Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation

A series of 3-substituted (5c-5f, 6c-6f) and 4-substituted (10a-10g) oxoisoaporphine derivatives were synthesized. It was found that all these synthetic compounds had IC₅₀ values at micro or nano molar range for cholinesterase inhibition, and most of them could inhibit amyloid β (Aβ) self-induced aggregation with inhibition ratio from 31.8% to 57.6%. The structure-activity relationship studies revealed that the derivatives with higher selectivity on AChE also showed better inhibition on Aβ self-induced aggregation. The results from cell toxicity study indicated that most quaternary methiodide salts had higher IC₅₀ values than the corresponding non-quaternary compounds. This study provided potentially important information for further development of oxoisoaporphine derivatives as lead compounds for the treatment of Alzheimer’s disease.     

Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines

New series of sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a]pyrimidine were synthesized and investigated as antitumor agents. Some of the newly prepared compounds were tested for their in vitro and in vivo antitumor activities. Preliminary biological studies revealed that compounds 4c, 4f, and 4j exhibited the highest affinity to DNA, while compounds 4h,i, 6a-c, 8 and 12-14 exhibited moderate activity. Also, compounds 4j, 4f and 4c showed the highest percentage increase in lifespan of mice inoculated with Ehrlich ascites cells over 5-flurouracil (positive control). The detailed synthesis, spectroscopic and biological data are reported.     

Synthesis, biological assessment and molecular modeling of new dihydroquinoline-3-carboxamides and dihydroquinoline-3-carbohydrazide derivatives as cholinesterase inhibitors, and Ca channel antagonists

The synthesis, biological evaluation, and molecular modeling of new 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides(4), 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (6), and some hexahydropyrimido[5,4-c]quinoline-2,5-diones (9) produced earlier by our laboratory, as AChE/BuChE inhibitors, is described. From these analyses compound 4c resulted equipotent regarding the inhibition of cholinesterases’; inhibitors 6k, 9a, 9b were selective for AChE, whereas product 4d proved selective for BuChE. Docking analysis has been carry out in order to identify the binding mode in the active site, and to explain the observed selectivities. Only compound 9a has been shown to decrease K⁺-induced calcium signals in bovine chromaffin cells.     

Anti-tubercular agents. Part 6: synthesis and antimycobacterial activity of novel arylsulfonamido conjugated oxazolidinones

As a part of investigation of new anti-tubercular agents in this laboratory, herein we describe the synthesis of a new class of arylsulfonamido conjugated oxazolidinones. The in vitro activity of these conjugated (6a-f, 7a-d, 9a-c and 11a-c) molecules against Mycobacterium tuberculosis H₃₇Rv by using rifampicin and linezolide as positive controls is discussed, compounds 7c and 9a-c are found to be the most active members in this series. Further, cytotoxicity of the potent conjugates of the series (7c, and 9a-c) was evaluated on human foreskin fibroblast (HFF) cells by using MTT assay. Finally, these studies suggest that compounds 7c and 9a may serve as promising lead scaffolds for further generation of new as anti-TB agents.     

Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities

Condensation of 3-N,N-diethylaminophenol (1) with α-cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) provided compounds 3a-f and 4a-c. 12H-Chromeno[2,3-d]pyrimidine derivatives 6, 11-13 and 16 were obtained by treatment of 4H-chromene compounds (3) with different electrophiles followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR, UV, ¹H NMR, ¹³C NMR and MS data. Some of the new compounds were evaluated for antimicrobial and cytotoxicity activities.     

Synthesis, characterization of some benzazoles bearing pyridine moiety: search for novel anticancer agents

Thirteen novel benzazole derivatives were synthesized as possible anticancer agents. The first intermediate 1,3-benzothiazol-2-ylacetonitrile (2) was synthesized via cyclodeamination reaction of o-aminothiophenol (1) with malononitrile. Also, the second intermediate 5,6-dimethyl-1H-benzimidazol-2-ylacetonitrile (10) was afforded via cyclocondensation reaction between 4,5-dimethyl-1,2-phenylenediamine (9) and ethylcyanoacetate. Nucleophilic reaction of benzimidazolyl NH of compound (10) with ethylcyanoacetate afforded benzimidazolyl-3-oxopropanenitrile (11). On the other hand, methylenation of CH₂ function of compound (10) with dimethylformamide/dimethylacetal afforded benzimidazolylprop-2-enenitrile 12. The synthesis of benzothiazoylpyridines 5a,b and 8a,b as well as benzimidazolylpyridines, 14a,b and 17a-d was carried out through Michael addition of compounds 2 or 10 with arylidenemalononitriles 3a,b and 4a-d. The combination of pharmacophoric anticancer moieties, pyridine and benzazoles was the base on which target compounds 5a,b, 8a,b, 14a,b and 17a-d were designed. Among the synthesized compounds, four derivatives 10 and 17b-d were selected by National Cancer Institute (NCI), USA to be screened for their anticancer activity at a single high dose (10⁻⁵ M) against a panel of 60 cancer cell lines. Compound 17b 4-[p-chlorophenyl]pyridine and 17d 4-[p- methoxyphenyl] pyridine exhibited a broad and moderate antitumor activity against 41 tumor cell lines belonging to the nine subpanels employed and are selected for further evaluation at five dose level screening.     

Design, synthesis and molecular docking studies of novel triazole as antifungal agent

In order to meet the urgent need for novel antifungal agents with improved activity and broader spectrum, a series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substituted trifluoromethyl phenyl)-piperazin-1-yl]-propan-2-ols were designed, synthesized and evaluated as antifungal agents. The MIC₈₀ values indicate that the compounds 7a-7q, 8a-8d showed higher antifungal activities against Candida albicans than 5a-5i, 6a-6j. Moreover, the molecular model for the binding between compound 5a, 7a and the active site of CACYP51 was provided based on the computational docking results, and the structure-activity relationship was analyzed.     

Design, synthesis and docking studies of quinoline-oxazolidinone hybrid molecules and their antitubercular properties

New series of quinoline-oxazolidinone hybrid molecules were synthesized based on the preliminary docking studies. All the newly synthesized compounds were characterized by spectral analyses. The newly synthesized compounds were screened for their antimycobacterial properties based on the promising preliminary antibacterial screening results. Amongst tested compounds, compounds 8a, 8j and 13a were active at 0.65 μg/mL against Mycobacterium tuberculosis H₃₇Rv strain. The mode of action of these active compounds was carried out by docking of receptor enoyl-ACP reductase with newly synthesized candidate ligands 8a, 8j and 13a. These compounds exhibited well established bonds with one or more amino acids in the receptor active pocket. From the docking studies, compound 8j was considered to be the best inhibitor.     

Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs

In order to identify new efficient prodrugs of 5-fluorouracil (5-FU) and to develop an original targeting approach using 2-fluoro-2-deoxyglucose (FDG) as a potential drug carrier, eight original 5-FU derivatives were synthesized: 5-FU was attached by the N1 position of the pyrimidinic ring to the C1 position of the FDG structure either by direct coupling (2a) or via various spacers (3, 6a-c, 10b and 19). A new sensitive high-performance liquid chromatography method was developed to simultaneously quantify 5-FU and its derivatives in human plasma and other relevant media at physiological temperatures. Half-lives were determined from the degradation profiles of these conjugates. Slow degradation of compounds 2a, 3, 10b and 19 was observed in vitro at 37 °C, but no 5-FU release was noticed. By contrast, the in vitro drug release profiles of compounds 6a-c followed pseudo-first-order kinetics, and 5-FU was found in all the media. The antiproliferative activity of the eight compounds was assessed in vitro by a fluorometric assay against two human solid cancer cell lines and one healthy cell line. A correlation was found between the activities of the compounds and their ability to release 5-FU efficiently.     

Synthesis, glucose uptake activity and structure-activity relationships of some novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties via two carbon acyl linker

Three series of novel glitazones were designed and prepared by using appropriate synthetic schemes to incorporate glycine, aromatic and alicyclic amines via two carbon linker. Compounds were synthesized both under conventional and microwave methods. Nineteen out of twenty four synthesized compounds were evaluated for their in vitro glucose uptake activity using isolated rat hemi-diaphragm. Compounds, 6, 9a, 13a, 13b, 13c, 13f and 13h exhibited significant glucose uptake activity. Illustration about their synthesis and in vitro glucose uptake activity is described along with the structure-activity relationships.     

Synthesis of new chalcone derivatives bearing 2,4-thiazolidinedione and benzoic acid moieties as potential anti-bacterial agents

A series of chalcone derivatives bearing the 2,4-thiazolidinedione and benzoic acid moieties (8a-s) were synthesized, characterized, and evaluated for their anti-bacterial activity. Among the tested compounds, the most effective were 8a, 8h, 8k, 8n and 8q with MIC value in the range of 0.5-4 μg/mL against six Gram-positive bacteria (including multidrug-resistant clinical isolates). None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 and E. coli 1682 at 64 μg/mL.     

Synthesis, antidepressant and antifungal evaluation of novel 2-chloro-8-methylquinoline amine derivatives

A new series of N-[(2-chloro-8-methylquinolin-3-yl)methyl]-(substituted)-aniline/butylamine/cyclohexylamine/benzylamine derivatives (4a-p) was synthesized by nucleophilic substitution reaction of 2-chloro-3-(chloromethyl)-8-methylquinoline 3 with various aliphatic and aromatic amines in absolute ethanol in the presence of triethylamine (TEA). The newly synthesized secondary amines were characterized by the combined use of IR, ¹H NMR, ¹³C NMR, mass spectral data and microanalyses. The antidepressant activity of the synthesized compounds (4a-p) was evaluated by Forced swim test in rats and their neurotoxicity was evaluated by the rotarod test. Test compounds and clomipramine were administered intraperitoneally at dose of 100 mg/kg and 20 mg/kg respectively. Preliminary antidepressant screening of compounds (4a-p) revealed that compounds 4b, 4c, 4d, 4e, 4i and 4o significantly (P < 0.01) reduces the duration of immobility time. These compounds were also tested in-vitro for MAO inhibitory effect. All the compounds were also screened for antifungal activity against Aspergillus niger MTCC 281, Aspergillus flavus MTCC 277, Monascus purpureus MTCC 369 and Penicillium citrinum NCIM 768 strains.     

Synthesis, antimicrobial, antioxidant, anti-hemolytic and cytotoxic evaluation of new imidazole-based heterocycles

In the present work, 1-(5-methyl-2-phenyl-1H-imidazol-4-yl)ethanone 1 was prepared and used as a precursor for the synthesis of new thiazole, arylidiene and coumarin derivatives. The antimicrobial, antioxidant, anti-hemolytic, and cytotoxic activities of new compounds have been screened. Compound 12 showed an excellent antibacterial activity for all the tested bacteria with minimal inhibitory concentration (MIC) ranged between 21.9 and 43.8 μg/mL. While, compounds 2, 8 and 10a were the best antioxidant reagents using the DPPH method. Compounds 6a and 10b proved to exhibit potent antioxidative activity as reflected in the ability to inhibit lipid per-oxidation in rat brain and kidney homogenates and rate erythrocyte hemolysis. Compounds 6a proved to have the highest cytotoxic activity (81.9%) followed by 2, 6c, 7b and 12 using in vitro Ehrlich ascites assay. The details synthetic methods, spectroscopic data and biological results are recorded.     

One-pot microwave assisted synthesis under green chemistry conditions, antioxidant screening, and cytotoxicity assessments of benzimidazole Schiff bases and pyrimido[1,2-a]benzimidazol-3(4H)-ones

The synthesis of a number of benzimidazole Schiff bases 3 and 3-oxo-pyrimido[1,2-a]benzimidazoles 4 in excellent yields by a one-step sequence from the reaction of 2-aminobenzimidazole under green chemistry conditions is described. Structural assignments of the new compounds as well as complete assignment of ¹H and ¹³C NMR signals have been unambiguously achieved based on the analysis of their ¹H and ¹³C NMR (1D and 2D), IR, MS and elemental analysis data. To the synthesized Schiff bases the E-configuration was assigned on the basis of comparison of experimental and calculated (DFT) ¹³C NMR chemical shifts. Compounds 3 and 4 were evaluated as inhibitors of lipoxygenase (LOX) and of lipid peroxidation (LPO). All the tested derivatives showed inhibition of lipid peroxidation, whereas most of them were found to have higher activation than the reference compound trolox; The Schiff bases 3e, 3h, and 3i, and the pyrimidobenzimidazoles 4a, 4e and 4f were found to be the most potent. The most potent LOX inhibitor within the subset of Schiff bases was found compound 3i, followed by 3f, whereas compounds 4a and 4g were found the most potent of the 3-oxo-pyrimido[1,2-a]benzimidazole group. Moreover, some cytotoxicity assessments were undertaken, whereupon it was found that Schiff base 3i and pyrimidobenzimidazoles 4e and 4f did not exhibit cytotoxicity at similar concentrations resembling thus the inhibitory activity of lipid peroxidation. The most cytotoxic Schiff base and pyrimidobenzimidazole were found to be 3d and 4c, respectively.     

Synthesis and antimicrobial properties of some new thiazolyl coumarin derivatives

Two novel series of hydrazinyl thiazolyl coumarin derivatives have been synthesized and fully characterized by IR, ¹H NMR, ¹³C NMR, elemental analysis and mass spectral data. The structures of some compounds were further confirmed by X-ray crystallography. All of these derivatives, 10a-d and 15a-h, were screened in vitro for antimicrobial activity against various bacteria species including Mycobacterium tuberculosis and Candida albicans. The compounds 10c, 10d and 15e exhibited very good activities against all of the tested microbial strains.     

Synthesis and identification of β-aryloxyquinolines and their pyrano[3,2-c]chromene derivatives as a new class of antimicrobial and antituberculosis agents

A new class of β-aryloxyquinolines 3a-i and their pyrano[3,2-c]chromene derivatives 6a-r incorporating a validated molecular target has been synthesized via a nucleophilic displacement and a one-pot multicomponent reaction respectively. In vitro antimicrobial activity of the synthesized compounds were investigated against a representative panel of pathogenic strains specifically Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae, Escherichia coli, Salmonella typhi, Vibrio cholera, Aspergillus fumigatus and Candida albicans. Compounds 3c, 3e, 3g, 6f, 6l and 6q exhibited excellent antibacterial activity while compound 6p exhibited more potent antifungal activity than that of first line standard drugs. In vitro antituberculosis activity was evaluated against Mycobacterium tuberculosis H37Rv and compound 6f is emerged as the promising antimicrobial member with better antitubercular activity. Majority of the compounds appears to be better antimicrobials but poor antituberculars.     

Synthesis and anti-microbial activity of some 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile derivatives

A new series of 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile such as hydrazide hydrazones 3a-h; ethane-1,2-diaminopyridine 6; phthalimidopyridines 8a,b; hydrazides 10a,b; urea 11a and thiourea 11b were synthesized in a good to excellent yield in step efficient process, using 1-amino-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) as a key intermediate. The antibacterial and antifungal activities of the synthesized compounds were evaluated. The obtained data indicated that the majority of the tested compounds exhibited both antibacterial and antifungal activities, particularly compounds 8a and 8b showed a comparable effect to a well known antibacterial and antifungal agents.     

Synthesis of substituted 3-amino-N-phenyl-1H-indazole-1-carboxamides endowed with antiproliferative activity

Several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanate derivatives 3a,b with 3-amino-1H-indazole derivatives 2c,e,g or 1H-indazole 2l respectively. Chemical transformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 5a,b, and 3,5-diamino-N-phenyl-1H-indazole-1-carboxamide derivatives 4i, j respectively. Finally, 3,5-diacetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 6a,b were prepared by acetylation of 4i, j. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell lines panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). Compound 1c, the most active of the series, was able to inhibit cell growth showing GI₅₀ values in the 0.041-33.6 μM range, mean GI₅₀ 1.90 μM, being very effective against colon and melanoma cell lines. Cell cycle analysis in K562 cells showed that 1c causes a marked increase of cells in G0-G1 phase. Moreover, it increases the ratio between hypophosphorylated pRb and total pRb.     

A regioselective synthesis of some new pyrazol-1'-ylpyrazolo[1,5-a]pyrimidines in aqueous medium and their evaluation as antimicrobial agents

An efficient and environmental benign regioselective synthesis of some new pyrazol-1′-ylpyrazolo[1,5-a]pyrimidines (7b-h) has been accomplished via treatment of 3(5)-amino-5(3)-hydrazinopyrazole dihydrochloride (5) with several unsymmetrical 1,3-diketones (6b-h) using water as a solvent without any catalysts or additives. The structure of 7b-h was established on the basis of rigorous analysis of ¹H, ¹³C NMR, IR spectral data and MS. Eight compounds (7a-h) were screened for their antibacterial activity against two gram-positive and two gram-negative bacteria and compounds (7a, b, d and e) for antifungal activity against four phytopathogenic fungi. Compounds 7c and 7e manifest rather broad antibacterial activity than standard antibiotics. One lead compound, 7a (10 mg/ml and 200 mg/ml) exhibited equipotent or more potent antifungal activity against all tested microorganisms than standard drug.     

Molecular modeling study and synthesis of quinazolinone-arylpiperazine derivatives as α1-adrenoreceptor antagonists

Three series of new 2-[(4-substituted piperazin-1-yl) methyl]quinazolin-4(3H)-ones 4a-c, Ethyl 6,7-dimethoxy-4-oxo-3-[2-(4-substituted piperazin-1-yl)acetamido/propanamido]-3,4-dihydroquinazoline-2-carboxylates 9a-f and their 2-methyl analogues 13a-l were designed and synthesized as promising α₁-adrenoceptor antagonists. The final compounds were evaluated for their in vivo hypotensive activity in normotensive cats. The most potent hypotensive quinazolinone derivatives 4b, 9e, 13i, 13j were further tested on isolated thoracic aortic rings of male Wister rats. All the tested compounds displayed α₁-blocking activity with IC₅₀ ranging from 0.2 to 0.4 mM less than prazosin. Furthermore, in the present work, molecular modeling study using Accelrys Discovery Studio 2.1 software was performed by mapping the synthesized compounds to the α₁-adrenoceptor antagonist hypothesis in order to predict their mechanism of action. Compound 13j which has the best-fitting score displayed the highest in vivo and in vitro activity among the tested compounds.