Preparation and preliminary biological screening of cholic acid-juvenoid conjugates

Steroidal compounds have been utilized as carriers and for modification of physico-chemical properties of model biologically active secondary alcohols - juvenoids. Juvenoids are juvenile hormone analogues - environmentally safe insecticides, possessing significant biological activity towards different arthropods groups in focus on insect pest species. Structure modification of juvenoids plays important role to control the rate of liberation and decomposition of juvenoid in digestive system and can also play important role in the mode of action towards selected insect. This study presents an approach to the synthesis of steroidal monomers and dimers carrying one and two molecules of a juvenoid in their structures. The prepared compounds were tested for their inhibition activity on reproduction of the blowfly Neobellieria (Sarcophaga) bullata. These steroid-juvenoid conjugates showed promising possibilities in synthesis of new unique biochemical insecticides. Preliminary biological test results of prepared compounds are presented.     

Structure and activity relationship of 2-(substituted benzoyl)-hydroxyindoles as novel CaMKII inhibitors

A series of novel 2-substituted-5-hydroxyindoles were synthesized and evaluated for their inhibitory activity against CaMKII. Structure and activity relationship results indicated that potent inhibitory activity could be achieved by modification at the para-position of the phenyl ring of the high throughput screening hit compound 2. Among the prepared compounds, we identified 14 as a novel CaMKII inhibitor with an activity stronger than that of KN-93, a known CaMKII inhibitor.     

Synthesis and antiproliferative activity of new 2-glyco-3-nitro-2H-chromenes

3-nitro-2H-chromenes and derivatives are compounds with diverse biological activity, among them, new 2-glyco-3-nitro-2H-chromenes have been prepared by one-pot oxa-Michael-Henry-dehydration reactions between carbohydrate-derived nitroalkenes and several salicylaldehydes, using a minimal amount of solvent and DBU as catalyst. The antiproliferative activity of these new compounds has been evaluated against a panel of six human solid tumor cell lines, and compared to pharmacological reference compounds, finding that their activities are in the low micromolar range and that some of them are more effective than the standards.     

Unsymmetrical 1,5-diaryl-3-oxo-1,4-pentadienyls and their evaluation as antiparasitic agents

In this work the synthesis and antiparasitical activity of new 1,5-diaryl-3-oxo-1,4-pentadienyl derivatives are described. First, compounds 1a, 1b, 1c and 1d were prepared by acid-catalyzed aldol reaction between 2-butanone and benzaldehyde, anisaldehyde, p-N,N-dimethylaminobenzaldehyde and p-nitrobenzaldehyde. Reacting each of the methyl ketones 1a, 1b, 1c and 1d with the p-substituted benzaldehydes under basic-catalyzed aldol reaction, we further prepared compounds 2a–2p. All twenty compounds were evaluated for antiproliferative activity, particularly for promastigote of Leishmania amazonensis and epimastigote of Trypanosoma cruzi. All compounds showed good activity while nitro compounds 2i and 2k showed inhibition activity at a few μM.     

Synthesis and in vitro antimicrobial and antitumor activity of some nitrogen heterocycles

5-Phenyl-2-[(3,4,5-trimethoxybenzylidene)hydrazino]-thiazole and 3-[(3,4,5-trimethoxybenzylidene)amino]-4-oxoimidazolidin-2-thione were prepared by cyclization of 1-[(3,4,5-trimethoxybenzyliden)amino]-thiourea with phenacyl bromide and ethyl chloroacetate in the presence of fused sodium acetate. Acetylation of the synthesized compounds with acetic anhydride gave corresponding N-acetyl derivatives. Condensation of the synthesized thione with aromatic aldehydes yielded two 3-substituted 5-arylidene-4oxo-imidazolidin-2-thiones. Acetylation of the latter compounds with acetic anhydride afforded the corresponding N-acetyl-4-oxo-imidazolidin-2-thiones. Some of the synthesized compounds exhibited antimicrobial activity. The cytotoxic activity of the prepared thiazole and imidazolidin-2-thione derivatives was studied on several tumor cell lines.     

Turning natural products into insecticide candidates: Design and semisynthesis of novel fraxinellone-based N-(1,3-thiazol-2-yl)carboxamides against two crop-threatening insect pests

To improve the insecticidal activities of fraxinellone, two series of fraxinellone-based N-(1,3-thiazol-2-yl)carboxamides containing 25 compounds were prepared by structural modification. Their structures were determined by melting point, optical rotation, IR, ¹H NMR and ESI-MS. The steric configurations of compounds 6i, 7d and 7i were unambiguously confirmed by X-ray diffraction further. The bioassay showed that compounds 6b and 6i exhibited more potent larvicidal and growth inhibitory activities against Plutella xylostella Linnaeus and Mythimna separata Walker, respectively. Moreover, compounds 6b and 6i also displayed low cytotoxicity to noncancerous mammalian cells. The structure–activity relationships (SARs) of all target compounds were also observed.     

Synthesis and glycosidase inhibitory activity of some N-substituted 5a-carba-β-fuco- and β-galactopyranosylamines, and selected derivatives

In the course of chemical modification of -fucosidase inhibitors of 5a-carba-fucopyranosylamine type, an N-dodecyl derivative of the enantiomer 6-deoxy-5a-carba-β-D-galactopyranosylamine demonstrated very strong inhibition of β-galactosidase and β-glucosidase. This finding led us to synthesize corresponding 6-hydroxy compounds, in order to elucidate structure–activity relationships for inhibitors of this type. Among four N-alkyl-5a-carba-β-D-galactopyranosylamines prepared, the N-octyl derivative could be demonstrated to possess moderate activity toward - and β-galactosidases, and β-glucosidase.     

Development of a 3′-amino linker with high conjugation activity and its application to conveniently cross-link blunt ends of a duplex

The 2-aminoethyl carbamate linker (ssH linker) exhibits high activity in modifying the 5′-termini of oligonucleotides; however, the ssH linker is not appropriate for 3′-terminal modification because it undergoes intramolecular trans-acylation under heat–aqueous ammonia conditions. We developed an N-(2-aminoethyl)carbamate linker (revH linker), in which the carbamate is oriented in the reverse direction relative to that in 2-aminoethyl carbamate. The revH linker was tolerant to heat–alkaline conditions and retained its high reactivity in conjugation with exogenous molecules. The 3′-revH linker was efficiently linked with the 5′-ssH linker at the termini of complementary double strands with a bifunctional molecule, producing a synthetic loop structure. An anti-microRNA oligonucleotide (AMO) was prepared from the chemical ligation of three-stranded 2′-O-methyl RNAs, and the AMO with two alkyl loops exhibited high inhibition activity toward miRNA function. The revH linker is not only useful for 3′-terminal modification of oligonucleotides but also expands the utility range in combination with the 5′-ssH linker.     

Synthesis,characterization and biological activity of ring-substituted 6-benzylamino-9-tetrahydropyran-2-yl and 9-tetrahydrofuran-2-ylpurine derivatives

In an attempt to improve specific biological functions of cytokinins routinely used in plant micropropagation, 33 6-benzylamino-9-tetrahydropyran-2-ylpurine (THPP) and 9-tetrahydrofuran-2-ylpurine (THFP) derivatives, with variously positioned hydroxy and methoxy functional groups on the benzyl ring, were prepared. The new derivatives were prepared by condensation of 6-chloropurine with 3,4-dihydro-2H-pyran or 2,3-dihydrofuran and then by the condensation of these intermediates with the corresponding benzylamines. The prepared compounds were characterized by elemental analyses, TLC, HPLC, melting point determinations, CI+ MS and ¹H NMR spectroscopy. The cytokinin activity of all the prepared derivatives was assessed in three classical cytokinin bioassays (tobacco callus, wheat leaf senescence and Amaranthus bioassay). The derivatives 6-(3-hydroxybenzylamino)-9-tetrahydropyran-2-ylpurine (3) and 6-(3-hydroxybenzylamino)-9-tetrahydrofuran-2-ylpurine (23) were selected, because of the high affinity of their parent compound meta-topolin (mT, 6-(3-hydroxybenzylamino)purine) to cytokinin receptors, as model compounds for studying their perception by the receptors CRE1/AHK4 and AHK3 in a bacterial assay. Both receptors perceived these two derivatives less well than they perceived the parent compound. Subsequently, the susceptibility of several new derivatives to enzyme degradation by cytokinin oxidase/dehydrogenase was studied. Substitution of tetrahydropyran-2-yl (THP) at the N⁹ position decreased the turnover rates of all new derivatives to some extent. To provide a practical perspective, the cytotoxicity of the prepared compounds against human diploid fibroblasts (BJ) and the human cancer cell lines K-562 and MCF-7 was also assayed in vitro. The prepared compounds showed none or marginal cytotoxicity compared to the corresponding N⁹-ribosides. Finally, the pH stability of the two model compounds was assessed in acidic and neutral water solutions (pH 3–7) by high-performance liquid chromatography (HPLC).     

Design,synthesis and biological evaluation of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment

A series of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment were designed, synthesized, and evaluated for their biological activity. Most compounds showed effective inhibitory activity against cancer cell lines of A549, HeLa and MCF-7. Among them, the most promising compound 40 showed excellent activity against A549, HeLa and MCF-7 cell lines with IC₅₀ values of 1.03, 1.15 and 2.59 μM, respectively, which was 2.606.95 times more active than that of Golvatinib. The structure-activity relationships (SARs) showed that the introduction of 5-methylpyridazin-3(2H)-one to “5-atom linker” and the modification of the amide with morpholine group were beneficial for enhancing the inhibitory activity of compounds. In addition, the further research on compound 40 mainly include c-Met kinase activity, concentration dependence, apoptosis (acridine orange staining), and molecular docking.     

Antiprotozoal activity of bicycles featuring a dimethylamino group at their bridgehead

Several dimethylamino-derivatives of the new compound-class 3-azabicyclo[3.2.2]nonanes were prepared. For better comparison of activity also a few analogues of bicyclo[2.2.2]octanes and 2-azabicyclo[3.2.2]nonanes were synthesized. Their activities were examined in vitro against the multiresistant K₁ strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). A couple of the newly synthesized compounds showed promising antiprotozoal activity and selectivity. The results of the biological tests of the novel compounds were compared with the activities of already synthesized compounds and of drugs in use. Structure–activity relationships were discussed.     

Antifungal and anthelmintic activity of novel benzofuran derivatives containing thiazolo benzimidazole nucleus: an in vitro evaluation

A novel series of thiazolo[3,2-a]benzimidazole derivatives containing benzofuran nucleus (5a–l) have been synthesized. The key intermediate, substituted benzimidazol-sulfanyl benzofuran ethanone (3a–d) was prepared by refluxing the mixture of substituted 2-acetyl benzofuran and substituted 2-mercaptobenzimidazole in acetic acid. The cyclisation of compounds (3a–d) using polyphosphoric acid furnished the corresponding 6-substituted benzofuran thiazolo[3,2-a]benzimidazoles (4a–d). Further, the cyclized compounds (4a–d) were subjected for Mannich reaction to give corresponding Mannich bases (5a–l). All newly synthesized compounds were screened for antifungal and anthelmintic activity. Amongst the tested compounds, 4b and 4d exhibited potential antifungal activity. From the anthelmintic activity data, it was found that the compounds 3a, 3b and 5i were found to be more effective against the tested earthworm Pheretima posthuma. In correlation to anthelmintic activity, the selected compounds were subjected for molecular docking studies and the compounds 3a and 5i have emerged as active anthelmintic agents with maximum binding affinity (?3.7 and ?5.4 kcal/mol).     

Selective activity against Mycobacterium tuberculosis of new quinoxaline 1,4-di-N-oxides

New series of 3-phenylquinoxaline 1,4-di-N-oxide with selective activity against Mycobacterium tuberculosis have been prepared and evaluated. Thirty-four of the seventy tested compounds showed an MIC value less than 0.2 μg/mL, a value on the order of the MIC of rifampicin. Furthermore, 45% of the evaluated derivatives showed a good in vitro activity/toxicity ratio. The most active and selective compounds carry a fluorine atom in the quinoxaline 7-position or in the phenyl substituent para-position. In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for synthesizing new analogues, particularly compound 7-methyl-3-(4’-fluoro)phenylquinoxaline-2-carbonitrile 1,4-di-N-oxide (MIC <0.2 μg/mL and SI >500).     

Antibacterial activities against Ralstonia solanacearum and Xanthomonas oryzae pv. oryzae of 6-chloro-4-(4-substituted piperazinyl)quinazoline derivatives

In this letter, a variety of simple 6-chloro-4-(4-substituted piperazinyl)quinazoline derivatives was prepared. Preliminary bioassays revealed that these compounds showed good antibacterial activities toward phytopathogens Ralstonia solanacearum and Xanthomonas oryzae pv. oryzae (Xoo). Among these derivatives, compounds 5a, 5d, 5e, 5f, 5p, 5q, 6b, and 6d exhibited potent inhibition effects against R. solanacearum with EC₅₀ within 4.60–9.94 µg/mL, especially, compound 5g exerted the strongest activity with EC₅₀ of 2.72 µg/mL; compound 6b possessed the best inhibitory activity toward Xoo with EC₅₀ of 8.46 µg/mL. Subsequently, a good predictive three-dimensional quantitative structure–activity relationship (3D-QSAR) model was constructed via CoMFA to direct the future structural modification and optimization. Furthermore, the pathogens’ topological studies were performed to explore the possible antibacterial mechanism. Given their simple frameworks and facile synthesis, title compounds can serve as the potential antibacterial leads.     

FR290581, a novel sordarin derivative: Synthesis and antifungal activity

Sordarin is a unique natural product antifungal agent that is an inhibitor of elongation factor 2. To improve biological activity, we synthesized various compounds by novel modification of the aglycone, sordaricin. As a result, we have discovered the novel sordarin derivative FR290581. This compound exhibited superior activity and a good pharmacokinetic profile, and also displayed good in vivo activity against Candida albicans.     

The role of C-terminal part of ghrelin in pharmacokinetic profile and biological activity in rats

Ghrelin is an endogenous ligand for growth hormone secretagogue receptor 1a (GHS-R1a), and consists of 28 amino acid residues with octanoyl modification at Ser³. The previous studies have revealed that N-terminal part of ghrelin including modified Ser³ is the active core for the activation of GHS-R1a. On the other hand, the role of C-terminal (8-28) region in ghrelin has not been clarified yet. In the present study, we prepared human ghrelin, C-terminal truncated ghrelin derivatives and anamorelin, a small molecular GHS compound which supposedly mimics the N-terminal active core, and examined GHS-R1a agonist activity in vitro, pharmacokinetic (PK) profile and growth hormone (GH) releasing activity in rats. All compounds demonstrated potent GHS-R1a agonist activities in vitro. Although the lack of C-terminal two amino acids did not modify PK profile and GH releasing activity, the deletion of C-terminal 8 and 20 amino acids affected them, and ghrelin(1-7)-Lys-NH₂ exhibited very short plasma half-life and low GH releasing activity in vivo. In rat plasma, ghrelin(1-7)-Lys-NH₂ was degraded more rapidly than ghrelin, suggesting that C-terminal part of ghrelin protected octanoylation of Ser³ from plasma esterases. Subdiaphragmatic vagotomy significantly attenuated GH response to ghrelin but not to anamorelin. These results suggest that the C-terminal part of ghrelin has an important role in the biological activity in vivo. We also found that ghrelin stimulated GH release mainly via a vagal nerve pathway but anamorelin augmented GH release possibly by directly acting on brain in rats.     

Position of lipidation influences anticancer activity of Smac analogs

A small group of lipid-conjugated Smac mimetics was synthesized to probe the influence of the position of lipidation on overall anti-cancer activity. Specifically, new compounds were modified with lipid(s) in position 3 and C-terminus. Previously described position 2 lipidated analog M11 was also synthesized. The resulting mini library of Smacs lipidated in positions 2, 3 and C-terminus was screened extensively in vitro against a total number of 50 diverse cancer cell lines revealing that both the position of lipidation as well as the type of lipid, influence their anti-cancer activity and cancer type specificity. Moreover, when used in combination therapy with inhibitor of menin–MLL1 protein interactions, position 2 modified analog SM2 showed strong synergistic anti-cancer properties. The most promising lipid-conjugated analogs SM2 and SM6, showed favorable pharmacokinetics and in vivo activity while administered subcutaneously in the preclinical mouse model. Collectively, our findings suggest that lipid modification of Smacs may be a viable approach in the development of anti-cancer therapeutic leads.     

The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A1 adenosine receptor

A series of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes were prepared and evaluated as potential allosteric modulators of the A₁ adenosine receptor (AR). The structure-activity relationships of the 3-position were explored along with varying the size of the cycloalkyl ring. 2-Aminothiophenes with amide and hydrazide groups in the 3-position were completely inactive in an A₁-AR-mediated ERK1/2 phosphorylation assay, yet most of the 3-benzoyl substituted compounds exhibited allosteric effects on responses mediated by the orthosteric agonist, R-PIA. Despite finding an increase in both agonistic and allosteric activities by going from a cyclopentyl ring to a cyclohexyl ring in the 3-benzoyl series, decreases were observed when further increasing the ring size. Varying the substituents on the phenyl ring of the 3-benzoyl group also affected the activity of these compounds.     

Comparison of cytokinin activities of naturally occurring ribonucleosides and corresponding bases

Cytokinin activities in the tobacco bioassay have been determined for four adenosine derivatives known to be components of wheat germ tRNA: 6-(4-hydroxy-3-methyl-2-butenylamino)-9-β-d-ribofuranosylpurine, 6-(3-methyl-2-butenylamino)-9-β-d-ribofuranosylpurine, 6-(4-hydroxy-3-methyl-2-butenylamino)- 2-methylthio-9-β-d-ribofuranosylpurine, and 6-(3-methyl-2-butenylamino)-2-methylthio-9-β-d-ribofuranosylpurine. Also determined and compared with the four natural components of tRNA were the activities of the four 3-methylbutylamino analogs of the naturally occurring species and the eight substituted purines corresponding to both sets of ribonucleosides. The systematic structural modifications within this group of sixteen compounds were reflected in the variations in cytokinin activity with the level of modification.     

New potent antibacterials against Gram-positive multiresistant pathogens: Effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles

The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.