Synthesis and in?vitro antimicrobial activity of benzo[b][1,4]thiazin-3(4H)-ones via smiles rearrangement

New benzo[b][1,4]thiazin-3(4H)-one derivatives (compounds 12a–p) were synthesized via Smiles rearrangement and assayed in vitro for their antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. The antimicrobial activity of the benzo[b][1,4]thiazin-3(4H)-ones showed, on the whole, potent toward all tested Gram-positive and Gram-negative microorganism (minimal inhibitory concentration ranging from 16 to 64 μg/ml), whereas weak effectiveness was exhibited against fungi. Data obtained suggested that 12g, 12i, and 12o exerted the best antibacterial activity against Gram-positive bacteria and compound 12b demonstrated the best inhibition of Gram-negative bacteria. These observations provide some predictions to design further antimicrobial active compounds prior to their synthesis following with molecular modeling studies.     

Synthesis, DNA affinity, and antimicrobial activity of 4-substituted phenyl-2,2′-bichalcophenes and aza-analogues

A series of bichalcophene monoamidines 4a–f were synthesized from the corresponding mononitriles 3a–f via a direct reaction with LiN(TMS)₂ followed by deprotection with ethanolic HCl (gas). Bichalcophene mononitriles 3a–f were synthesized via palladium-catalyzed coupling reactions. Thus, a Stille coupling reaction was performed to prepare 6-[5-(thiophen-2-yl)furan-2-yl]nicotinonitrile (3e), when 6-(5-bromofuran-2-yl)nicotinonitrile was allowed to react with 2-n-tributyltin thiophene. The tested bichalcophenes showed a wide range of DNA and protein degradation effect as judged from agarose gel and SDS-PAGE, respectively. Bichalcophenes 3a–f and 4a–f have broad-spectrum antibacterial efficacy being highly active against both Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, and Escherichia coli) bacterial strains. The antifungal activity of these bichalcophene series against Saccharomyces cerevisiae was demonstrated. The MIC of bichalcophenes 3a–f and 4a–f against various microorganisms was also determined. The tested bichalcophenes mimic SOD like activity and inhibited the superoxide radical generation.     

Synthesis, antioxidant evaluation, and quantitative structure�Cactivity relationship studies of chalcones

Synthesis, antioxidant activity, and quantitative structure–activity relationship (QSAR) of 25 of chalcone derivatives is reported here. They were synthesized by Claisen–Schmidt reaction and were characterized by FTIR, NMR, and mass spectroscopy. Antioxidant activity is evaluated through four different methods namely, superoxide radical-scavenging, hydrogen peroxide scavenging, reducing power, and DPPH radical-scavenging assays. Generally, compounds with –SCH₃ and –OCH₃ in the para position of the A-ring and –OH in the B-ring were more active than others. In few cases some of the compounds were more active than ascorbic acid or butylated hydroxytoluene. QSAR was developed correlating the antioxidant activity with the structural features of the compounds and the predictive capability of the models was estimated using internal and external validation methods. All the predictions were within the 99% confidence level. Spatial, structural, and lipophilic properties of the compounds determine their antioxidant properties.     

Synthesis and structure–activity relationship studies on novel 8-amino-3-[2-(4-fluorophenoxy)ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione derivatives as anticonvulsant agents

A series of novel 8-amino-3-[2-(4-fluorophenoxy)ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione derivatives 7–36 was synthesized and their pharmacological activity was determined with the objective to better understand their structure–activity relationship for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) test and their neurotoxic effects were determined by rotarod test. Majority of the compounds were active in MES tests. Compounds 24, 27, and 34 showed a significant and protective effect on seizure, when compared with standard drug phenytoin. The compounds having amide bond showed moderate protective effect on MES induced seizures compared to sulfonamide.     

Synthesis, antitumor activity of 2-amino-4H-benzo[h]chromene derivatives, and structure–activity relationships of the 3- and 4-positions

Several 2-amino-4H-benzo[h]chromenes (3a–i) and (5a–h) were obtained by reaction of 4-chloro-1-naphthol (1) with α-cyanocinnamonitrile (2a–i) or ethyl α-cyanocinnamate derivatives (4a–h), respectively. Structures of these compounds were established on the basis of spectral data. The antitumor activity of the synthesized compounds was investigated in comparison with Vinblastine, Colchicine, and Doxorubicin well-known anticancer drugs, using MTT colorimetric assay. Among them, the compounds 5e, 3c, 5f, b, d, 3d, 5c, a were the most active against MCF-7, 5a against HCT-116 and 5a, 3e, a against HepG-2 as compared with the standard drug Vinblastine, while the compounds 5e, 3c, 5f, b, d, 3d, 5c, a, h, 3i, g, a, e were the most active against MCF-7, 5a, c, e, f, b, 3e, c, g, b, 5d, h, 3d, i, 5g against HCT-116, 5a, 3e, a, 5e, 3c, 5d, c, f, 3b, 5g, 3g, 5h against HepG-2 as compared with the standard drug Colchicine. The structure–activity relationships of the 3- and 4-positions were discussed.     

Structure–activity relationship investigation of methoxy substitution on anticancer pyrimido[4,5-c]quinolin-1(2H)-ones

Pyrimido[4,5-c]quinolin-1(2H)-one derivatives were shown to exert interesting biological activities including anticancer, antimicrobial, and cardiovascular. Substitution with methoxy groups played a crucial role in the anticancer activity of known anticancer agents. This study explores the contribution of diverse-positioned methoxy substituents to the antimigratory and cytotoxic activities of this class. Synthesized analogues were tested in the MTT, cell cycle, and wound-healing assays. Previous studies on this class reported weak to medium antimitotic activity. Therefore, all compounds were subjected to tubulin polymerization assay and in silico molecular docking study at the colchicine binding site of tubulin. The 2-methoxy and 2,4-dimethoxy substitutions at the 2-arylpyrimido functionality enhanced the antimigratory activity in the 9-methoxy-substituted series like 6 and 9. The 3,4,5-trimethoxy substitutions at the 2-arylpyrimido group also significantly improved the antimigratory activity in the presence or absence of the 9-methoxy substitution as represented by 13 and 22, respectively. Docking experiments showed two distinct orientations at the colchicine binding site of tubulin. The first, achieved by 7 and 16–20, coincides with that of colchicine and positions the methoxy-substituted 2-aryl ring deep in the highly hydrophobic narrow end of the funnel-shaped binding pocket. On the other hand, 5, 6, 9–14 and 21, were oriented towards the wider opening of the binding pocket. Pyrimido[4,5-c]quinolin-1(2H)-ones are promising antimigratory hits with potential for future use to control metastatic breast cancers.     

Classes of sigma2 (σ2) receptor ligands: structure affinity relationship (SAfiR) studies and antiproliferative activity

Although several pieces of information are still missing about sigma-2 (σ2) receptor, the production of high affinity 2 receptor ligands allowed important acquisitions. Morphans such as CB64D and CB184 were the first truly σ2-selective ligands synthesized, and their use in cell cultures highlighted the relationship between σ2 receptors and cell proliferation, shedding light on important diagnostic and therapeutic potentials with which σ2 ligands are endowed. The most significant classes of compounds are herein discussed. The design and Structure-Affinity Relationship studies (SAfiR) of σ2 receptor ligands belonging to the classes of morphans, indoles (siramesine analogues), granatanes, flexible benzamides and N-cyclohexylpiperazines are reported, together with the biological results which these compounds provided giving a crucial contribution to the 2 receptor research. The pharmacophore models which were generated on the basis of different classes of the σ2 ligands and the attempts for σ2 receptor purification are briefly described.     

Synthesis, antitumor activity, and structure–activity relationship of some 4H-pyrano[3,2-h]quinoline and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives

Several 4H-pyrano[3,2-h]quinoline (3a–d, 4a, 7a,b, 9a–c, 10a,b, 11a,b, and 13a–c) and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives (8a–c) were obtained by treatment of 8-hydroxyquinoline (1a) and 8-hydroxy-2-methylquinoline (1b) with α-cyano-p-chloro/bromocinnamonitrile (2a,b) or 4H-pyrano[3,2-h]quinoline derivatives (3a,c,d) with different electrophilic reagents followed by nucleophilic reagents. Structures of these compounds were established on the basis of spectral data. The antitumor activity of the synthesized compounds was investigated in comparison with Vinblastine. Among them, compounds 3c,d, 4a, 8b, 9b,c, 11a,b, and 13a,c inhibited the growth of cancer cells compared to Vinblastine. The structure–activity relationships were discussed.     

CsF�CCelite catalyzed facile N-alkylation of 2(3H)-benzoxazolones and antimicrobial properties of 2-substituted benzoxazole and 3-substituted-2(3H)-benzoxazolone derivatives

The synthesis and antimicrobial activity studies of a new series of cyclic amine containing benzoxazoles and benzoxazolone-2(3H)-ones derivatives were described. The alkylation of benzoxazolone was carried out using cesium fluoride–Celite. The newly synthesized compounds with the influence of the induction of the cyclic amine moiety in the benzoxazole scaffold have been evaluated with respect to the antibacterial and antifungal activity. The 2-cyclic amine-1,3-benzoxazoles (5a–l), 5-chloro-3-alkyl substituted-1,3-benzoxazol-2(3H)-ones (8a–f), and 3-[3-(cyclic amine)propyl]-1,3-benzoxazol-2(3H)-ones (9a–f) were synthesized. These derivatives were tested for antibacterial and antifungal activity. Among the compounds tested, 8c and 9f showed moderate to good antibacterial and antifungal activity. Compound 8a showed good antifungal activity.     

Synthesis and anti-microbial activity of some imidazo[ 1′,2′:5,6]pyrimido[ 4,5-c] pyridazines and related heterocycles

The synthesis of the title heterocycles was achieved using 3-amino-5,6-diphenylpyridazine-4-carbonitrile (4) as a starting material. This compound was converted into the corresponding 4-imidazolinyl derivative 5 which was then subjected to cyclization reactions to afford the title compounds.     

Synthesis,structure–activity relationship and antinociceptive activities of some 2-(2′-pyridyl) benzimidazole derivatives

In the present study, a new series of 2-(2′-pyridyl) benzimidazole derivatives 1–11 were resynthesized and evaluated for analgesic activity. The 2-(2′-pyridyl) benzimidazole was quaternized at its nitrogen atom in the ring with various substituted and unsubstituted phenacyl halides. As a result, eleven novel derivatives were synthesized. The structures of these new synthetic derivatives of 2-(2′-pyridyl) benzimidazole were confirmed by using different spectroscopic techniques i.e., UV/Visible, IR, ¹HNMR and Mass spectroscopy. Percentage of carbon, hydrogen and nitrogen was also determined by elemental analysis. All the synthetic compounds showed significant analgesic activity with dose-dependent manner.     

Synthesis and in vitro antitumor activity of new quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs

New series of quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs have been synthesized and characterized by analytical and spectrometrical methods (IR, ¹H NMR, ¹³C NMR, MS). Fifteen of the newly synthesized compounds; namely, 3a, b, 4b, 6a, b, 10a–f, and 14a–d were evaluated for their in vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 4b and 10f are the most active members in this study, demonstrating significant broad spectrum antitumor activity against most of the tested sub-panel tumor cell lines. The detailed synthesis, spectroscopic, and biological data are described.     

Docking and quantitative structure–activity relationship studies for imidazo[1,2-a]pyrazines as inhibitors of checkpoint kinase-1

We have performed docking of imidazo[1,2-a]pyrazines complexed with checkpoint kinase1 (Chk1) to better understand the structural requirements and preferred conformations of these inhibitors. The study was performed on a selected set of 33 compounds with variation in structure and activity. In addition, the predicted inhibitor concentrations (IC₅₀) of the imidazo[1,2-a]pyrazines as Chk1 inhibitors were obtained by comparative molecular similarity analysis (CoMSIA). The best CoMSIA model included electrostatic and hydrophobic fields, had a good Q ² value of 0.589, and adequately predicted the compounds contained in the test set. Furthermore, plots of the CoMSIA fields allowed conclusions to be drawn for the selection of suitable inhibitors.     

Synthesis and Anticonvulsant Activity of Pyrano[4′,3′:4,5]pyrido[2,3-b]furo[3,2-d]pyrimidine and Pyrano[4′,3′:4,5]pyrido[2,3-b]furo[3,2-d]pyridine Derivatives

Pharmaceutical Chemistry Journal -     

Synthesis and anticonvulsant evaluation of A series of (R)- and (S)-N-Cbz-α-aminosuccinmide and their structure activity relationship

A series ofN-Cbz-α-aminosucinimides (1), combining common moieties of various anticonvulsants such as N-CO-C-N and cyclic imide in a single molecule, were synthesized from the corresponding (R)- and (S)-N-Cbz-aspartic acid (2). And theirin vivo anticonvulsant evaluations in MES and PTZ test were investigated. And also the rotorod test for neurotoxicity was investigated. All the tested compounds (1), except1c and1f, showed significant anticonvulsant activities in both MES and PTZ test. And the most active compound among them in MES test was (R)-N-Cbz-α-amino-N-methylsuccinimide (1b) (ED₅₀=52.5 mg/kg) and (S)-N-Cbz-aminosuccinimide((1d) was most active in PTZ test (ED₅₀=78.1 mg/kg). And the TD₅₀ values of the tested compounds were above 117.5 mg/kg. These pharmacological data were comparable to those of currently available anticonvulsants. And also we found that the pharmacological effects were dependent on theirN-substituted alkyl chains and their stereochemistry.