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Archiv der Pharmazie



Wiley Online Library : Archiv der Pharmazie



Published: 2017-09-01T00:00:00-05:00

 



Evaluation of β-Aminocarboxylic Acid Derivatives in Hippocampal Excitatory Synaptic Transmission

2017-09-05T07:06:11.936641-05:00

β-Aminocarboxylic acid derivatives (LINS04 series) were screened with the aim to explore their potential functional role in excitatory synaptic transmission in the central nervous system. We used field recordings in rat hippocampal slices to investigate the effects of the LINS04 series on the synaptic transmission at hippocampal CA1 synapses. We found that LINS04008 and LINS04009 increase the size of the evoked field excitatory postsynaptic potential (EPSP) in a dose-dependent manner. The concentration–response curve shows that the efficacy of LINS04008 is highest in the series (EC50 = 91.32 µM; maximum fEPSP 44.97%). The esters LINS04006 and LINS04005 did not affect the synaptic evoked activity. These data provide the first evidence of synaptic activity enhancement by these compounds and the importance of the acidic group to the activity. This set of data may provide direction for a strategic procedure to restore the glutamate synaptic transmission; however, further studies are needed to establish a more complete picture of how these molecules act on the glutamate transmission, which are in our mind for the next steps. β-Aminocarboxylic derivatives were screened in hippocampal CA1 slices as modulators of glutamatergic neurotransmission. LINS04008 (EC50 = 91.32 μM; maximum evoked field excitatory postsynaptic potential 44.97%) was the most promising stimulant of the synaptic activity, while the ester derivatives LINS04006 and LINS04005 were inactive.



Design, Synthesis, and Biological Evaluation of New Peptide Analogues as Selective COX-2 Inhibitors

2017-09-05T07:05:57.267076-05:00

A new class of peptide derivatives possessing SO2Me and N3 pharmacophores at the para position of a phenyl ring bound to different aromatic amino acids were synthesized based on solid-phase synthesis methodology, and evaluated as selective cyclooxygenase-2 (COX-2) inhibitors. One of the analogues, i.e., compound 2a as the representative of this series, was recognized as the highest selective COX-2 inhibitor with a COX-2 selectivity index of >500. The structure–activity relationships (SARs) acquired indicated that compound 2a containing a 4-(methylsulfonyl)benzoyl group as a pharmacophore and tyrosine as a ring bearing amino acid in the second position and glutamic acid as the C-terminal amino acid can give the essential geometry to provide selective COX-2 inhibitory activity. Antiproliferative activity of the synthesized peptides (1a–7b) was also determined against four different human cancer cell lines, including MCF-7, HepG2, A549, and HeLa. According to our results, A549, HepG2, and MCF7 seemed to be more sensitive cell lines than HeLa cells encountering these compounds, which gave inhibitory action with IC50 values from 4.8 to 64.4 µM. In this regard, compounds 3a and 2b displayed the best inhibitory activity against the cell lines. Moreover, a good correlation was observed between the antiproliferative potency and the COX-2 inhibitory activity of compounds 1a, 2a, 2b, and 5b. Such findings suggest that one of the mechanism of anticancer activity of these peptides may be through the COX-2 inhibitory action. A new class of peptide derivatives possessing SO2Me and N3 pharmacophores at the para position of a phenyl ring bound to different aromatic amino acids were synthesized by solid-phase synthesis methodology and evaluated as selective cyclooxygenase-2 (COX-2) inhibitors and anticancer agents. Compounds 3a and 2b displayed the best potency against the studied cancer cell lines. Compounds 1a, 2a, 2b, and 5b showed good correlation between their antiproliferative and COX-2 inhibitory activity.



Design, Synthesis, and Pharmacological Screening of Pyridazinone Hybrids as Anticonvulsant Agents

2017-09-01T14:41:58.056118-05:00

A series of new hybrid benzimidazole containing pyridazinones derivatives were designed and synthesized in accordance with the pharmacophoric requirements essential for the anticonvulsant activity. The synthesized compounds were evaluated for anticonvulsant activity on mice by the gold standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models. Among the compounds tested, SS-4F showed significant anticonvulsant activity in both the screens with ED50 values of 25.10 and 85.33 mg/kg in the MES and scPTZ screens, respectively. Compound SS-4F emerged as safer and effective anticonvulsant due to its several-fold higher protective indices. Further, the gamma-aminobutyric acid (GABA) estimation result showed a marked increase in the GABA level (1.7-fold) as compared to the control, which was further confirmed by good binding properties with the GABAA receptor. A series of new hybrid benzimidazole containing pyridazinones derivatives were designed and synthesized, and evaluated for anticonvulsant activity on mice based on the standard MES and scPTZ-induced seizure models. Compound SS-4F showed significant anticonvulsant activity with ED50 values of 25.10 and 85.33 mg/kg in the MES and scPTZ screen, respectively. It also had the highest protective indices.



The Effect of Carboxamide/Sulfonamide Replacement in Arylpiperazinylalkyl Derivatives on Activity to Serotonin and Dopamine Receptors

2017-08-28T05:34:48.792086-05:00

A series of carboxamide and sulfonamide alkyl (p-xylyl and benzyl) 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1-(2,3-dichlorophenyl)piperazine (2,3-DCPP) analogs were prepared and tested for their affinity to bind to serotonin 5-HT1A/5-HT6/5-HT7 and dopamine D2 receptors. This chemical modification let us explore the impact of the replacement of the carboxamide by the sulfonamide group on the affinity changes. In both the o-OMe-PhP and 2,3-DCPP series, the relative activities of the carboxamides versus sulfonamides toward the 5-HT1A/5-HT6/5-HT7 and D2 receptors show similar trends. Varied or similar activities for particular receptors were found for the carboxamides/sulfonamides with p-xylyl spacer, while of the two classes of carboxamides and sulfonamides examined, benzyl derivatives of the sulfonamides displayed the highest serotoninergic affinity, in particular to the 5-HT7 receptors (Ki 8–85 nM). The Ki values revealed that, irrespective of the carboxamide/sulfonamide zone, both p-xylyl and benzyl derivatives had the highest affinity for the dopamine D2 receptor (i.e., 16 out of 24 compounds investigated have an affinity below 100 nM). A molecular modeling study of carboxamide 9a and sulfonamide 9b showed that their binding effects to each of 5-HT1AR and D2R created binding modes interaction with different conserved receptors residues. Structural similarities of carboxamide 9a in complexes with a 5-HT1AR (9aI) and D2R (9aII) are over 83%, while the respective similarities of sulfonamide 9b structures (9bI/9bII) are only about 40%. New carboxamide and sulfonamide alkyl (p-xylyl and benzyl) 1-(2-methoxyphenyl)piperazine and 1-(2,3-dichlorophenyl)piperazine analogs were tested for their affinity to the serotonin 5-HT1A/5-HT6/5-HT7 and dopamine D2 receptors, allowing exploration of the impact of the replacement of the carboxamide by the sulfonamide group on receptor affinity. Benzyl derivatives of the sulfonamides displayed the highest serotoninergic affinity.



Delivery of Therapeutic Proteins Using Electrospun Fibers—Recent Developments and Current Challenges

2017-08-28T05:31:50.280788-05:00

Proteins play a vital role within the human body by regulating various functions and even serving as structural constituent of many body parts. In this context, protein-based therapeutics have attracted a lot of attention in the last few decades as potential treatment of different diseases. Due to the steadily increasing interest in protein-based therapeutics, different dosage forms were investigated for delivering such complex macromolecules to the human body. Here, electrospun fibers hold a great potential for embedding proteins without structural damage and for controlled release of the protein for therapeutic applications. This review provides a comprehensive overview of the current state of protein-based carrier systems using electrospun fibers, with special emphasis on discussing their potential and key challenges in developing such therapeutic strategies, along with a prospective view of anticipated future directions. Electrospun fibers hold great potential for embedding proteins for controlled release of the protein for therapeutic applications. This review provides a comprehensive overview of the current state of protein-based carrier systems using electrospun fibers with special emphasis on their potential and the key challenges in developing such therapeutic strategies.



Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti-Hyperlipidemic and Antioxidant Agents

2017-08-24T13:05:56.199637-05:00

Hyperlipidemia and oxidative stress have been implicated as contributing factors to the development of atherosclerosis and cardiovascular diseases (CVDs). Currently, a large number of antihyperlipidemic medications are conveniently available in the market. Nonetheless, the majority of antihyperlipidemics lack the desired safety and efficacy. Thus, the present study was undertaken to evaluate the potential effect of novel N-(benzoylphenyl)pyridine-4-carboxamide and N-(9,10-dioxo-9,10-dihydroanthracenyl)pyridine-4-carboxamide derivatives in controlling hyperlipidemia and oxidative stress using the Triton WR-1339-induced hyperlipidemic rat model for antihyperlipidemic activity and the DPPH radical scavenging assay for antioxidant activity. This study revealed the antihyperlipidemic activities of some of the newly synthesized, novel carboxamide derivatives, mainly C4 and C12 (p < 0.05). The majority of the compounds displayed a relatively low or no DPPH radical scavenging effect, with C20 possessing the best radical scavenging effect (22%) among all. This research opens the door for new potential antihyperlipidemic compounds derived from isonicotinic acid. N-(3-Benzoylphenyl)pyridine-4-carboxamide (C4) was found to have promising lipid-lowering and antioxidant effects, which may create a protective effect against CVDs, by reducing the LDL-C levels and diminishing the generation of reactive oxygen species. Novel N-(benzoylphenyl)pyridine-4-carboxamide and N-(9,10-dioxo-9,10-dihydroanthracenyl)pyridine-4-carboxamide derivatives were studied for their activities in controlling hyperlipidemia and oxidative stress. N-(3-Benzoylphenyl)pyridine-4-carboxamide showed promising lipid-lowering and antioxidant effects, which may provide protection against cardiovascular diseases.



Molecular Engineering of Tetracyclic 2,3-Dihydro-1H-benzo[2,3]-benzofuro[4,5-e][1,3]oxazine Derivatives: Evaluation for Potential Anticancer Agents

2017-08-23T12:26:36.160828-05:00

Water-mediated one-pot Mannich type condensation of dibenzo[b,d]furan-2-ol with different amines resulted in a large library of novel 2,3-dihydro-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives in moderate to excellent yields. The ortho-aminomethylation of the dibenzofuranols proceeded smoothly in the presence of various aromatic/aliphatic amines and paraformaldehyde, followed by cyclization. All the newly synthesized tetracyclic 2,3-dihydro-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives were chemically characterized and screened for their cytotoxicity activity by cell viability assay (MTT test) against three human cancer cell lines and antibacterial activity by determining the minimum inhibitory concentration (MIC) against four bacterial strains. Among all the derivatives, MCV-24 showed promising anticancer activity by inhibiting the cell proliferation of an ovarian cancer cell line (SKOV3) with an IC50 value at 7.5 µM, whereas MCV-24 to MCV-30 derivatives showed moderate activity against a lung cancer cell line (A549) with an IC50 value ranging from 11 to 15.9 µM. Besides MCV-29, -30, and -31 also exhibited broad-spectrum antibacterial activity. Among all new compounds, MCV-24–30 showed promising anticancer and MCV-29–31 antibacterial activity. Water-mediated one-step Mannich type condensation of dibenzo[b,d]furan-2-ol with different amines gave a large library of novel 2,3-dihydro-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives. Among these, MCV-24 showed promising anticancer activity by inhibiting the cell proliferation of the SKOV3 ovarian cancer cell line at IC50 = 7.5 μM. Derivatives MCV-24 to MCV-30 showed moderate activity against the lung cancer cell line A549.



Aromatic Regions Govern the Recognition of NADPH Oxidase Inhibitors as Diapocynin and its Analogues

2017-08-21T07:51:18.265945-05:00

Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O2•−). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2–C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes π–π interactions principally with W193, W263, and Y279, which form an aromatic-rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity. Compound C8, one of the 18 designed compounds with chemical relationship to the NOX2 inhibitor diapocynin (C1), forms π–π interactions with the NOX2 subunit p47phox and exhibits antioxidant properties by inhibiting ROS production in endothelial cells. Targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity.



Cover Picture: Arch. Pharm. Chem. Life Sci. (9/2017)

2017-09-01T01:47:51.951451-05:00







Mannich Ketones as Possible Antimycobacterial Agents

2017-07-28T03:55:29.636518-05:00

Twenty-three known unsaturated and fused Mannich ketones and their reduced derivatives (amino alcohols) were selected for an antituberculotic study. They were screened against several mycobacterial strains including Mycobacterium tuberculosis, M. xenopi, and M. gordonae, and minimum inhibitory concentration values were also determined using the standard antituberculotic drug isoniazid (INH) as a reference. Structure–activity relationships were also studied. The mode of action of the test compounds was investigated using transmission electron microscopy, high-performance liquid chromatography, and matrix-assisted desorption/ionization mass spectrometry. Several test substances proved to be as potent as INH, but their antimycobacterial spectra were broader than that of INH. Our findings suggest that their mode of action is probably through the inhibition of mycobacterial cell wall biosynthesis. The antimycobacterial activities of (E)-2-phenylmethylene-6-morpholin-1-ylmethyl-cyclohexanone (1), cis-(E)-2-phenylmethylene-6-morpholin-1-ylmethyl-cyclohexanol (8) and trans-(E)-2-phenylmethylene-6-morpholin-1-ylmethyl-cyclohexanol (9) are compared. Compound 1 is a ketone with a MIC value of 100 µg/mL against the standard Mycobacterium tuberculosis H37Rv strain, while the aminoalcohols 8 and 9 were more efficient (MIC: 12.5 µg/mL). The test compounds may interfere with mycolic acid biosynthesis.



Some Novel Mannich Bases of 5-(3,4-Dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one and Their Anti-Inflammatory Activity

2017-08-04T06:45:21.849987-05:00

Non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of rheumatic arthritis, pain, and many different types of inflammatory disorders, cause serious gastrointestinal (GI) side effects. The free carboxylic acid group existing on their chemical structure is correlated with GI toxicity related with all routine NSAIDs. Replacing this functional group with the 1,3,4-oxadiazole bioisostere is a generally used strategy to obtain an anti-inflammatory agent devoid of GI side effects. In the present work, a novel group of 5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one Mannich bases were synthesized and characterized on the basis of IR, 1H NMR, and elemental analysis results. The target compounds were first tested for cytotoxicity to determine a non-toxic concentration for anti-inflammatory screening. Anti-inflammatory effects of the compounds were evaluated by in vitro lipopolysaccharide (LPS)-induced NO production and in vivo carrageenan footpad edema with ulcerogenic profile. In LPS-induced RAW 264.7 macrophages, most of the compounds showed inhibitory activity on nitrite production while compounds 5a, 5h, and 5j exhibited the best profiles by suppressing the NO production. To evaluate the in vivo anti-inflammatory potency of the compounds, the inflammatory response was quantified by increment in paw size in the carrageenan footpad edema assay. The anti-inflammatory data scoring showed that compounds 5a–d, 5g, and 5j, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5g was comparable to that of the reference drug indomethacin with 53.9% and 55.5% inhibition in 60 and 120 min, respectively. A series of novel 1,3,4-oxadiazole-2-one derivatives was synthesized by Mannich reaction of 5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one and different substituted piperidines. The synthesized compounds were tested for their in vivo and in vitro anti-inflammatory and ulcerogenic profiles. Preliminary pharmacological evaluation of the compounds showed that some of the compounds possess good to moderate anti-inflammatory activity.



Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

2017-07-31T03:41:45.066811-05:00

A series of new pyrimidine–triazine hybrids (4a–t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED50), 285.02 and 293.42 mg/kg (scPTZ ED50), and 389.11 and 412.16 mg/kg (TD50), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABAA receptor as a possible mechanism of their anticonvulsant action, and in silico ADME studies were carried out to predict the safety and stability of the molecules. The increased GABA level in the experimental animals in the neurochemical estimation assay confirmed their GABAergic modulating activity. The most potent compounds were also evaluated for their neurotoxic and hepatotoxic effects. Fortunately, they did not show any sign of neurotoxicity or hepatotoxicity, suggesting that they have a broad spectrum of anticonvulsant activity with a large safety margin. Together, this research suggested that 4o and 4s may serve as leads in the discovery and development of new anticonvulsant drugs. A series of new pyrimidine–triazine hybrids (4a–t) was designed and synthesized, and their anticonvulsant effects were tested in comparison to the standard drugs, phenytoin and carbamazepine. Two compounds (4o and 4s) emerged as the most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED50), 285.02 and 293.42 mg/kg (scPTZ ED50), and 389.11 and 412.16 mg/kg (TD50), respectively, without showing neurotoxic and hepatotoxic effects.



New Coumarin Derivatives as Anti-Breast and Anti-Cervical Cancer Agents Targeting VEGFR-2 and p38α MAPK

2017-08-08T08:25:37.676838-05:00

Breast and cervical cancers are the most common gender-specific cancers affecting women worldwide. In this investigation, we highlighted the synthesis, VEGFR-2 and p38α MAPK inhibitory activity of new series of fluorinated coumarin-based derivatives featuring a variety of bioactive chemical moieties attached or fused to the coumarin nucleus at the 3 and/or 4 position. The bioactive inhibitors were further assessed for their anti-proliferative effect against human MCF-7 breast cancer and HeLa cervical cancer cell lines, respectively. Most of the tested compounds showed potent preferential inhibition effects against human VEGFR-2 and remarkable anticancer activities in the human breast cancer cell line MCF-7. Compounds 29, 24, and 2 displayed the highest inhibitory activity against VEGFR-2 (94% inhibition) and they were the most potent anticancer agents toward MCF-7 cancer cells with IC50 values of 7.90, 8.28, and 8.30 μg/mL, respectively. Compound 13 inhibited p38α MAPK phosphorylation with a significant reduction in % cell viability against HeLa cancer cells at 10 and 30 µM. Docking experiments carried out on VEGFR-2 and p38 MAPK crystallographic structures revealed that the active compounds bind to the active sites through H-bonds, arene–cation, and hydrophobic π–π interactions. QSAR analysis demonstrated considerable correlation coefficient (R2 = 0.76969) and root mean square error (RMSE = 0.10446) values. Also, the residual values between the experimental pIC50 and predicted pIC50 are very close, indicating the reliability of the established QSAR model. The VEGFR-2 and p38α MAPK inhibitory activities of new series of fluorinated coumarin-based derivatives with bioactive chemical moieties attached or fused to the coumarin nucleus at the 3 and/or 4 position are explored. Compounds 29, 24, and 2 displayed the highest inhibitory activity against VEGFR-2 (94% inhibition); they were also the most potent anticancer agents towards MCF-7 cancer cells (IC50 = 7.90, 8.28, and 8.30 μg/mL, respectively).



Design, Synthesis, and the Biological Evaluation of a New Series of Acyclic 1,2,3-Triazole Nucleosides

2017-08-01T08:20:29.280442-05:00

A new strategy for the synthesis of N3-benzoylated- and N3-benzylated N1-propargylquinazoline-2,4-diones 30a−d and 31a−d from isatoic anhydride 41 is reported. The alkynes 30a−d and 31a−d were applied in the 1,3-dipolar cycloadditions with azides 27 and 28 to synthesize acyclic 1,2,3-triazole nucleosides. The obtained alkynes and 1,2,3-triazole were evaluated for antiviral activity against a broad range of DNA and RNA viruses. The alkyne 30d showed activity against adenovirus-2 (EC50 = 8.3 μM), while compounds 37a and 37d were also active toward herpes simplex virus-1 wild-type and thymidine kinase deficient (HSV-1 TK−) strains (EC50 values in the range of 4.6–13.8 μM). In addition, compounds 30a, 30b, 37b, and 37c exhibited activity toward varicella-zoster virus (VZV) TK+ and TK− strains (EC50 = 2.1–9.5 μM). The compound 30b proved to be the most selective against VZV and displayed marginal activity against human cytomegalovirus (HCMV). Although the compound 30a had improved anti-HCMV activity, the increase in anti-HCMV activity was accompanied by significant toxicity. Compounds 37a and 37d showed inhibitory effects toward the human T lymphocyte (CEM) cell line (IC50 = 21 ± 7 and 22 ± 1 μM, respectively), while compound 35 exhibited cytostatic activity toward HMEC-1 cells (IC50 = 28 ± 2 μM). Alkyne 30a exhibited activity against adenovirus-2 (EC50 = 8.3 μM), while compounds 30a, 30b, 36b, and 36c were active toward varicella-zoster virus TK+ and TK− strains with EC50 values in the range of 2.1–9.5 μM. Compounds 36a and 36d showed activity against herpes simplex virus-1 (HSV-1 TK–) strains (EC50 = 4.6–13.8 μM) and inhibitory effects toward the human T lymphocyte (CEM) cell line (EC50 = 21 ± 7 μM and 22 ± 1 μM, respectively).



Diarylpyrazole Ligated Dihydropyrimidine Hybrids as Potent Non-Classical Antifolates and Their Efficacy Against Plasmodium falciparum

2017-08-10T08:46:55.956584-05:00

A series of diarylpyrazole clubbed dihydropyrimidine derivatives (J1–J30) was synthesized under microwave-assisted heating conditions by employing Biginelli reaction methodology and utilizing triethylammonium acetate both as a catalyst and as reaction medium, leading towards a greener reaction pathway. The synthesized entities were screened for their antimalarial efficacy against a Plasmodium falciparum strain in vitro. The active entities (J9, J15, J21, J25, and J27) obtained out of the in vitro screening were further evaluated for their enzyme inhibitory potency against the Pf-DHFR enzyme in vitro as well as in silico using Glide. Furthermore, the active scaffolds were tested for their cytotoxicity against Vero cells, proving their nontoxic behavior and selectivity. The ADME parameters were also evaluated and predicted in silico, indicating good oral bioavailability of the compounds. Novel hybrid diarylpyrazole clubbed dihydropyrimidine motifs were synthesized under microwave irradiation using TEAA as reaction medium, and screened for their antimalarial efficacy, revealing five active scaffolds: J9, J15, J21, J25, and J27. Enzyme inhibitory studies against Pf-DHFR proved their potency as dihydrofolate reductase inhibitors. The obtained ADME parameters predicted oral bioavailability of these active molecules.



Synthesis of Some Novel 2,6-Disubstituted Pyridazin-3(2H)-one Derivatives as Analgesic, Anti-Inflammatory, and Non-Ulcerogenic Agents

2017-08-09T06:10:27.682225-05:00

Some novel 2,6-disubstituted pyridazine-3(2H)-one derivatives were synthesized and evaluated for in vitro cyclooxygenase-2 (COX-2) inhibitory efficacy. Compounds 2-{[3-(2-methylphenoxy)-6-oxopyridazin-1(6H)-yl]methyl}-1H-isoindole-1,3(2H)-dione (5a), 2-propyl-6-(o-tolyloxy)pyridazin-3(2H)-one (6a), and 2-benzyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one (16a) showed the most potent COX-2 inhibitory activity with IC50 values of 0.19, 0.11, and 0.24 μM, respectively. The synthesized compounds with the highest COX-2 selectivity indices were evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities. Compounds 6a and 16a demonstrated the most potent and consistent anti-inflammatory activity over the synthesized compounds, which was significantly higher than that of celecoxib in the carrageenin rat paw edema model and with milder ulcer scoring than that of indomethacin in the ulcerogenicity screening. Novel 2,6-disubstituted pyridazine-3(2H)-one derivatives were synthesized and evaluated for their in vitro COX-2 inhibitory efficacy. The three most potent compounds showed IC50 values of 0.19, 0.11, and 0.24 μM, respectively. In addition, compounds 6a and 16a demonstrated anti-inflammatory activities higher than that of celecoxib, with milder ulcer scoring than that of indomethacin.