Antimicrobial activity of 2,4-dihydro-[1,2,4]triazol-3-one derivatives

Antibacterial and antifungal activity of 2,4-dihydro- [1,2,4]triazol-3-one derivatives were examined by the disc-diffusion method (growth inhibition zone diameter in agar medium). The MIC's for the most active agents were determined. Of all the tested compounds, aminomethyl derivatives of 2,4-dihydro-[1,2,4]triazol-3-one exhibit activity against the majority of microorganisms studied.     

Synthesis and antihepatotoxic activity of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-substituted-phenyl-4,5-dihydro-1H-pyrazole derivatives

In continuance of our search for newer antihepatotoxic agents some novel pyrazoline derivatives containing 1,4-dioxane ring system were synthesized starting from 3-(2,3-dihydro-1,4-benzodioxane-6-yl)-1-substituted-phenylprop-2-en-1-one. Some of the synthesized compounds were evaluated for antihepatotoxic activity against CCl(4)-induced hepatotoxicity in rats. Among them some compounds have shown significant antihepatotoxic activity comparable to standard drug silymarin.     

2-Phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives as new inhibitors of bacterial cell wall biosynthesis

Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC <32 microg/mL.     

Synthesis, structure analysis, and antitumor activity of 3,6-disubstituted-1,4-dihydro-1,2,4,5-tetrazine derivatives

Fourteen compounds of 3,6-disubstituted-1,4-dihydro-1,2,4,5-tetrazine derivatives were prepared and their structures were confirmed by single-crystal X-ray diffraction and the semi-empirical calculation of PM3 method. This reaction yields the 1,4-dihydro derivatives rather than the 1,2-dihydro derivatives. The central six-membered ring of 1,4-dihydro-1,2,4,5-tetrazine has a chair conformation and therefore is not homoaromatic. Their antitumor activities were evaluated in vitro by SRB method for A-549 and BEL-7402 cells, and MTT method for P-388 and HL-60 cells. The results show that there is one compound which is highly effective against P-388 cells and one compound which is highly effective against HL-60 cells. So it is a kind of compound which possesses potential antitumor activities and is worth to research further.     

Synthesis, X-ray crystallographic analysis, and antitumor activity of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines

Eleven compounds of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines were prepared from 3,6-disubstituted phenyl-1,2-dihydro-1,2,4,5-tetrazines and anhydrides or acyl chlorines, and their structures were confirmed by single-crystal X-ray diffraction and the semi-empirical calculation of PM3 method. This reaction yields the 1,4-dihydro derivatives rather than the 1,2-dihydro derivatives. The central six-membered ring of these compounds has an obvious boat conformation and therefore is not homoaromatic. Their antitumor activities were evaluated in vitro by the SRB method for A-549 cell and the MTT method for P-388 cells. The results show that there is one compound which is highly effective against A-549 cells and two compounds which are highly effective against P-388 cells. Thus, this compound possesses potential antitumor activities and is worth researching further.     

Synthesis, molecular modeling and preliminary biological evaluation of a set of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole as potential antibacterial, anti-Trypanosoma cruzi and antifungal agents

A series of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives was synthesized and their activity screened in vitro against Staphylococcus aureus, Trypanosoma cruzi, and Candida albicans. The bioactivity was expressed as minimum inhibitory concentration (MIC) for S. aureus strains, and as fifty-percent inhibitory concentration (IC(50)) of parasite population growth for T. cruzi. A molecular modeling approach was performed to establish qualitative relationships regarding the biological data and the compounds' physicochemical properties. The 5-(4-OC(4)H(9)Ph, 5l), and 5-(4-CO(2)CH(3)Ph, 5o) derivatives were the most active compounds for S. aureus ATCC 25923 (MIC=1.95-1.25 μg/mL) and T. cruzi (IC(50)=7.91 μM), respectively. Also, a preliminary evaluation against C. albicans involving some compounds was performed and the 5-(4-CH(3)Ph, 5e) derivative was the most active compound (MIC=3.28-2.95 μg/mL). In this preliminary study, all synthesized 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives were active against all microorganisms tested.     

Discovery of novel antitubercular 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues

In the present investigation, a series of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues were synthesized and were evaluated for antitubercular activity by two fold serial dilution technique. All the newly synthesized compounds showed low to high inhibitory activities against Mycobacterium tuberculosis H(37)Rv and INH resistant M. tuberculosis. The compound 3-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carbothioamide (4o) was found to be the most promising compound active against M. tuberculosis H(37)Rv and isoniazid resistant M. tuberculosis with minimum inhibitory concentration 3.12 μM and 6.25 μM, respectively.     

Antimycobacterial activities of novel 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid

Various 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid derivatives were synthesized from 2-aminothiophenol by a five-step reaction, evaluated for in-vitro and in-vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC2), and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the thirty-four synthesized compounds, 2-(3-(diethylcarbamoyl)piperidin-1-yl)-)-3-fluoro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid (7l) was found to be the most active compound in vitro with MIC of 0.18 and 0.08 microM against MTB and MTR-TB, respectively. Compound 7l was found to be 2 and 570 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in-vivo animal model 7l decreased the bacterial load in lung and spleen tissues with 2.78 and 3.12-log10 protections, respectively, at the dose of 50 mg/kg body weight.     

Synthesis and positive inotropic activity of N-(4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)acetamide derivatives

A series of N-(4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)acetamide derivatives were synthesized and their positive inotropic activity was evaluated by measuring left atrium stroke volume on isolated rabbit heart preparations. Several compounds showed favorable activity compared with the standard drug, milrinone, among which N-(1-benzyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(4-benzylpiperazin-1-yl)acetamide 6j was found to be the most potent with the 13.2% increased stroke volume (milrinone 4.7%) at concentration of 3x10(-5) M in our in vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: promising anticancer agents

A series of 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives was synthesized and 13 of them were selected by the National Cancer Institute (NCI) and evaluated for their in vitro anticancer activity. Seven of the investigated compounds, 3i, 3j, 3k, 3o, 3p, 3q, and 3r, displayed high anticancer activity in the primary assay. These compounds have been selected for a full anticancer screening against a 60-cell panel assay where they showed non-selective broad spectrum and promising activity against all cancer cell lines. Compounds 3j and 3k proved to be the active members in this study compared to 5-fluorouracil and cyclophosphamide as reference drugs, respectively. Compounds 3j and 3k were identified as promising lead compounds.     

Discovery and optimization of 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives as mTORC1/mTORC2 dual inhibitors

New potent mTORC1/mTORC2 dual inhibitors, 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives, were obtained by optimizing functional groups on our previously reported PI3Kα inhibitor. All the target compounds were synthesized and structural optimization on the structure of the lead compound based on cytotoxic activity. The results showed that some of the target compounds exhibited moderate to high cytotoxic activity against cell line U87MG and PC-3. The activities against mTOR kinase were investigated and the compound 12q showed excellent activity with an IC₅₀ value of 54 nM in the same level of the positive control BEZ235 with IC₅₀ value of 55 nM under the same test conditions. The western blot and cell cycle results demonstrate that compound 12q is a candidate as an mTORC1/mTORC2 dual-target inhibitor. The theoretical calculations were also performed to better understanding the binding modes of the compound 12q in the mTOR active site.     

Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones

To further investigate anticonvulsant activity of quinoline derivatives, a series of 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one derivatives was synthesized starting from 7-hydroxyl-3,4-dihydro-2(1H)-quinoline. In initial (phase I) screening and quantitative (phase II) evaluation, compound 7-benzyloxyl-4,5-dihydro-[1,2,4]thiazolo[4,3-a]quinoline-1(2H)-one (3f) was among the most active but also has the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED(50)) of 12.3 mg/kg, median toxicity dose (TD(50)) of 547.5 mg/kg, and the protective index (PI) of 44.5, which is much greater than PI of the prototype drugs phenytoin, phenobarbital, carbamazepin, and valproate. Compound 3f was chosen for further evaluation. In phase III pharmacological test, the compound had median hypnotic dose (HD(50)) and median lethal dose (LD(50)) of 1204 mg/kg and >3000 mg/kg, respectively, thus demonstrating much greater margin of safety compared to prototype drugs. The compound 3f also showed significant oral activity against MES-induced seizures and low oral neurotoxicity in mice in phase IV pharmacological test. Possible structure-activity relationship was discussed.     

Synthesis and cytotoxicity of 2-methyl-1-substituted-imidazo [4,5-g]quinoline-4,9-dione and 7,8-dihydro-10H-[1,4]oxazino[3',4':2,3]imidazo[4,5-g]quinoline-5,12-dio ne derivatives

2-Methyl-1-substituted-imidazo[4,5-g]quinoline-4,9-diones and 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5, 12-dione (19) derivatives have been synthesized from 6,7-dichloro-5,8-quinolinedione for developing the new anticancer drugs. Our study on the cytotoxicity of imidazoquinolinedione derivatives has revealed that 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5, 12-dione (19), a tetracyclic heteroquinone analogue, exhibited high cytotoxicity on human colon tumor cell (HCT 15) in vitro SRB assay. The IC50 value of this compound was 0.026 microg/mL whereas those of doxorubicin and cisplatin were 0.023 microg/mL and 1.482 microg/mL, respectively. Meanwhile compounds 5-7 and 12 in the series of 1-substituted-imidazoquinolinediones showed relatively good activity on human brain tumor cell lines (XF 498).     

Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists

Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.     

Antifungal and antimycobacterial activity of 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives

1-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives were synthesized and tested for their in vitro antifungal and antimycobacterial activities. These imidazole derivatives showed an excellent antifungal activity against a clinical strain of Candida albicans and an interesting antitubercular activity against Mycobacterium tuberculosis H(37)Rv reference strain.     

Design,synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1-benzoxazepines

A series of 11 new substituted 1,5-dihydro-4,1-benzoxazepine derivatives was synthesised to study the influence of the methyl group in the 1-(benzenesulphonyl) moiety, the replacement of the purine by the benzotriazole bioisosteric analogue, and the introduction of a bulky substituent at position 6 of the purine, on the biological effects. Their inhibition against isolated HER2 was studied and the structure–activity relationships have been confirmed by molecular modelling studies. The most potent compound against isolated HER2 is 9a with an IC₅₀ of 7.31 µM. We have investigated the effects of the target compounds on cell proliferation. The most active compound (7c) against all the tumour cell lines studied (IC₅₀ 0.42–0.86 µM) does not produce any modification in the expression of pro-caspase 3, but increases the caspase 1 expression, and promotes pyroptosis.     

Synthesis and antimicrobial activity of N¹-benzyl or N¹-benzyloxy-1,6-dihydro-1,3,5-triazine-2,4-diamines

The emergence and spread of multidrug-resistant strains of Staphylococcus aureus and Mycobacterium tuberculosis are generating a threat to public health worldwide. In the current study, a series of N(1)-benzyl and N(1)-benzyloxy-1,6-dihydro-1,3,5-triazine-2,4-diamine derivatives were synthesized and investigated for their antimicrobial activity against S. aureus, and Mycobacterium smegmatis which is taxonomically related to M. tuberculosis. Most of the compounds exhibited good activity against M. smegmatis as determined by comparison of diameters of the zone of inhibition of test compounds and standard antibiotics. Compound 7o showed potent antimycobacterial activity against M. smegmatis without mammalian DHFR inhibition liability. The results from this study indicate that 1-benzyl derivatives of 1,6-dihydro-1,3,5-triazine-2,4-diamines may be used as lead compounds for the discovery of antimycobacterial agents.     

Design, synthesis, and preliminary biological evaluation of 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine derivatives

We synthesized a series of novel small molecules, 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine derivatives, by tandem reduction-oxirane opening of 2-nitroaroxymethyloxiranes in moderate or excellent yields. We investigated the effects of all of the compounds on HUVEC apoptosis and A549 cell growth. The results showed that 6,8-dichloro-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine was the most effective small molecule in promoting HUVEC apoptosis and inhibiting A549 cell proliferation, but 6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine could remarkably inhibit HUVEC apoptosis and might induce the formation of microvessel.     

Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.     

Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety

Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a–j, 13a–j). All the compounds were evaluated for the IC₅₀ values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC₅₀ values of 1.1 μM, 0.92 μM and 8.77–14.3 μM. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities.