Synthesis,anti-inflammatory,analgesic, and antibacterial activities of some triazole,triazolothiadiazole, and triazolothiadiazine derivatives

This study is concerned with the synthesis of new 1,2,4-triazoles, 1,3,4-thiadiazoles, and 1,3,4-thiadiazines derivatives. Derivatives 3a–i were obtained by condensation of 4-amino-3-(4-pyridine)-5-mercapto-1,2,4-triazole 1 with the appropriate aldehyde. Compounds 4a–i were synthesized in a one pot reaction involving compounds 3a–i, formaldehyde, and morpholine. Condensation of compound 1 with the appropriate acids or 4-substituted phenacyl bromide gave compounds 6a–d and 8a–f respectively. The chemical structures of the newly synthesized derivatives were elucidated using different spectral and elemental methods of analysis. All compounds were evaluated for their anti-inflammatory activity and the most potent derivatives were tested for their analgesic activity using indomethacin as a reference drug. In addition, ulcerogenicity and LD₅₀ for the most active compounds were evaluated. Moreover, the antibacterial activities of the newly synthesized derivatives were investigated.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Synthesis of certain mercapto-and aminopyrimidine derivatives as potential antimicrobial agents

Reaction of ethyl 4-chloro-2-phenylpyrimidine-4-carboxylate (4) with 5-chloro-2-methylthiophenol or 3-aryl-4-phenyl-1,2,4-triazole-5-thiol yielded the corresponding thioethers (5) and (8a, b), respectively. Careful alkaline hydrolysis of (5) yielded the corresponding carboxylic acid (6). Reaction of (4) withp-aminoacetophenone yielded compound (10) which was reacted with certain aromatic aldehydes to afford the α, β-unsaturated ketones (11a–d). Condensation of (11a–d) with malononitrile or phenylhydrazine yielded the 2-amino-3-cyanopyridines (12a–f) or the 2-pyrazolines (13a, b), respectively. Seven representative compounds were tested for theirin vitro antimicrobial activity against some pathogenic micro-organisms, some of them were proved to be active.     

Synthesis of novel isatin-thiazoline and isatin-benzimidazole conjugates as anti-breast cancer agents

A series of new isatin-thiazoline 3a–h and isatin-benzimidazole 4a–h derivatives were synthesized via condensation of isatin Mannich bases 2a–h with either 2-aminothiazoline or 2-aminobenzimidazole. The structures of the newly synthesized compounds were characterized by spectral data. The anti-breast cancer activity of some of the synthesized compounds was assessed in the MCF-7 human breast cancer cell line. The results showed that compounds 4b, 4d and 4g possess significant antiproliferative activity against MCF-7 cells.     

Triazenoindazoles and triazenopyrazolopyridines: Design,synthesis, and cytotoxic activity

Several triazenoindazoles 3a–e and triazinopyrazolopyridines 6a–i were prepared through the reaction of the corresponding 3-amino-4-chloroindazole and 3-aminopyrazolopyridine diazonium salts 2 and 5 with a number of secondary amines. All compounds were evaluated for their in vitro cytotoxic activity on three cell lines, HepG2, MCF7, and HeLa. Most compounds inhibited cell growth with IC₅₀ less than 0.1 μM. Compound 6d was the most potent, with an IC₅₀ of 0.03 μM against HepG2 and 0.05 μM against MCF7 and HeLa cells.     

The effect ofN-alkyloxycarbonyl group on the anticonvulsant activities ofN-alkyloxycarbonyl-α-aminoglutarimides

In connection with the development of new anticonvulsant agents with a broad spectrum, we reported thatN-Cbz-α-aminoglutarimides, combining common structures of other anticonvulsants such as N-CO-C-N and cyclic imides in a single molecule, showed significant anticonvulsant activities in the MES (maximal electroshock seizure) and PTZ (pentylenetetrazole induced seizure) tests. In these studies, a series of (R) and (S)N-alkyloxycarbonyl-α-aminoglutarimides7a∼7e and8a∼8e, which were substituted with various alkyloxycarbonyl group instead ofCbz group, were prepared from the corresponding (R) and (S)N-Cbz-glutamic acid3 and4, and were evaluated with their anticonvulsant activities against the MES and PTZ tests, including neurotoxicity, in order to define the effect ofN-alkyloxycarbonyl group on the anticonvulsant activities ofN-alkyloxycarbonyl-α-aminoglutarimides. Among them, (S)N-4-nitrobenzyloxycarbonyl-α-amino-N-methylglutarimide8e was the most active in MES (ED₅₀=35.6 mg/kg, Pl=2.7) and PTZ tests (ED₅₀=15.6, Pl=6.1). Interestingly, (R) and (S)N-4-nitrobenzyloxycarbonyl-α-amino-N-methylglutarimide7e and8e and (R)N-phenoxycarbonyl-α-amino-N-methylglutrimide7d showed significant anticonvulsant activities in both the MES and PTZ tests and other compounds showed anticonvulsant activities in only the PTZ test. In addition, it was found that their anticonvulsant activities were dependent on their stereochemistries andN-substituted alkyloxycarbonyl groups.     

Synthesis and antimicrobial activities of 2-azetidinyl-4-quinazolinone derivatives of diclofenac analogue

A new class of 2-azetidinyl-4-quinazolinones 6a–k was synthesized by multi-step process, starting from 2-[2-(2,6-dichlorophenyl)amino]phenyl acetic acid 1. Acid 1 was easily converted to acid chloride 2, which on cyclization reaction with 5-bromo anthranilic acid yielded benzoxazinone 3. The condensation reaction of 3 with benzene-1,4-diamine afforded 4-quinazolinone 4. Finally the title compound 6a–k was synthesized from 4-quinazolinone 4 by Schiff base formation 5a–k with aromatic aldehyde and then cyclization reaction with chloroacetylchloride. The in vitro antimicrobial activity of compounds 5a–k and 6a–k were tested. These compounds showed pronounced antimicrobial activity when 4-Cl and 4-OCH ₃ groups were present.     

EGFR tyrosine kinase targeted compounds: synthesis, docking study, and in vitro antitumor activity of some new quinazoline and benzo[d]isothiazole derivatives

The preparation of new quinazoline and benzo[d]isothiazole-based antitumor agents is described. The target compounds fall into three groups including the N-substituted derivatives 2a–d, the substituted amino derivatives 4–6a–d, and the dimeric compounds 7–9a,b. Docking study of the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. All compounds were tested, in vitro, for their activity against human mammary carcinoma cell line (MCF7) in which EGFR is highly expressed. All compounds showed significant growth inhibitory activity. The remarkable activity of the bis quinazoline derivative 8a (IC₅₀ = 0.06 μg/ml; 1.64 nmol/ml) is to be noted.     

Dimethylamino-functionalised and <Emphasis Type="Italic">N</Emphasis>-heteroaryl-substituted titanocene anticancer drugs: synthesis and cytotoxicity studies

Summary From the carbolithiation of 6-N,N-dimethylamino fulvene (3a) and different lithiated N-heterocyclic compounds (N,N-dimethylaminomethylpyrrole, 1-methylimidazole and 2,4-[bis(N′,N′-dimethylaminomethyl)]-N-methyl pyrrole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl₄ resulting in dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against LLC-PK cells, the IC₅₀ values obtained were of 13, and 63 μM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper (5a) with an IC₅₀ value of 6.8 μM is found to be almost as cytotoxic as cis-platin, which showed an IC₅₀ value of 3.3 μM, when tested on the epithelial pig kidney LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself.     

Synthesis and cytotoxicity of 1-phenylethanolamine carboxamide derivatives: effects on the cell cycle

Seven novel analogues of 1-phenylethanolamine carboxamide derivatives, 3a–3g, related to carboxamides isolated from Isodon excisus were synthesized and evaluated for their cytotoxic and apoptosis-induction properties against murine B16 and leukemia L1210 cell lines. Compounds containing no substitution at the 4′-position (3a–3d) or containing a 4′-amino (3e–3g) group were investigated. Generally, the amino-containing compounds were slightly more active than their unsubstituted congeners. Also, the indole-containing compounds 3c and 3f gave the strongest cytotoxic activity (IC₅₀ = 25–87 μM) against the growth of L1210 and B16 cancer cells. Compound 3f was subjected to flow cytometry studies and it was found to induce L1210 cells grown in culture to undergo apoptosis.     

Conventional and microwave-assisted synthesis of imidazole and guanidine derivatives and their biological evaluation

A number of imidazole derivatives 3a–f and 4a–f have been synthesized by the condensation of 3-methylthiophen-2-carboxaldehyde 1a, 5-methylthiophen-2-carboxaldehyde 1b, N-methylpyrrol-2-carboxaldehyde 1c, 1-naphthaldehyde 1d, 2-naphthaldehyde 1e, and 2-hydroxy-1-naphthaldehyde 1f with 1,2-diaminoanthraquinone 2a and 2,3-diaminophenazine 2b, respectively. Condensation of 2-guanidinobenzimidazole with functionalized aldehydes 1a–f leads to the formation of guanidine derivatives 5a–f. Both imidazole (3a–f, 4a–f) and guanidine derivatives (5a–f) were synthesized in good yields using conventional heating and microwave irradiation techniques. Structures assigned to compounds 3a–f, 4a–f and 5a–f are supported by correct spectral and analytic data. On screening for anti-inflammatory and anticancer activities, compounds 3e, 4a and 5a exhibited good anti-inflammatory and compounds 3d, 3f, 4d and 4f showed very good anticancer activity.     

New triterpenoid saponins from <Emphasis Type="Italic">Argania spinosa</Emphasis>

Five new triterpene saponins, arganine L (1), O (2), P (3), Q (4) and R (5), were isolated from the barks of Argania spinosa (L.) Skeels. Arganines L-P and R are bidesmosidic saponins. The structures of 1–5 were elucidated as 3-O-[β-d-xylopyranosyl-(1–4)-β-d-glucuronopyranosyl]-28-O-[β-d-apiofuranosyl-(1–3)-β-d-xylopyranosyl-(1–4)-α-l-rhamnopyranosyl-(1–2)-α-l-arabinopyranosyl] bayogenin, 3-O-[β-d-xylopyranosyl-(1–4)-β-d-glucuronopyranosyl]-28-O-[β-d-xylopyranosyl-(1–4)-α-l-arabinopyranosyl] bayogenin, 3-O-[β-d-xylopyranosyl-(1–4)-β-d-glucuronopyranosyl]-28-O-[α-l-arabinopyranosyl] bayogenin, 3-O-[β-d-xylopyranosyl-(1–4)-β-d-glucuronopyranosyl] bayogenin, and 3-O-[β-d-apiofuranosyl-(1–4)-β-d-glucuronopyranosyl]-28-O-[β-d-xylopyranosyl-(1–4)-α-l-rhamnopyranosyl-(1–2)-α-l-arabinopyranosyl] bayogenin, respectively, mainly on the basis of their spectroscopic data.     

Synthesis of 6-aziridlnylbenzimidazole derivatives and theirin vitro antitumor activities

In search for new antitumor agents, twelve 6-aziridinylbenzimidazole derivatives were synthesized and their cytotoxicities were tested against three cancer cell lines (mouse lymphocytic leukemia P388 and B16, and human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a–d) were obtained by Phillips reaction. These benzimidazoles were then reacted with Fremy's salt to give a mixture of three 2-(acetoxymethyl) (8a–c) and four 2-(hydroxymethyl)benzimidazole-4,7-diones (9a–d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a–c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4,7-diones (11a–d). Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters10d and13e–h were prepared by the sequential reactions of esterification and addition. The synthesized compounds show potent cytotoxicity against all of three cell lines tested. The cytotoxicities of10a–d or11a–d against SNU-16 were superior to those of13e–h, and were equal to or slightly higher than that of mitomycin C. Compounds11a–d were slightly more cytotoxic than10a–d in all cell lines tested.     

Synthesis of new pyrazole,triazole, and thiazolidine-pyrimido [4, 5-b] quinoline derivatives with potential antitumor activity

2-Hydrazinyltetrahydropyrimido [4, 5-b] quinolin-4(3H)-one (3) was prepared by desulfurization reaction of S- and N-dimethyl derivatives 2 with hydrazine hydrate. Reactions of (3) with malonitrile, carbondisulfide, potassium thiocyanate, phthalic anhydride and aromatic aldehydes afforded 3, 5-di aminopyrazolopyrimido [4, 5-b] quinoline (4), triazolotetrahydropyrimido [4, 5-b] quinoline (5), aminotriazolopyrimido [4, 5-b] quinoline (6), aminophthalimidopyrimido [4, 5-b] quinoline (7) and N-arylidene hydrazinepyrimido [4, 5-b] quinoline 8a–d, respectively. Furthermore, 8a–d reacted with mercaptoacetic acid gave the thiazolidinonepyrimido [4, 5-b] quinoline 9a–d, which afforded the thiazolotriazolopyrimido [4, 5-b] quinolinone 10a–d upon treatment with ethanolic potassium hydroxide. The newly synthesized compounds were characterized by elemental analyses, IR, 1H-NMR, 13C-NMR and mass spectrometer. The investigated compounds were screened for their cytotoxicity. Compounds 4, 6 and 5 exhibited potent antitumor activity.     

Synthesis,antioxidant and antimicrobial evaluation of simple aromatic esters of ferulic acid

Aromatic ester derivatives of ferulic acid where the phenolic hydroxyl is free (6a–d) or acetylated (5a–d) were evaluated for their antioxidant and antimicrobial properties. The superoxide radical scavenging capacity of compounds 5d and 6d–e (IC₅₀ of 0.19, 0.27 and 0.20 mM, respectively) was found to be twice as active as α-tocopherol (IC₅₀ = 0.51 mM). DPPH radical scavenging capacity was moderate and only found in compounds bearing free phenolic hydroxyl groups (6a–e). With regard to antimicrobial properties, compounds 6b and 6c displayed significant activity against Enterococcus faecalis (MICs = 16 μg/mL) and vancomycin-resistant E. faecalis (MIC for 6b, 32 and for 6c, 16 μg/mL). Compound 6c also demonstrated prominent activity against planktonic Staphylococcus aureus with a MIC value of <8 μg/mL and it inhibited bacterial biofilm formation by S. aureus with a MBEC value of <8 μg/mL, which was 64 and 128 times more potent than ofloxacin and vancomycin, respectively.     

Anticonvulsant and anxiolytic-like effects of compounds isolated from <Emphasis Type="Italic">Polygala sabulosa</Emphasis> (Polygalaceae) in rodents: in vitro and in vivo interactions with benzodiazepine binding sites

Rationale Polygala sabulosa, a folk medicine, presents dihydrostyryl-2-pyrones (DST) and styryl-2-pyrones (STY), compounds structurally similar to kavalactones. Our previous study showed that the ethyl acetate fraction (EA) and these constituents present anxiolytic-like, hypno-sedative, and anticonvulsant effects in mice. Objectives This study investigated the role of benzodiazepine binding site (BDZ-bs) in the central effects of either EA or three DST (1, 2, and 3) and three STY (4, 5, and 7), using in vivo and in vitro assays. Methods and results In the elevated plus-maze (EPM), flumazenil (FMZ), a BDZ antagonist, partially blocked the anxiolytic-like effect of DST-3 or STY-4 and STY-7, but not DST-1. Using electroencephalogram (EEG), EA protected against pentylenetetrazole (PTZ)-induced convulsion in rats, an effect partially blocked by FMZ, suggesting the participation of the BDZ-bs in this action. EA also protected against the maximal electroshock (MES)-induced convulsions in mice, a profile distinct from diazepam (DZP). DST and STY compounds inhibited the [³H]-flunitrazepam ([³H]-FNZ) binding to BDZ-bs in rat cortical synaptosomes with K _i higher than 100 μM (DST-1), 41.7 μM (DST-2), 35.8 μM (DST-3), 90.3 μM (STY-4), 31.0 μM (STY-5) and 70.0 μM (STY-7). In the saturation assay, DST-3 and STY-7 competitively inhibited the binding of [³H]-FNZ to BDZ-bs with a significant decrease in apparent affinity (K _d) and no change in maximal binding (B _max). Conclusions The present data support a partial BDZ-bs mediation of the anxiolytic-like and anticonvulsant effects of EA of P. sabulosa and its main isolated constituents, DST and STY.     

Synthesis,antiproliferative activity,acute toxicity and assessment of the antiandrogenic activities of new androstane derivatives

A number of 17-oxo-5-androsten-3β-yl esters (9a–9f) and 3β-alkoxy-5-androsten-17-ones (11a–11e) were synthesized from commercially available (25R)-5-spirosten-3β-ol (Diosgenin) (4) as starting material. The synthesized compounds were evaluated for their antiproliferative activity against the prostate-specific cancer cell line DU-145, acute toxicity and effect on serum androgen levels, and compared with finasteride as positive control. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data and biological activity of the synthesized compounds are reported.     

Anti-inflammatory and analgesic components from “hierba santa,” a traditional medicine in Peru

“Hierba santa,” a Peruvian herbal medicine, is used to alleviate many symptoms, including headache, hemorrhoids, fever, and rheumatism. Several Cestrum species are said to be the origin of hierba santa. Three lots of hierba santa: Cestrum auriculatum (herb 1 and herb 2) and C. hediundinum (herb 3), which were purchased from Peruvian markets at Cuzco (Andes area) and Equitos (Amazon area), respectively, were examined for their pharmacological activities and active components. Herbs 1–3 showed anti-inflammatory and analgesic activities in the in vivo writhing inhibition test in mouse and inhibited prostaglandin E₁-, E₂-, or ACh-induced contractions of guinea pig ileum in the Magnus method. Activity-based separation of each extract yielded cestrumines A and B, cestrusides A and B, a mixture of (+)- and (−)-pinoresinol glucosides, nicotiflorin, rutin, sinapoyl glucose, ursolic acid, β-sitosteryl glucoside, and 2-sec-butyl-4,6-dihydroxyphenyl-β-d-glucopyranoside. Among them, cestrumine A and cestrusides A and B are new compounds. All three lots of hierba santa do not contain exactly the same active components. This work is dedicated to the late Mr. Tetsuo Shiota, one of the authors.     

Synthesis of 2-substituted-6-(4<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazol-4-yl)benzo[<Emphasis Type="Italic">d</Emphasis>]oxazoles as potential anticonvulsant agents

A series of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles were synthesized. The anticonvulsant effect and neurotoxicity of the compounds (intraperitoneally) were evaluated with the maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests in mice. 2-Phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3g) was the most active and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED₅₀) of 29.5 mg/kg, a median toxicity dose (TD₅₀) of 285 mg/kg, and a protective index (PI) of 9.7, which is greater than the reference drug, carbamazepine, which has a PI of 6.4.