calculated from absorption studies were found to be 1.1 × 10⁴ and 1.0 × 10⁴ M^?1 for compounds 2a and 2b suggesting that compound 2a binding abilities with DNA were stronger than the compound 2b. Our studies showed that the presented compounds interact with DNA through groove binding. Molecular docking studies were carried out to predict the binding between Ct‐DNA and test compounds. Interestingly, in silico predictions were corroborated with in vitro DNA‐binding conclusions. Furthermore, the title compounds displayed remarkable antioxidant activity compared with reference standard.     

Synthesis of a New Series of 1H‐Imidazol‐1‐yl Substituted 8‐Phenylxanthines as Adenosine Receptor Ligands

A new series of 1H‐imidazol‐1‐yl substituted 8‐phenylxanthine analogs has been synthesized to study the effects of the imidazole group on the binding affinity of compounds for adenosine receptors. Competition binding studies of these compounds were carried out in vitro with human cloned receptors using [³H]DPCPX and [³H]ZM 241385 as radioligands at A₁ and A_2A adenosine receptors, respectively. The effect of the substitution pattern of the (imidazolyl)alkoxy group on various positions of the phenyl ring at C(8) was also studied. The xanthine derivatives displayed varying degrees of affinity and selectivity towards A₁ and A_2A receptor subtypes despite a common but variedly substituted Ar C(8).     

Novel Nucleolipids of Pyrimidine β‐D‐Ribonucleosides: Combinatorial Synthesis,Spectroscopic Characterization,and Cytostatic/Cytotoxic Activities

Four series of nucleolipids with either uridine, 5‐methyluridine, 5‐fluorouridine, and 6‐azauridine as β‐D ‐ribonucleoside component have been prepared in a combinatorial (not parallel!) manner (see Formulae). All compounds have been characterized by elemental analyses, ESI mass spectrometry as well as by ¹H‐, and ¹³C‐NMR, and UV spectroscopy. A selection of eight nucleolipids with different lipophilizing moieties, based on earlier findings, as well as of 5‐fluorouridine as control were first tested on their cytotoxic effect towards PMA‐differentiated human THP‐1 macrophages. Those compounds which did not exhibit a significant inhibitory effect on the survival of the macrophages were next tested on their cytostatic/cytotoxic effect towards the human astrocytoma/oligodendroglioma GOS‐3 cells as well as against the rat malignant neuroectodermal BT4Ca cell line. Additionally, induction of apoptosis of the cell lines was evaluated. It turned out that particularly a combined lipophilization of the nucleosides by an 2′,3′‐O‐ethyl levulinate residue plus a farnesyl moiety at N(3) of the pyrimidine moiety of the corresponding nucleolipids leads to an active compound with the highest probability.     

Biologically Active Heterocyclic Hybrids Based on Quinazolinone,Benzofuran and Imidazolium Moieties: Synthesis,Characterization, Cytotoxic and Antibacterial Evaluation

Cytotoxic and antimicrobial agents structurally based on quinazolinone, benzofuran and imidazole pharmacophores, have been designed and synthesized. Spectral (IR, ¹H‐NMR) and elemental analysis data established the structures of these novel 3‐[1‐(1‐benzofuran‐2‐yl)‐2‐(4‐oxoquinazolin‐3(4H)‐yl)ethyl]‐1‐methyl‐1H‐imidazol‐3‐ium chloride hybrid derivatives. All the synthesized compounds were evaluated for in vitro cytotoxicity and antimicrobial activities. Cytotoxic evaluation using MTT assay revealed that compounds 12c , 12g and 12i exhibited significant cytotoxicity with IC₅₀ values 1, 1, and 0.57 μm on this cell line, respectively. Biological activity of the synthesized compounds as antibacterial agent were also evaluated against three Gram‐negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram‐positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast‐like fungi (Candida albicans) strains. All compounds 12a  –  12i showed slightly higher activity against Gram‐positive bacteria than the Gram‐negative one. Among the nine new compounds screened, 3‐[1‐(5‐bromo‐1‐benzofuran‐2‐yl)‐2‐(6‐chloro‐4‐oxoquinazolin‐3(4H)‐yl)ethyl]‐1‐methyl‐1H‐imidazol‐3‐ium chloride ( 12e ) has pronounced higher antimicrobial activity against all tested strains. These results demonstrated potential importance of molecular hybridization in the development of new lead molecules with major cytotoxicity and antimicrobial activity.     

Synthesis of 8‐Substituted 2′‐Deoxyisoguanosines via Unprotected 8‐Brominated 2‐Amino‐2′‐deoxyadenosine

A variety of applications of 8‐alkynylated nucleosides has prompted the synthesis of new purine analogues. Bromination of unprotected 2‐amino‐2′‐deoxyadenosine with Br₂/AcOH/AcONa gives 2‐amino‐8‐bromo‐2′‐deoxyadenosine (87%). The brominated derivative is converted to 8‐alkynylated 2‐amino‐2′‐deoxyadenosines by palladium‐catalyzed Sonogashira cross‐coupling reaction via microwave assistance (81 – 95%). The resulting compounds are further transformed to 8‐alkynylated 2′‐deoxyisoguanosines (52 – 70%). The physical properties of new compounds are investigated.     

Nucleosides. IX. Synthesis of Purine N 3,5′‐Cyclonucleosides and N 3,5′‐Cyclo‐2′,3′‐seconucleosides via Mitsunobu Reaction as TIBO‐like Derivatives

The Mitsunobu reaction was applied to prepare, in one step, purine N ³,5′‐cyclonucleosides 10a–d. A subsequent ring opening in the ribose moiety of the resultant N ³,5′‐nucleosides by sodium periodate led to the corresponding N ³,5′‐cyclo‐2′,3′‐seconucleosides. These products consist of 5‐, 6‐, and 7‐membered tricyclic system which is the basic skeleton of TIBO derivatives, known antiviral agents.     

Design,Synthesis and in Vitro Tumor Cytotoxicity Evaluation of 3,5‐Diamino‐N‐substituted Benzamide Derivatives as Novel GSK‐3β Small Molecule Inhibitors

Glycogen synthase kinase‐3 (GSK‐3) plays an important regulatory role in various signaling pathways; such as PI3 K/AKT, which is closely related to the occurrence and development of tumors. At present, the most reported active GSK‐3 inhibitors have the same structure: lactam ring or amide structure. To find out the GSK‐3β small molecule inhibitor with novel, safe, efficient and more uncomplicated synthesis method, we analyzed in‐depth reported crystal‐binding patterns of GSK‐3β small molecule inhibitor with GSK‐3β protein, and designed and synthesized 17 non‐reported 3,5‐diamino‐N‐substituted benzamide compounds. Their structures were confirmed by ¹H‐NMR, ¹³C‐NMR, and HR‐MS. The preliminary screening of tumor cytotoxicity of compounds in vitro was detected by MTT, and their structure–activity relationships were illustrated. The results have shown that 3,5‐diamino‐N‐[3‐(trifluoromethyl)phenyl]benzamide ( 4d ) exhibited significant tumor cytotoxicity against human colon cancer cells (HCT‐116) with IC₅₀ of 8.3 μm and showed commendable selectivity to GSK‐3β. In addition, Compound 4d induced apoptosis to some extent and possessed modest PK properties.     

Regioselective Synthesis of Indazole N 1‐ and N 2‐(β‐d‐Ribonucleosides)

The regioselective synthesis of 4‐nitroindazole N ¹‐ and N ²‐(β‐d‐ribonucleosides) (8, 9, 1b and 2b) is described. The N ¹‐regioisomers are formed under thermodynamic control of the glycosylation reaction [fusion reaction or Silyl Hilbert‐Johnson glycosylation for 48 h (66%)], while the kinetic control (Silyl Hilbert‐Johnson glycosylation for 5 h) afforded only the N ²‐isomer (64%). The structures of the nucleosides 1b and 2b were assigned by single crystal X‐ray analyses. The 4‐amino‐N ¹‐(β‐d‐ribofuranosyl)‐1H‐indazole (3b) was obtained from the nitro nucleoside 1b by catalytic hydrogenation. Compound 3b shows fluorescence while the 4‐nitroindazole nucleosides 1b and 2b do not possess this property.     

Ring inversion barrier of diazepam and derivatives: An ab Initio study

Systematic ab initio calculations were performed to investigate the ring inversion process of various 1,4‐diazepines including diazepam, N¹‐desmethyldiazepam, and 3‐methyl‐N¹‐desmethyldiazepam. The diazepine ring adopts a shape of a boat; owing to asymmetric substitution two such boats are possible in mirror image relation to each other. In the present study both structural and solvent effects were investigated on the energetics of ring inversion of nine diazepine derivatives. The calculated ring inversion barriers for diazepam (17.6 kcal/mol) and N¹‐desmethyldiazepam (10.9 kcal/mol) are in good agreement with the corresponding experimental data. In the cases of diazepam and N¹‐desmethyldiazepam, the calculated minimum energy path of the ring inversion is asymmetric contrary to the fact that the terminals (M and P conformers) are equienergetic. Chirality 11:651–658, 1999. © 1999 Wiley‐Liss, Inc.     

A review on the nucleic acid constituents in mushrooms: nucleobases,nucleosides and nucleotides

Mushrooms have become increasingly important as a reliable food source. They have also been recognized as an important source of bioactive compounds of high nutritional and medicinal values. The nucleobases, nucleosides and nucleotides found in mushrooms play important roles in the regulation of various physiological processes in the human body via the purinergic and/or pyrimidine receptors. Cordycepin, a 3′-deoxyadenosine found in Cordyceps sinensis has received much attention as it possesses many medicinal values including anticancer properties. In this review, we provide a broad overview of the distribution of purine nucleobases (adenine and guanine); pyrimidine nucleobases (cytosine, uracil, and thymine); nucleosides (uridine, guanosine, adenosine and cytidine); as well as novel nucleosides/tides in edible and nonedible mushrooms. This review also discusses the latest research focusing on the successes, challenges, and future perspectives of the analytical methods used to determine nucleic acid constituents in mushrooms. Besides, the exotic taste and flavor of edible mushrooms are attributed to several nonvolatile and water-soluble substances, including the 5′-nucleotides. Therefore, we also discuss the total flavor 5′-nucleotides: 5′-guanosine monophosphate (5′-GMP), 5′-inosine monophosphate (5′-IMP), and 5′-xanthosine monophosphate (5′-XMP) in edible mushrooms.     

Synthesis of D‐Altritol Nucleosides with a 3′‐O‐Tert‐Butyldimethylsilyl Protecting Group

Four D‐altritol nucleosides with a 3′‐O‐tert‐butyldimethylsilyl protecting group are synthesized (base moieties are adenine, guanine, thymine and 5‐methylcytosine). The nucleosides are obtained by ring opening reaction of 1,5:2,3‐dianhydro‐4,6‐O‐benzylidene‐D‐allitol. Optimal reaction circumstances (NaH, LiH, DBU, phase transfer, microwave irridation) for the introduction of the heterocycles are base‐specific. For the introduction of the 3′‐O‐silyl protecting group, long reaction times and several equivalents of tert‐butyldimethylsilyl chloride are needed.     

Brain Pharmacokinetics of Non‐Imidazole Biphenyl H3 Receptor Antagonists: a Liquid Chromatography/Electrospray‐Mass Spectrometry and ex vivo Binding Study in Rats

In the present article, we report on the kinetics of brain penetration in rats of the H3R antagonist 1,1′‐[1,1′‐biphenyl‐4,4′‐diylbis(methylene)]bis‐[piperidine] ( 1 ), which had shown a favorable in vitro pharmacological profile and in vivo potency in preventing scopolamine‐induced amnesia. Two different approaches were employed: high‐performance liquid chromatography/electrospray‐mass spectrometry (HPLC/ESI‐MS) and ex vivo binding against the labeled agonist [³H]‐(R)‐α‐methylhistamine ([³H]RAMHA). Starting from the structure of 1 , the rigid piperidine ring was replaced by a flexible dipropylamino group (see 2 ) or by a morpholino ring (see 3 ), endowed with lower basicity. The effect of replacement on rat plasma and brain disposition in the 24 h after administration was analyzed. High (μM ) and persistent concentrations of 1 were found in rat plasma, while plasma levels were significantly lower (range: 0–200 nM ) for the other two derivatives. This could be explained, among other factors, by the higher stability, observed for 1 , to liver metabolic cleavage. The applied chemical modulation had an important effect on in vivo brain disposition, as, despite the comparable physico‐chemical properties, 2 did not show the tendency to accumulate within the brain, as stated by its brain vs. plasma concentration ratios, if compared to 1 . These structure? property relationships should be taken into account in the pharmacokinetic optimization of new series of H3 receptor antagonists.     

Analysis of [SWI+] formation and propagation events

The budding yeast, Saccharomyces cerevisiae, harbors several prions that are transmitted as altered, heritable protein conformations. [SWI⁺] is one such prion whose determinant is Swi1, a subunit of the evolutionarily conserved chromatin‐remodeling complex SWI/SNF. Despite the importance of Swi1, the molecular events that lead to [SWI⁺] prionogenesis remain poorly understood. In this study, we have constructed floccullin‐promoter‐based URA3 reporters for [SWI⁺] identification. Using these reporters, we show that the spontaneous formation frequency of [SWI⁺] is significantly higher than that of [PSI⁺] (prion form of Sup35). We also show that preexisting [PSI⁺] or [PIN⁺] (prion form of Rnq1), or overproduction of Swi1 prion‐domain (PrD) can considerably promote Swi1 prionogenesis. Moreover, our data suggest a strain‐specific effect of overproduction of Sse1 – a nucleotide exchange factor of the molecular chaperone Hsp70, and its interaction with another molecular chaperone Hsp104 on [SWI⁺] maintenance. Additionally, we show that Swi1 aggregates are initially ring/ribbon‐like then become dot‐like in mature [SWI⁺] cells. In the presence of [PSI⁺] or [PIN⁺], Swi1 ring/ribbon‐like aggregates predominantly colocalize with the Sup35 or Rnq1 aggregates; without a preexisting prion, however, such colocalizations are rarely seen during Swi1‐PrD overproduction‐promoted Swi1 prionogenesis. We have thus demonstrated a complex interacting mechanism of yeast prionogenesis.     

Synthesis,Molecular Structure,and Chiroptical Properties of Dibenzylidene Derivatives of Bicyclo[3.3.1]nonane and Brexane

Synthesis of several enantiomerically pure unsaturated bicyclo[3.3.1]nonane and related brexane (tricyclo[4.3.0.0^3,7]nonane) derivatives bearing exocyclic benzylidene substituents from readily available (+)‐(1S,5S)‐bicyclo[3.3.1]nonane‐2,6‐dione was accomplished. Molecular geometry and chiroptical properties of compounds with enone and styrene chromophores were studied by X‐ray diffraction analysis, molecular modeling, and circular dichroism (CD) spectroscopy. Difunctional 3,7‐dibenzylidenebicyclo[3.3.1]nonanes, such as 2 and 7 , 8 , 9 , exhibited intense CD couplets, arising from the exciton coupling between the two unsaturated chromophores. The observed negative sign of the exciton couplets is congruent with the negative twist (negative chirality) defined by the two interacting transition dipoles. The sign of the Cotton effect corresponding to the π→π* transitions in the CD spectra of monoenone 4 and tricyclic brexane acetate 11 was correlated with the intrinsic dissymmetry (helicity) of the styrene chromophore. Chirality 27:728–737, 2015. © 2015 Wiley Periodicals, Inc.