Analogues 1a Research Articles

Synthesis of Bis{(S‐methyl)azolespoly(ethylene oxide)} from 3,6‐dioxa‐1,8‐octanedithiol

Bis(1,3,4‐oxadiazoles) 4, 5 and bis(1,2,4‐triazoles) 6a, 6b have been prepared from 3,6‐dioxa‐1,8‐octanedithiol 1 through a multistep reaction sequence. Compound 4 reacted with the appropriate alkyl halide in the presence of potassium carbonate in refluxing acetone to give the corresponding bis(S‐alkylated‐1,3,4‐oxadiazoles) 7a, 7b. The title compound 8 was prepared by condensing 4 with benzoyl bromide in the presence of triethylamine. Further, 6,9‐dioxa‐3,12‐dithiotetradecanedihydrazide 3 was converted to bis{N′‐(phenylaminocarbonyl) hydrazides} and bis{N′‐(phenylaminocarbonothioyl)hydrazides} 9a, 9b using phenylisocyanate and phenylthioisocyanate, respectively, which underwent cyclization in alkaline medium to produce 6,9‐dioxa‐3,12‐dithiotetradecane bis(4‐phenyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐one) and their 3‐thio analogs 10a, 10b. The new compounds 4, 5, 6, 7, 8, 9, 10 were characterized by their IR, 1H‐NMR, 13C‐NMR, MS, and elemental analyses.

Synthesis, structure–activity relationships and biological evaluation of barbigerone analogues as anti-proliferative and anti-angiogenesis agents

A series of barbigerone analogues (7a–7w, 13a–13x) were designed, synthesized and biologically evaluated for their anti-proliferative and anti-angiogenic activities. Among these compounds, compound 13a exhibited the most potent inhibitory effect on the proliferation of HUVECs, HepG2, A375, U251, B16, and HCT116 cells (IC50=3.80, 0.28, 1.58, 3.50, 1.09 and 0.68μM, respectively). Compound 13a inhibited the angiogenesis in zebrafish embryo assay in a concentration-dependent manner. Furthermore, 13a also effectively inhibited the migration and capillary like tube formation of human umbilical vein endothelial cell in vitro. These results support the further investigation of this class of compounds as potential anti-proliferative and anti-angiogenesis agents.

Design, synthesis, antiviral activity, and SARs of 13a-substituted phenanthroindolizidine alkaloid derivatives

On the basis of our previous structure–activity relationship (SAR) and antiviral mechanism studies, a series of 13a-substituted phenanthroindolizidine alkaloid analogues (3a–16a, 3b, 4b, 6b, 7b, 10b, and 14b) were designed targeting tobacco mosaic virus (TMV) RNA, synthesized, and evaluated for their antiviral activity against TMV for the first time. The bioassay results showed that most of the synthesized compounds (such as 4a, 6a, 7a, 11a, 14a, 6b, and 14b) exhibited good to excellent antiviral activity against TMV both in vitro and in vivo. Especially, for inactivation effect and curative effect, compounds 4a, 6a, 7a, 11a, 14a, and 14b showed higher activity at both concentrations (500μgmL−1 and 100μgmL−1) than commercial Ningnanmycin. Preliminary SARs showed that the substituted groups with hydrogen donor at 13a position were found to be favorable for keeping high antiviral activity. The present work demonstrates that 13a-substituted phenanthroindolizidines can be used as possible lead compounds for developing anti-TMV agents.

Synthesis, anti-inflammatory and antioxidant activity of ring-A-monosubstituted chalcone derivatives

A library of ring-A-monosubstituted chalcone derivatives (4a–4i, 5a and 5b) was designed and synthesised. The structures as well as the identities of these compounds were established on the basis of spectral (1H NMR, 13C NMR, FT-IR and Mass) and elemental (C, H, N) analyses. All the derivatives were evaluated for their anti-inflammatory and antioxidant activities in vitro using the inhibition of protein denaturation and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays, respectively. The results indicated a promising anti-inflammatory activity for most of the synthesised compounds with many derivatives showing activities similar to or greater than that of the standard. The sulphonamide-substituted chalcones 4h, 4i, 5a and 5b were found to be the most active derivatives across the concentration range tested. However, all the derivatives exhibited rather mild antioxidant activity compared to the ascorbic acid standard. Interestingly, it was observed that the unsubstituted parent chalcone was one of the optimal compounds with only the trifluoromethyl analogue 4a showing better activity as an antioxidant. The two regioisomeric aminochalcones and 4′-cyanochalcone 4b also seemed to possess decent antioxidant potential.

COMPUTER ASSISTED THERAPY FOR AUDITORY HALLUCINATIONS: THE AVATAR CLINICAL TRIAL

Total synthesis of a focused set of 10 nannocystin analogues 3a–3j modified at the polyketide phenyl moiety was reported. These compounds were evaluated against three cancer cell lines. Compared with the naturally occurring congener 3a, the other synthetic variants either preserved or lose antiproliferative activity at varying degrees. Moreover, the potent analogues also displayed comparable levels of cytotoxicity toward two normal cell lines.

Effect of the 3- and 4-Methyl Groups on the Opioid Receptor Properties of N-Substituted trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines

N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a,b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a,b, we synthesized analogues of 2a,b that lacked the 4-methyl (5a,b), 3-methyl (6a,b), and both the 3- and 4-methyl group (7a,b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were nonselective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts, and (3) compounds 2a,b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogues 5a,b, 6a,b, and 7a,b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a,b) gives (4a,b), which are opioid antagonists.

Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells.

We report the antitumor effects of nitric oxide (NO) releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N–N(O)=NO– group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 inducing cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.

Design, Synthesis, Antiviral Activity, and Structure–Activity Relationships (SARs) of Two Types of Structurally Novel Phenanthroindo/quinolizidine Analogues

To investigate the influence of the variation of the original skeletons of natural phenanthroindo/quinolizidine alkaloids on antiviral activities, two types of structurally totally novel analogues 7a, 7b, 16a, and 16b were designed, synthesized, and evaluated against tobacco mosaic virus (TMV) for the first time. Bioassay results indicated that all four of the newly designed analogues showed good to excellent antiviral activities, among which analogue 16a dispalyed comparable activity with that of ningnanmycin, perhaps one of the most successful commercial antiviral agents, thus emerging as a potential inhibitor of plant virus and serving as a new lead for further optimization. Further structure-activity relationships are also discussed, demonstrating for the first time that the same changes of the original skeletons of phenanthroindolizidine and phenanthroquinolizidine exihibted totally different antiviral activities results, providing some original and useful information about the preferential conformation for maintaining high activities.

Synthesis and tumor inhibitory activity of novel coumarin analogs targeting angiogenesis and apoptosis

A sequence of coumarin analogs 5a–j was obtained by multi step synthesis from hydroxy benzophenones (1a–j). The in vitro antiproliferative effect of the title compounds was tested against Ehrlich ascites carcinoma (EAC) and Daltons lymphoma ascites (DLA) cell lines. Among the series, compound 5c with bromo group in the benzophenone moiety was endowed with excellent antiproliferative potency with significant IC50 value. Further, in vivo antitumor effect of compound 5c against murine EAC and solid DL tumor model system was evident by the extended survivality. The tumor inhibitory mechanism of compound 5c was due to the antiangiogenesis and promotion of apoptosis. These results suggest possible applications of compound 5c which could be developed as a potent anticancer drug in the near future.

Synthesis and Olfactory Characterization of Sila-Methyl Pamplemousse and Related Odorants with a 2,2,5-Trimethyl-2-silahex-4-ene Skeleton

The synthetic grapefruit odorant methyl pamplemousse (1a) has lately become an important trend odorant, and the related 2,2,5-trimethylhex-4-enes 2a–4a also possess interesting olfactory properties of fresh hesperidic and fruity-agrestic character. On the basis of the carbon/silicon switch strategy, the silicon-containing analogues sila-methyl pamplemousse (1b) and 2b–4b were synthesized and studied for their olfactory properties (olfactory evaluation of the C/Si pairs 1a/1b–4a/4b). Sila substitution (C/Si exchange) was demonstrated to affect the olfactory properties substantially. The C/Si analogues 1a and 1b were found to be genuine grapefruit odorants, with the silicon compound 1b showing additional agrestic facets. As a proof of principle, it was demonstrated that C/Si analogues can display a different mechanism and rate of degradation (degradation studies with 1a and 1b under acidic conditions).

Synthesis and biological evaluation of substituted N-alkylphenyl-3,5-dinitrobenzamide analogs as anti-TB agents

Here, a medicinal chemistry study of an N-alkylphenyl-3,5-dinitrobenzamide (DNB) scaffold as a potent anti-TB agent is presented. A series of chemical modifications were performed and forty-three new molecules were synthesized to study the structure–activity relationship (SAR) by evaluating against a sensitive strain (H37Rv) of Mycobacterium tuberculosis (MTB). Potent DNB analogs 4b, 7a, 7c, 7d, 7j, 7r and 9a were further tested against resistant strains of MTB. Their intracellular as well as bactericidal potential was also evaluated. Cytotoxicity and in vivo pharmacokinetic studies suggested that DNB analogs have an acceptable safety index, in vivo stability and bio-availability. From the present work, two compounds 7a and 7d have shown nanomolar to sub micro-molar MIC in extracellular and intracellular assays.

Synthesis, antibacterial, antioxidant activity and QSAR studies of novel 2-arylidenehydrazinyl-4-arylthiazole analogues.

A novel series of 2-arylidenehydrazinyl-4-arylthiazole analogues (3a-p) was designed and synthesized in excellent yields using a rapid, simple, efficient methodology. Sixteen novel compounds were screened for in vitro antimicrobial activities against eleven bacteria, namely, Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Bacillus subtilis, Klebsiella pneumonia, Citrobacter freundii, Cronobacter sakazakii, Salmonella enteritidis, Escherichia coli, Yersinia pestis, and Pseudomonas aeruginosa. All 16 compounds showed significant anti-bacterial activities against both Gram-positive and Gram-negative bacteria. In particular, compound 3g showed potent inhibition of E. coli and K. pneumonia, compound 3i inhibited E. faecalis, compound 3n S. tythi and E. faecalis, and compound 3c E. coli and C. sakazakii. In fact, our results indicate that most of the compounds synthesized exhibit strong antibacterial activity. The qualitative structure-antibacterial activity relationships (QSAR) were studied using the physicochemical and quantum-chemical parameters of the ab initio Hartree-Fock model at the RHF/6-31G level of theory. A good qualitative correlation between predicted physicochemical parameters (log P and polar surface area (PSA)) and antibacterial activity has been found. The synthesized compounds were also evaluated for antioxidant activity. Compounds 3j, 3a and 3i exhibited the greatest antioxidant activity, with IC50 values of 0.66, 0.81, and 1.08 µM, respectively, which were comparable to that of ascorbic acid (IC50 0.87 µM). The promising antibacterial and antioxidant activities of some of these synthesized 2-arylidenehydrazinyl-4-arylthiazole derivatives, together with the results of quantum-chemical studies, could be helpful for the development of drugs to combat diseases caused by microorganisms and oxidative stress.

Synthesis, insecticidal activity, structure–activity relationship (SAR) and density functional theory (DFT) of novel anthranilic diamides analogs containing 1,3,4-oxadiazole rings

A series of anthranilic diamides analogs (5a–x) containing 1,3,4-oxadiazole rings were synthesized, and their insecticidal activities were evaluated. The density functional theory (DFT) studies was used to understand the various insecticidal activities.

Rotational Energy Barrier around the C1–C11 Single Bond in Lamellarins: A Study by Variable-Temperature NMR

In order to estimate the free energy barrier to rotation around the C1–C11 single bond in lamellarins, new lamellarin analogues (1a), (1b), (2a), and (2b) possessing diastereotopic protons or carbons at the C1 aryl moiety were synthesized. Variable-temperature H and C NMR measurements of these analogues revealed that the free energy barriers to rotation around the C1–C11 axis in 5,6-saturated and 5,6-unsaturated lamellarins were around 72–74 and 83–87 kJ/mol, respectively. INTRODUCTION The lamellarins constitute an important class of natural products of marine origin. Up to now, approximately fifty lamellarins have been characterized since the first isolation of lamellarins A–D from Lamellaria sp. in 1985. These lamellarins exhibit a number of interesting biological activities such as potent cytotoxicity against cancer cell lines, multi-drug resistance (MDR) reversal activity, anti-HIV activity, topoisomerase I inhibitory activity, inhibition of mitochondrial function, and protein kinases inhibitory activity. Lamellarins possess a unique 14-phenyl-6H-[1]benzopyrano[4’,3’:4,5]pyrrolo[2,1-a]isoquinolin-6-one ring system (Figure 1). They are divided into two structural types different in the degree of unsaturation at 5,6-bond. The naturally occurring lamellarins are highly substituted by oxygen functionalities (OH and OMe) on this scaffold. The biological activities are dependent on the position and the number of OH and OMe groups. According to X-ray crystallographic analyses of several lamellarins, the aryl group attached to C1 is This paper is dedicated to Professor Dr. Victor Snieckus on the occasion of his 77 birthday. HETEROCYCLES, Vol. 88, No. 2, 2014 1121

Synthesis and Structural Analysis of (Imido)vanadium(V) Dichloride Complexes Containing Imidazolin-2-iminato- and Imidazolidin-2-iminato Ligands, and their Use as Catalyst Precursors for Ethylene (Co)polymerization

A series of (imido)vanadium(V) dichloride complexes containing 1,3-imidazolin-2-iminato or 1,3-imidazolidin-2-iminato ligands of the type, V(NR')Cl2(L) [R' = 2,6-Me2C6H3, L = 1,3-R2(CHN)2C═N (1a-c,e) or 1,3-R2(CH2N)2C═N (2a-d), R = (t)Bu (a), 2,6-Me2C6H3 (b), 2,6-(i)Pr2C6H3 (c), C6H5 (d), 2,6-(Ph2CH)2-4-MeC6H2 (e); L = 1,3-(2,6-(i)Pr2C6H3)2(CHN)2C═N, R' = 1-adamantyl (Ad, 3c), C6H5 (4c); L = 1,3-(2,6-(i)Pr2C6H3)2(CH2N)2C═N, R' = Ad (5c)], were prepared and characterized. The molecular structures of 1a, 2a,c,d, 3c, 4c, and 5c were determined by X-ray crystallography. All complexes showed high catalytic activity for ethylene polymerization especially in the presence of Et2AlCl cocatalyst; the 2,6-R2C6H3 analogues (R = Me, (i)Pr; 1b,c, 2b,c) exhibited higher catalytic activities than the (t)Bu analogues (1a, 2a), which display rather unique (small) V-N-C(imido) bond angles in the solid state. A good correlation between the activity and the (51)V NMR chemical shift was found for the (arylimido)vanadium precatalysts (1a-c,e, 2a-d, and 4c). These complexes showed high catalytic activity for the copolymerization of ethylene with norbornene (NBE), affording ultrahigh molecular weight copolymers with uniform molecular weight distributions. The activities were affected by the imido ligand as well as by the substituents in the anionic ligand, and the 2,6-(i)Pr2C6H3 analogues (especially 2c and 4c) showed the higher activities. The complexes 2c and 4c also showed high activities with efficient comonomer incorporation for the ethylene copolymerization with 5-ethylidene-2-norbornene (ENB) in the presence of Et2AlCl; both the comonomer incorporation and the molecular weight in the resulting polymers were affected by the comonomer employed (NBE vs ENB).

Synthesis of Novel 2'-Fluoro-5'-deoxyphosphonic Acids and Bis(SATE) Adenine Analogue as Potent Antiviral Agents

Novel 5'-deoxythreosyl purine phosphonic acid analogues containing a 2'-electropositive moiety such as fluorine atom, were designed and synthesized from commercially available 1,3-dihydroxy acetone. Condensation successfully proceeded from a glycosyl donor 6 under Vorbruggen conditions and cross-metathesis gave the desired phosphonate analogues 7a, 7b, 17a and 17b. The synthesized nucleoside phosphonic acid analogues 13, 16, 23, 26, 28 were subjected to antiviral screening against HIV-1. The bis(SATE) adenine analogue 28 exhibited significant in vitro activities against HIV-1.

Synthesis, anticonvulsant activity and molecular properties prediction of dialkyl 1-(di(ethoxycarbonyl)methyl)-2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-dicarboxylates

The synthesis and anticonvulsant properties of new N-diethylmalonyl derivatives of nifedipine and other isosteric analogues (7a–7n) were described. Anticonvulsant screening was performed by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizures tests. Majority of the compounds were effective in scPTZ and MES screens. Compound 7k showed good activity displaying maximum protection, which may be due to the presence of styryl moiety at position 4 of 1,4-dihydropyridine nucleus and the methyl groups of diester functionality. Compounds 7a–7d, 7g, 7i and 7k obeyed the Lipinski's “rule of five” and have drug-likeness. Based on computational prediction of molecular and pharmacokinetic properties, it was found that the compounds have good oral absorption.

Synthesis and molecular modeling of six novel monastrol analogues: evaluation of cytotoxicity and kinesin inhibitory activity against HeLa cell line

Background and the purpose of the studyA common approach in cancer chemotherapy is development of drugs that interrupt the mitosis phase of cell division. Dimethylenastron is a known kinesin inhibitor. In this study, six novel dimethylenastron analogues (4a-f), in which 3-hydroxyphenyl substituent has been replaced with substituted benzylimidazolyl, were synthesized through Biginelli reaction.MethodsSix novel Biginelli compounds (4a-f) were synthesized through one step Biginelli reaction of imidazole aldehydes (3a-c), dimedone and urea or thioura. In vitro cytotoxicities of prepared compounds were investigated using MTT assay. Furthermore the ELIPA kit was implemented to study inhibitory effects of synthesized compounds on ATPase activity of kinesin by measuring of organic phosphate.ResultsOur results indicated that analogue 4c is the most toxic and analogues 4f, 4b and dimethylenasteron were less cytotoxic in compare with other analogues. On the other hand, analogue 4a, 4b, 4c and 4e showed stronger Kinesin inhibition as compared with analogue 4f and dimethylenasteron. None of synthesized compounds were as potent kinesin inhibitor as Taxol. Docking analysis revealed that hydrogen bond formation and hydrophobic interactions were the key factors affecting inhibitory effects of these compounds.ConclusionNewly synthesized compounds were found to have moderate to good cytotoxicity against HeLa cancer cell. Our results may be helpful in further design of dihydropyrimidine as potential anticancer agents.

A stereoselective approach to peptidomimetic BACE1 inhibitors

Aiming at identifying new scaffolds to generate beta-secretase (BACE1) inhibitors we developed peptidomimetics based on a 1,4-benzodiazepine core (3a–d), their seco-analogs (4a–b), and linear analogs (5a–h), by stereoselective approaches. We herein discuss the synthesis, molecular modeling and in vitro studies for the newly developed ligands. Compounds 5c and 5h behaved as BACE1 inhibitors on the isolated enzyme and in cellular studies. Particularly, for its low molecular weight, inhibitor 5h is a prototypic hit to develop a series of BACE1 inhibitors more potent and active on whole-cells.

Discotic derivatives of 6-oxoverdazyl radical

Substitution of each phenyl in 1,3,5-triphenyl-6-oxoverdazyl with three alkoxy groups induces an ordered columnar hexagonal phase (Colh(o)) below 130°C in 1b[n], while in the alkylsulfanyl analogues 1a[n] additional periodicity along the columns was found rendering the phase a true three-dimensional columnar hexagonal phase (Colh(3D)) below 60°C. Both series exhibit broad absorption bands in the visible region with maxima at 540 and 610 nm in series 1a[n] and at 486 and 614 nm in series 1b[n]. Unusual reversible thermochromism is observed in series 1b[n], in which the dark green isotropic phase turns red in the discotic phase. Analysis of 1a[8] revealed redox potentials E0/+11/2 = +0.99 V and E0/ −11/2 = –0.45 V vs. saturated calomel electrode (SCE), while the potentials in the alkoxy analogue 1b[8] are shifted cathodically by 0.16 V. Photovoltaic studies of 1a[8] demonstrated hole mobility of μh = 1.52 × 10−3 cm2 V−1 s−1 in the mesophase with an activation energy Ea = 0.06 ± 0.01 eV. Magnetisation studies of 1a[8] revealed nearly ideal paramagnetic behaviour in either the solid or fluid phase above 200 K and weak antiferromagnetic interactions at low temperatures. In contrast, a noticeable drop of about 4% in μeff was observed during the I→Col phase transition in 1b[8], which coincide with the thermochromic effect.