Showing papers in "Archiv Der Pharmazie in 2015"

Recent Advances in the Chemistry and Biology of Benzothiazoles

Abstract: Benzothiazole is a privileged heterocyclic scaffold having a benzene ring fused with a five-membered thiazole ring. This moiety has attracted considerable attention because of its wide range of pharmacological activities such as antitubercular, antimicrobial, antimalarial, anticonvulsant, anthelmintic, analgesic, anti-inflammatory, antidiabetic, antitumor activity, etc. In the last few years, some novel benzothiazoles have been developed with varied biological activities. To access this scaffold in high yield and to introduce diversity, a variety of new synthetic methods have been invented. In this review, we highlight the development of novel benzothiazoles for various biological activities along with the best synthetic protocols for their synthesis.

Recent Progress on Pyrazole Scaffold-Based Antimycobacterial Agents

Abstract: New and reemerging infectious diseases will continue to pose serious global health threats well into the 21st century and according to the World Health Organization report, these are still the leading cause of death among humans worldwide. Among infectious diseases, tuberculosis claims approximately 2 million deaths per year worldwide. Also, agents that reduce the duration and complexity of the current therapy would have a major impact on the overall cure rate. Due to the development of resistance to conventional antibiotics there is a need for new therapeutic strategies to combat Mycobacterium tuberculosis. Subsequently, there is an urgent need for the development of new drug candidates with newer targets and alternative mechanism of action. In this perspective, pyrazole, one of the most important classes of heterocycles, has been the topic of research for thousands of researchers all over the world because of its wide spectrum of biological activities. To pave the way for future research, there is a need to collect the latest information in this promising area. In the present review, we have collated published reports on the pyrazole core to provide an insight so that its full therapeutic potential can be utilized for the treatment of tuberculosis. In this article, the possible structure-activity relationship of pyrazole analogs for designing better antituberculosis (anti-TB) agents has been discussed and is also helpful for new thoughts in the quest for rational designs of more active and less toxic pyrazole-based anti-TB drugs.

Acetylcholinesterase Inhibitory and Antioxidant Activities of Novel Symmetric Sulfamides Derived from Phenethylamines

Abstract: The antioxidant and acetylcholinesterase inhibitory properties of novel symmetric sulfamides derived from phenethylamines were evaluated. Phenethylamines 8-11 were reacted with SO2Cl2 in the presence of Et3N to afford sulfamides in good yields. The synthesized sulfamides were converted to their phenolic derivatives with BBr3. We elucidated the antioxidant activity of novel symmetric sulfamides by using different bioanalytical assays. For this purpose, the radical scavenging activities of the novel symmetric sulfamides were assessed by DPPH(•), ABTS(•+), DMPD(•+), and O2(•-) radical scavenging tests. In addition, the reducing abilities of the novel symmetric sulfamides were evaluated by Fe(3+)-Fe(2+) reducing, Cu(2+)-Cu(+) reducing, and [Fe(3+)-(TPTZ)2](3+)-[Fe(2+)-(TPTZ)2](2+) reducing activity tests. Also, the Fe(2+) chelating activity by the pipyrdyl reagent and the acetylcholinesterase inhibitory activities of the novel symmetric sulfamides were studied. Especially, the novel phenolic and symmetric sulfamides 16-19 showed high antioxidant and acetylcholinesterase inhibitory properties. On the other hand, IC50 values were calculated for the DPPH(•), ABTS(•+), DMPD(•+), and O2(•-) scavenging, the metal chelating, and the acetylcholinesterase inhibition effects of the novel symmetric sulfamides.

1,8‐Naphthyridine Derivatives: A Review of Multiple Biological Activities

Abstract: The 1,8-naphthyridine group of compounds have gained special attention of researchers on account of their demonstrating a variety of interesting biological activities. A wide range of biological properties establishes them as potent scaffolds in therapeutic and medicinal research. The broad spectrum of activities primarily includes antimicrobial, antiviral, anticancer, anti-inflammatory, and analgesic activities. 1,8-Naphthyridine derivatives have also exhibited potential applications in neurological disorders such as Alzheimer's disease, multiple sclerosis, and depression. In addition, these synthetic derivatives have been found to possess activities such as anti-osteoporotic (α(v)β(3) antagonists), anti-allergic, antimalarial, gastric antisecretory, bronchodilator, anticonvulsant, anti-hypertensive, platelet aggregation inhibition, anti-oxidant, EGFR inhibition, protein kinase inhibition, ionotropic agent, β-3 antagonist, MDR modulator, adenosine receptor agonist, adrenoceptor antagonist, and pesticide activities. In spite of the widespread application of the 1,8-naphythyridine scaffolds, only a limited number of review articles are available till date. In this review, we attempt to compile and discuss the key data available in the literature for the multiple biological activities of 1,8-naphthyridine derivatives, in a chronological manner. This review compilation (with 199 references) may be helpful in understanding the diverse biological properties of 1,8-naphthyridines and provide insights into their mechanism of action. This may direct future research in the synthesis of new derivatives and exploring this scaffold for other possible biological activities.

Cytotoxic and antimicrobial evaluations of novel apoptotic and anti-angiogenic spiro cyclic 2-oxindole derivatives of 2-amino-tetrahydroquinolin-5-one.

Abstract: A novel series of cyclic 2-oxindole derivatives incorporating 2-amino-tetrahydroquinolin-5-one were prepared. The structures of the prepared compounds were elucidated using different spectral tools. The regio-orientation of the reaction products was elucidated through NOE difference experiments and through using substituents on the ortho position to affect further cyclization. Antitumor and antimicrobial evaluations were performed on the prepared compounds. Most of these compounds exhibited high to moderate antimicrobial activity. With respect to the antitumor activity, the compounds showed more potent cytotoxic effect only toward the human breast cancer cell line MCF-7. Also, we found that derivatives containing an ester group (8c, 11b, 14b, and 15b) are more active than those containing a cyanide group (8a, 11a, 14a, and 15a). Moreover, compounds 15b and 8b are the most active derivatives in this group. These two compounds showed apoptotic inhibition of the proliferation of human breast adenocarcinoma MCF-7 cells through DNA fragmentation, induction of the tumor suppressor protein p53, induction of caspase-9, and finally the inhibition of angiogenesis by decreasing vascular endothelial growth factor expression and secretion.

Design, Synthesis and In Vitro Antiproliferative Activity of Novel Isatin‐Quinazoline Hybrids

Abstract: Using a molecular hybridization approach, a new series of isatin-quinazoline hybrids 15a-o was designed and synthesized via two different synthetic routes. The target compounds 15a-o were prepared by the reaction of quinazoline hydrazines 12a-e with indoline-2,3-diones 13a-c or by treating 4-chloroquinazoline derivatives 11a-e with isatin hydrazones 14a-c. The in vitro anticancer activity of the newly synthesized hybrids was evaluated against the liver HepG2, breast MCF-7 and colon HT-29 cancer cell lines. A distinctive selective growth inhibitory effect was observed towards the HepG2 cancer cell line. Compounds 15b, 15g and 15l displayed the highest potency, with IC50 values ranging from 1.0 ± 0.2 to 2.4 ± 0.4 μM, and they were able to induce apoptosis in HepG2 cells, as evidenced by enhanced expression of the pro-apoptotic protein Bax and reduced expression of the anti-apoptotic protein Bcl-2, in addition to increased caspase-3 levels.

The Gene bldA, a regulator of morphological differentiation and antibiotic production in streptomyces.

Abstract: Streptomyces species are well known for their particular features of morphological differentiation. On solid agar, a mold-like aerial mycelium is formed and spores are produced, in which the bld genes play a crucial role. In S. coelicolor, mutations in one specific bld gene called bldA led to a “naked” phenotype lacking aerial hyphae and spores. This peculiar behavior became a major interest for scientific research in the past and it was revealed that bldA is coding for a unique tRNA able to translate a UUA codon into the amino acid leucine. UUA codons are a very rare property of G + C-rich Streptomyces genomes. The impact of bldA on morphology can in parts be attributed to the regulatory effect of bldA on the translational level, because TTA-containing genes can only be translated into their corresponding protein in the presence of a fully functioning bldA gene. In addition to the visible effect of bldA expression on the phenotype of S. coelicolor, bldA mutants were also deficient in antibiotic production. This led to the assumption that the role of bldA must exceed translational control. Many TTA-containing genes are coding for transcriptional regulators which are activating or repressing the transcription of many more genes. Proteomics and transcriptomics are two powerful methods for identifying bldA target genes and it was possible to assign also post-translational regulation to bldA. This review wants to give a short overview on the importance of bldA as a regulator of morphological differentiation and antibiotic production by switching on “silent” gene clusters in Streptomyces.

New Coumarin Derivatives as Potent Selective COX-2 Inhibitors: Synthesis, Anti-Inflammatory, QSAR, and Molecular Modeling Studies.

Abstract: Two new series of coumarin derivatives incorporating thiazoline and thiazolidinone moieties were designed, synthesized, and investigated in vivo for their anti-inflammatory activities using the carrageenan-induced rat paw edema model and in vitro for their inhibitory activities against the human cyclooxygenase (COX)-1 and COX-2 isoforms. Most of the synthesized compounds demonstrated exceptionally high in vivo anti-inflammatory activity and displayed superior GI safety profiles (0-7% ulceration) as compared to indomethacin. All the bioactive compounds showed in vitro high affinity and selectivity toward the COX-2 isoenzyme, compared to the reference celecoxib with IC50 values ranging from 0.31 to 0.78 μM. The ethyl thiosemicarbazone 2b, thiazoline derivatives 3a, 3b, 5b, 6a, and 7f, and the thiazolidinone compounds 8b and 9a showed the highest in vivo and in vitro anti-inflammatory activities with remarkable COX-2 selectivity. Quantitative structure-activity relationship study (QSAR) was done and resulted in a highly predictive power R(2) (0.908). A molecular docking study revealed a relationship between the docking affinity and the biological results.

Synthesis, Antimicrobial, Antiquorum‐Sensing, and Cytotoxic Activities of New Series of Isoindoline‐1,3‐dione, Pyrazolo[5,1‐a]isoindole, and Pyridine Derivatives

Abstract: New series of isoindoline-1,3-diones 2-9, pyrazolo[5,1-a]isoindoles 10-14, and pyridines 16-18 were synthesized. Twenty of the synthesized compounds were screened for their antibacterial activity against S. aureus, B. cereus, and E. coli. Compound 5 was proved to be the most active member in this study, showing the highest antibacterial activity against the three selected microorganisms. The antifungal activity of these compounds was also tested against C. albicans and A. flavus 3375. Compounds 4, 5, 8, and 17a exhibited the best antifungal activity against A. flavus 3375. The same compounds were examined for their antiquorum-sensing activity against Ch. violacium ATCC 12472, whereas compound 5 displayed strong antiquorum-sensing activity. The in vitro cytotoxicity testing of compounds 4-9 and 17a against human normal lung fibroblast (W138) cell line revealed that compounds 4, 5, and 8 are the least cytotoxic analogs in this study. In vivo acute toxicity testing of compounds 4, 5, and 8 was performed. The DNA-binding affinity of compounds 4-9 and 17a was also tested and the obtained results showed that all tested compounds have moderate DNA-binding affinity.

Synthesis of Tolmetin Hydrazide-Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells.

Abstract: Tolmetin hydrazide and a novel series of tolmetin hydrazide-hydrazones 4a-l were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR) methods. N'-[(2,6-Dichlorophenyl)methylidene]-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetohydrazide (4g) was evaluated in vitro using the MTT colorimetric method against the colon cancer cell lines HCT-116 (ATCC, CCL-247) and HT-29 (ATCC, HTB-38) to determine growth inhibition and cell viability at different doses. Compound 4g exhibited anti-cancer activity with an IC50 value of 76 μM against colon cancer line HT-29 (ATCC, HTB-38) and did not display cytotoxicity toward control NIH3T3 mouse embryonic fibroblast cells compared to tolmetin. In addition, this compound was evaluated for caspase-3, caspase-8, caspase-9, and annexin-V activation in the apoptotic pathway, which plays a key role in the treatment of cancer. We demonstrated that the anti-cancer activity of this compound was due to the activation of caspase-8 and caspase-9 involved in the apoptotic pathway. In addition, in this study, we investigated the catalytical effect of COX on the HT-29 cancer line, the apoptotic mechanism, and the moleculer binding of tolmetin and compound 4g on the COX enzyme active site.

Synthesis, Biological Activity, and Docking Study of Novel Isatin Coupled Thiazolidin-4-one Derivatives as Anticonvulsants.

Abstract: A series of 2-(substituted-phenyl)-3-(2-oxoindolin-3-ylidene)amino)-thiazolidin-4-one derivatives were designed and synthesized under microwave irradiation, using an eco-friendly, efficient, microwave-assisted synthetic protocol that involves cyclocondensation of 3-substituted benzylidine-hydrazono-indolin-2-one 3a-j with thioglycolic acid in dimethyl formamide (DMF) as solvent and anhydrous zinc chloride as a catalyst, keeping in view the structural requirement of the pharmacophore. The intermediate compounds 3a-j were obtained by condensation of the hydrazone of indoline-2,3-dione with aromatic aldehydes. The synthesized derivatives were evaluated for CNS depressant activity and anticonvulsant activity in mice using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) induced seizure tests. All the derivatives showed good CNS depressant activity and showed protection in the MES test, indicative of their ability to inhibit the seizure spread. A histopathological study was performed to evaluate liver toxicity caused by the synthesized compounds. The compounds were nontoxic. A computational study was performed, in which log P values were calculated experimentally. Virtual screening was performed by molecular docking of the designed compounds into the ATP binding sites of the NMDA and AMPA receptors, to predict if these compounds have analogous binding modes.

9H-Carbazole Derivatives Containing the N-Benzyl-1,2,3-triazole Moiety as New Acetylcholinesterase Inhibitors.

Abstract: A series of triazole-containing carbazole derivatives were designed as new anti-acetylcholinesterase (AChE) agents. The target compounds 6a-q were simply prepared via a one-pot three-component click reaction of N-propargyl-9H-carbazole, sodium azide, and an appropriate benzyl halide. The in vitro anti-cholinesterase assay showed that the unsubstituted benzyl derivative 6p along with the 2-F, 2-Me, 3-Me, 3-MeO, and 3-F analogs (6a, 6c, and 6g-i) had significant anti-AChE activity (IC50s ≤ 3.8 μM). Among them, the 2-methylbenzyl derivative 6c with an IC50 value of 1.9 μM was the most active compound. The SAR studies revealed that small halogen atoms such as the fluorine atom or electron-donating groups such as methyl or methoxy at the ortho or meta positions of the benzyl pendent group could be tolerated or improved the anti-AChE activity.

MLL leukemia and future treatment strategies.

Abstract: Chromosomal rearrangements of the MLL gene are associated with high-risk infant, pediatric, adult, and therapy-induced acute leukemias. So far, about 80 different direct MLL fusions and about 120 reciprocal MLL fusions have been characterized at the molecular level. The common theme in these leukemia-associated genetic rearrangements is the genetic disruption of the MLL gene. This leads to MLL-X fusion proteins that still bind to nuclear factors (e.g., MEN1, LEDGF), which in turn allow them to target promoters and cause ectopic gene transcription. In addition, the most frequent MLL fusions (MLL-AF4, MLL-AF9, MLL-AF10, and MLL-ENL) are all recruiting the wild-type AF4 multiprotein complex that contains the target proteins P-TEFb, BRD4, and DOT1L. Vice versa, reciprocal X-MLL fusions exhibit a PHD domain (H3K4me3 reader domain), sequester the histone acetyltransferases CREBBP and MOF1 and bear a histone methyltransferase domain at their very C-terminus (SET domain). Except for AF4-MLL, the functional consequences deriving from reciprocal fusion proteins are not very well understood. However, based on our knowledge about the above-mentioned MLL fusions, it is reasonable to inhibit their oncogenic activity in a targeted fashion. Recent efforts in developing such inhibitors and their mode of action will be critically discussed.

Design, Synthesis and In Vitro Study of 5,6-Diaryl-1,2,4-triazine-3-ylthioacetate Derivatives as COX-2 and β-Amyloid Aggregation Inhibitors

Abstract: In order to find novel cyclooxygenase (COX)-2 inhibitors for treating inflammatory-based diseases such as Alzheimer's disease (AD), an ethyl carboxylate side chain was added to 5-(4-chlorophenyl)-6-(4-(methylsulfonyl)phenyl)-3-(methylthio)-1,2,4-triazine (lead compound II) to maintain residual inhibition of COX-1 through interacting with Arg120. A preliminary molecular docking study on both the COX-1/COX-2 active sites truly confirmed our hypothesis. Accordingly, a series of ethyl 5,6-diaryl-1,2,4-triazine-3-ylthioacetate derivatives were synthesized and their chemical structures were confirmed by NMR, IR and MS spectra. Further in vitro COX-1/COX-2 evaluations revealed that compound 6c (COX-2 IC50 = 10.1 μM, COX-1 IC50 = 88.8 μM) is the most selective COX-2 inhibitor while maintaining residual inhibition of COX-1. In order to evaluate their potential use against AD, an in vitro evaluation of β-amyloid fibril formation was performed. The results indicated that the prototype compounds 6 are effective β-amyloid destabilizing agents while compound 6c could inhibit 94% of the β-amyloid fibril formation after 48 h. Finally, the in silico assessment results of their blood-brain barrier permeability were satisfactory.

Novel 4‐Thiazolidinones as Non‐Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA‐Dependent RNA Polymerase

Abstract: In continuation of our efforts to develop new derivatives as hepatitis C virus (HCV) NS5B inhibitors, we synthesized novel 5-arylidene-4-thiazolidinones. The novel compounds 29–42, together with their synthetic precursors 22–28, were tested for HCV NS5B inhibitory activity; 12 of these compounds displayed IC50 values between 25.3 and 54.1 µM. Compound 33, an arylidene derivative, was found to be the most active compound in this series with an IC50 value of 25.3 µM. Molecular docking studies were performed on the thumb pocket-II of NS5B to postulate the binding mode for these compounds.

The Old Made New: Natural Compounds against Erectile Dysfunction

Abstract: The interest toward sex-related diseases keeps growing through the years. In this review, we focus our attention on erectile dysfunction (ED), a condition that caught much attention especially after the introduction on the market of phosphodiesterase 5 inhibitors such as the well-known sildenafil. Here, we briefly describe both the etiology of ED and the available treatments, examining then extensively some natural derivatives that, coming from traditional medicine, could represent promising starting points for the development of alternative remedies. In fact, herbal remedies from several parts of the world have been traditionally known for long, and were recently reconsidered and are now being studied to demonstrate their eventual potential in the treatment of ED. Among the various examples reported in the literature and reviewed here, plants and extracts containing polyphenols—especially a class of compounds called kraussianones—appear to be particularly effective and promising against ED.

New benzo[d]thiazol-2-yl-aminoacetamides as potential anticonvulsants: synthesis, activity and prediction of molecular properties.

Abstract: A series of N-(substituted-2-oxo-4-phenylazetidin-1-yl)-2-((6-substitutedbenzo[d]thiazol-2-yl)amino)acetamide derivatives were synthesized using pharmacophoric features with aromatic hydrophobic aryl ring (A), NHCO as hydrogen bonding domain, the nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). The synthesized molecules were initially screened for anticonvulsant activity using the maximal electroshock seizure (MES) test and the subcutaneous pentylenetetrazole test in albino mice. An acute neurotoxicity study on the synthesized molecules was also carried out using the rotarod test. The results of these tests revealed that two compounds, 5b and 5q, showed promising activity with ED50 values of 15.4 and 18.6 mg/kg and protective indices of 20.7 and 34.9 in the MES test, respectively, which are found to be approximately fourfold higher than those of the standard drugs phenytoin (6.9) and carbamazepine (8.1). These molecules may act as lead of the designed scheme. The pharmacokinetic profiles of all the synthesized compounds were estimated using Molinspiration software. None of the compounds violated Lipinski's “rule of five”. The possible structure–activity relationship was discussed. In conclusion, this manuscript shows that the developed model has a highly prognostic power for the further investigation of better benzothiazole derivatives for future discovery and development.

Antimicrobial and Antiquorum-Sensing Studies. Part 3: Synthesis and Biological Evaluation of New Series of [1,3,4]Thiadiazoles and Fused [1,3,4]Thiadiazoles

Abstract: New series of [1,3,4]thiadiazoles and fused [1,3,4]thiadiazoles were synthesized. The newly synthesized compounds were screened for their antibacterial activity against Staphylococcus aureus, Bacillus cereus, and Escherichia coli. Compounds 3b and 10a displayed the highest activity against E. coli with MIC value of 78.125 μg/mL. In addition, compound 10a exhibited the highest activity against B. cereus with MIC value of 156.25 μg/mL. The antifungal activity of these compounds was also tested against Candida albicans and Aspergillus flavus 3375. Compounds 3b, 5a, 10a, and 12b showed the best activity against A. flavus 3375 with MIC value of 19.531 μg/mL. The same compounds were examined for their antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, whereas compounds 3b, 5a, and 12b exhibited moderate activity. In vitro cytotoxicity testing of compounds 3b,c, 5a, 6a, 10a, and 12a,b against human normal lung fibroblast (W138) cell line was performed. The in vivo acute toxicity of the same compounds was also tested and the obtained results indicated that compound 10a is the least toxic analog. The same compounds were studied for their DNA-binding affinity and the obtained results showed that compounds 3b, 10a, and 12a,b have moderate DNA-binding affinity.

Synthesis and Anticonvulsant Activity Evaluation of 4‐Phenyl‐[1,2,4]triazolo[4,3‐a]quinazolin‐5(4H)‐one and Its Derivatives

Abstract: A series of 4-(substituted-phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones (6a-x) with triazole and other heterocyclic substituents (7-14) were synthesized and the compounds were evaluated for their anticonvulsant activity and neurotoxicity by maximal electroshock (MES) and rotarod neurotoxicity tests. Among the compounds studied, 6o and 6q showed wide margins of safety with protective indices (PIs) that were much higher than those of currently used drugs (PI6o > 25.5, PI6q > 26.0). Compounds 6o and 6q showed significant oral activity against MES-induced seizures in mice, with ED50 values of 88.02 and 94.6 mg/kg, respectively. The two compounds were also found to have potent activity against seizures that were induced by pentylenetetrazole and bicuculline.

N-(2-(Piperazin-1-yl)phenyl)arylamide Derivatives as β-Secretase (BACE1) Inhibitors: Simple Synthesis by Ugi Four-Component Reaction and Biological Evaluation

Abstract: A novel series of N-(2-(piperazin-1-yl)phenyl)aryl carboxamide derivatives were simply synthesized by Ugi-multicomponent reaction as β-secretase (BACE1) inhibitors. The BACE1 inhibitory activity of the synthesized compounds was examined using a Forester resonance energy transfer (FRET)-based assay. Among the tested compounds, the N-(5-bromo-2-(4-phenylpiperazine-1-yl)phenyl)thiophene-carboxamide derivative 14 containing the N-cyclohexyl indole acetamide moiety showed superior BACE1 inhibition at 10 and 40 µM. The results of the molecular docking study indicated that compound 14 establishes favorable hydrogen bonding interactions with the catalytic amino acid residues Asp228 and Thr72 and could be well accommodated in the flap region and P2 and P′2 pockets of the BACE1 active site.

Novel antiviral compounds against gastroenteric viral infections.

Abstract: Viral gastroenteritis is a serious viral infection which affects a large number of individuals around the world, most of them being children. The infection may occur due to different viruses, for example, coxsackievirus, adenovirus, and rotavirus. There is no available cure for such infections, and the treatment mainly depends on hospitalization and administration of nutritional supports. A new antiviral agent against gastroenteritis viral infection will be a breakthrough in healthcare. Pyrrole and pyrrolopyrimidine derivatives are well known for their biological activity as antibacterial, antifungal, and anticancer agents. These compounds also proved to possess antiviral activity. Here, we synthesized novel pyrrole and pyrrolopyrimidine compounds and examined their antiviral activity. We synthesized several new pyrrole, pyrrolo[2,3-d]pyrimidine, and pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives. The characterization of all synthesized compounds was based on microanalysis and spectral data. Moreover, we determined the non-toxic doses of these compounds on BGM, Hep-2, and MA-104 cells. We tested all the synthesized compounds for their antiviral activities against coxsackievirus B4, adenovirus type 7, and rotavirus Wa strain. Several compounds exhibited significant activities as antiviral agents.

Synthesis and Evaluation of Chroman-4-One Linked to N-Benzyl Pyridinium Derivatives as New Acetylcholinesterase Inhibitors.

Abstract: A novel series of chroman-4-one derivatives containing the N-benzyl pyridinium moiety were designed, synthesized, and evaluated for their acetylcholinesterase (AChE) inhibitory activities. Among the various synthesized compounds, (E)-1-(2,3-dibromobenzyl)-4-((7-ethoxy-4-oxochroman-3-ylidene)methyl)pyridinium bromide (8l) depicted the most potent anti-AChE activity (IC50 = 0.048 μM). In addition, the molecular modeling study allowed us to detect possible binding modes that are in full compliance with the observed results through in vitro experiments.

Monte carlo method-based QSAR modeling of penicillins binding to human serum proteins.

Abstract: The binding of penicillins to human serum proteins was modeled with optimal descriptors based on the Simplified Molecular Input-Line Entry System (SMILES). The concentrations of protein-bound drug for 87 penicillins expressed as percentage of the total plasma concentration were used as experimental data. The Monte Carlo method was used as a computational tool to build up the quantitative structure–activity relationship (QSAR) model for penicillins binding to plasma proteins. One random data split into training, test and validation set was examined. The calculated QSAR model had the following statistical parameters: r2 = 0.8760, q2 = 0.8665, s = 8.94 for the training set and r2 = 0.9812, q2 = 0.9753, s = 7.31 for the test set. For the validation set, the statistical parameters were r2 = 0.727 and s = 12.52, but after removing the three worst outliers, the statistical parameters improved to r2 = 0.921 and s = 7.18. SMILES-based molecular fragments (structural indicators) responsible for the increase and decrease of penicillins binding to plasma proteins were identified. The possibility of using these results for the computer-aided design of new penicillins with desired binding properties is presented.

One-pot multi-component synthesis of 1,4-dihydropyridines using Zn(2+) @KSF and evaluating their antibacterial and antioxidant activities.

Abstract: New 5-aryl-10-(4-(4-methoxyphenyl)thiazole-2-yl)-9,10-dihydropyrido[2,3-d:5,6-d']dipyrimidinone-2,4,6,8-(1H,3H,5H,7H)-tetraones 6a-d were synthesized through one-pot four-component reaction of aldehydes, barbituric acid, and thiazole using Zn(2+) @KSF under reflux condition. The key features of this reaction are: incorporating four heterocyclic rings, using a heterogeneous and efficient catalyst, high yield, and easy-to-setup reaction. The structure of the products was confirmed by FT-IR, (1)H NMR, and (13)C NMR spectra. The antibacterial activities of compounds 6a-d were screened against Escherichia coli, Micrococcus luteus, Pseudomonas aeruginosa, and Staphylococcus aureus bacterial strains using the zone inhibition method. Also, the 2,2-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities of compounds 6a-d were evaluated. All compounds showed good antioxidant capacity in comparison to ascorbic acid. The IC50 values of the antioxidant activity were calculated. The proposed mechanism for antioxidant activity is discussed.

Synthesis and Anticonvulsant Activity of Substituted-1,3-diazaspiro[4.5]decan-4-ones

Abstract: A series of novel spiroimidazolidinone derivatives 6a-d and 8a-x were synthesized and biologically evaluated for their anticonvulsant activity in the maximal electroshock seizure (MES) assay and the subcutaneous pentylenetetrazole (scPTZ) screening test. Compound 8w was the most active derivative in the scPTZ screening test with an ED50 value by about 5- and 83.6-fold lower than those of phenobarbital and ethosuximide as reference drugs, respectively. Most of the tested compounds exhibited moderate to weak activity in the MES screen test, except for 8a which displayed 100% protection at 0.09 mmol/kg. Moreover, all the test compounds did not show any minimal motor impairment in the neurotoxicity test.

Design, Synthesis, and Evaluation of Novel 1,2,3-Triazole-Tethered Glycolipids as Vaccine Adjuvants.

Abstract: A Cu-mediated azide-alkyne click chemistry protocol was employed for the synthesis of a focused library of novel 1,2,3-triazolyl conjugates bearing various carbohydrate-steroid/triterpenoid entities. The immunogenicity of these compounds was examined initially by ex vivo assays. The lead compound 15g was further subjected to in vivo evaluation in BALB/c mice immunized with ovalbumin. These in vivo biological studies revealed an increase in B cell-mediated proliferation, higher expression levels of IL-2, TNF-α, IL-12, and IFN-γ indicating Th1 activation, together with an enhanced OVA-specific antibody (IgG) response compared to alum, affirming adjuvanticity of these glycolipids. The primary indications of response skewed toward Th1 immunity induced by the new triazoyl analogs indicate the potential of these molecules for possible application as adjuvants.

Thiomorpholine Derivatives with Hypolipidemic and Antioxidant Activity.

Abstract: A number of thiomorpholine derivatives that are structurally similar to some substituted morpholines possessing antioxidant and hypocholesterolemic activity were synthesized. The new compounds incorporate an antioxidant moiety as the thiomorpholine N-substituent. The derivatives were found to inhibit the ferrous/ascorbate-induced lipid peroxidation of microsomal membrane lipids, with IC50 values as low as 7.5 µΜ. In addition, these compounds demonstrate hypocholesterolemic and hypolipidemic action. The most active compound (5) decreases the triglyceride, total cholesterol, and low-density lipoprotein levels in the plasma of Triton WR-1339-induced hyperlipidemic rats, by 80, 78, and 76%, respectively, at 56 mmol/kg (i.p.). They may also act as squalene synthase inhibitors. The above results indicate that the new molecules may be useful as leads for the design of novel compounds as potentially antiatherogenic factors.

Synthesis of Desaza Analogues of Annomontine and Canthin-4-one Alkaloids

Abstract: 1-Acetylcarbazoles are readily converted to 3-desazacanthin-4-ones upon treatment with Bredereck's reagent, but in contrast to canthin-4-ones, these do not undergo ring transformation reactions with guanidine. Only after N-protection (methyl or 2-(trimethylsilyl)ethoxymethyl group), 2-desaza analogues of the alkaloid annomontine are accessible via the enaminoketones obtained by condensation with Bredereck's reagent. One of the annomontine analogues is an inhibitor of the Plasmodium falciparum CDC-like kinases (CLK) and shows antimalarial activity.

Synthesis and Cytotoxic Activity of Pentacyclic Triterpenoid Sulfamates

Abstract: Methyl triterpenoates derived from oleanolic, ursolic, betulinic, glycyrrhetinic, platanic, or maslinic acid were converted into their corresponding sulfamates and carbamoylsulfamates. The sulfamates were screened in photometric sulforhodamine assays for cytotoxic activity employing several human tumor cell lines. Many of the compounds showed EC50 values in one-digit μM concentration. Of special interest seems methyl (3β) 3-(aminosulfonyloxy)-11-oxo-oleanoate (18) showing good cytotoxicity for the human adenocarcinomic alveolar basal epithelial cell line A549 while being less toxic for non-malignant NIH 3T3 mouse fibroblasts.

Synthesis and Screening of Human Monoamine Oxidase-A Inhibitor Effect of New 2-Pyrazoline and Hydrazone Derivatives.

Abstract: A group of 3,5-diaryl-2-pyrazoline and hydrazone derivatives was prepared via the reaction of various chalcones with hydrazide compounds in ethanol Twenty original compounds were synthesized Ten of these original compounds have a pyrazoline structure, nine of these original compounds have a hydrazone structure, and one of these original compounds has a chalcone structure Structural elucidation of the compounds was performed by IR, (1)H NMR, (13)C NMR, mass spectral data, and elemental analyses These compounds were tested for their inhibitory activities toward the A and B isoforms of human monoamine oxidase (MAO) Except for 3k and 6c, all compounds were found to be competitive, reversible, and selective inhibitors for either one of the isoforms (hMAO-A or MAO-B) Compounds 3k and 6c were found to be competitive, reversible, but non-selective MAO inhibitors Compound 6h showed hMAO-B inhibitory activity whereas the others potently inhibited hMAO-A Compound 5c showed higher selectivity than the standard drug moclobemide According to the experimental K(i) values, compounds 6i, 6d, and 6a exhibited the highest inhibitory activity toward hMAO-A The AutoDock 42 program was employed to perform automated molecular docking The calculated results obtained computationally were in good agreement with the experimental values