Synthesis and antibacterial activity of N-[2-(5-bromothiophen-2-yl)-2-oxoethyl] and N-[(2-5-bromothiophen-2-yl)-2-oximinoethyl] derivatives of piperazinyl quinolones

A series of N-[2-(5-bromothiophen-2-yl)-2-oxoethyl] and N-[2-(5-bromothiophen-2-yl)-2-oximinoethyl]derivatives of piperazinyl quinolones were synthesized and evaluated for antimicrobial activity against Gram-positive and Gram-negative microorganisms. Some of these derivatives exhibit comparable or better activity against Gram-positive bacteria, Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis, than ciprofloxacin, norfloxacin and enoxacine as reference drugs.     

Synthesis and antibacterial activity of N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-thiadiazol-2-yl)piperazinyl quinolone derivatives

A series of N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-thiadiazol-2-yl) derivatives of piperazinyl quinolones was synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative microorganisms. Some of these derivatives exhibit high activity against Gram-positive bacteria; Staphylococcus aureus and Staphylococcus epidermidis, comparable or more potent than their parent N-piperazinyl quinolones norfloxacin and ciprofloxacin as reference drugs. The SAR of this series indicates that both the structure of the benzyl unit and the S or SO(2) linker dramatically impact antibacterial activity.     

Synthesis and antibacterial activity of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones

A series of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones were synthesized and tested to demonstrate in vitro antimicrobial activity. Some of these compounds exhibited a good activity against Staphylococcus aureus, S. epidermidis and Bacillus subtilis.     

Synthesis and in-vitro anti-leishmanial activity of (4-arylpiperazin-1-yl)(1-(thiophen-2-yl)-9H-pyrido[3,4-b]indol-3-yl)methanone derivatives

In the present study, we have reported synthesis and biological evaluation of a series of fifteen 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole derivatives against both promastigotes and amastigotes of Leishmania parasites responsible for visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis. Among these reported analogues, compounds 7b, 7c, 7f, 7g, 7i, 7j, 7m, 7o displayed potent activity (15.55, 7.70, 7.00, 3.80, 14.10, 9.25, 3.10, 4.85 μM, respectively) against L. donovani promastigotes than standard drugs miltefosine (15.70 μM) and pentamidine (32.70 μM) with good selectivity index. In further, in-vitro evaluation against amastigote forms, two compounds 7g (8.80 μM) and 7i (7.50 μM) showed significant inhibition of L. donovani amastigotes. Standard drug amphotericin B is also used as control to compare inhibition potency of compounds against both promastigote (0.24 μM) and amastigote (0.05 μM) forms.     

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.     

Synthesis and KCNQ2 opener activity of N-(1-benzo[1,3]dioxol-5-yl-ethyl, N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl, and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl acrylamides

Bioisosteric replacement studies led to the identification of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide ((S)-3) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide ((S)-4), and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-5) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 microM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (+/-)-3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds (S)-4 and (S)-5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.     

(+)-3-[2-(Benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane as potent agonists for the alpha7 nicotinic acetylcholine receptor

A series of 3-substituted 1-azabicyclo[2.2.2]octanes was discovered as the alpha7 nicotinic acetylcholine (alpha7) receptor agonists. It was found that (+)-3-[2-(benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane (+)-15b has potent agonistic activity for the alpha7 receptor.     

Synthesis and antibacterial activity of a new series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives

A series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one (4a–k) were synthesized by reaction of 3-[2,3-dibromo-3-(substituted phenyl)propanoyl]-2H-chromen-2-one (3 a-k) with phenyl hydrazine in presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in vitro antibacterial activity against gram-positive and gram-negative bacteria. Among the series, compounds 4d, 4h and 4i displayed an encouraging antibacterial activity profile as compared to reference standard drug ciprofloxacin against tested bacterial strains.     

Chronobiotic activity of N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]-propanamide. Synthesis and melatonergic pharmacology of fluoren-9-ylethyl amides

A series of fluoren-9-yl ethyl amides (2) were synthesized and evaluated for human melatonin MT(1) and MT(2) receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide (2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT(1) and MT(2) receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.     

Synthesis and preliminary screening of novel N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides as potential atypical antipsychotic agents

A series of N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides were synthesized as prospective novel atypical antipsychotic agents. Microwave irradiation of acetyl glycine (I) with substituted piperazines in the presence of DCC in DMF for about 3-5 min gave the titled compounds (P:1-7). All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D₂ antagonism studies were performed using the climbing mouse assay model and 5-HT_2A antagonism studies were performed using quipazine induced head twitches in mice. Among the synthesized compounds P4 was found to be the most active compound.     

Synthesis and preliminary screening of novel N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides as potential atypical antipsychotic agents

A series of N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides were synthesized as prospective novel atypical antipsychotic agents. Microwave irradiation of acetyl glycine (I) with substituted piperazines in the presence of DCC in DMF for about 3-5 min gave the titled compounds (P:1-7). All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D(2) antagonism studies were performed using the climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine induced head twitches in mice. Among the synthesized compounds P4 was found to be the most active compound.     

Synthesis and antibacterial activity of benzyl-[3-(benzylamino-methyl)-cyclohexylmethyl]-amine derivatives

A series of benzyl-[3-(benzylamino-methyl)-cyclohexylmethyl]-amine derivatives with different substitution pattern on the aromatic ring have been prepared and evaluated for their antibacterial activity against Gram-positive and Gram-negative bacterial strains. Most of the compounds exhibit potent activity against Pseudomonas aeruginosa and Staphylococcus epidermidis while compounds 6l and 6m showed antibacterial activity against all the four bacterial strains with MIC values ranging from 0.002 to 0.016 μg/mL and no hemolytic activity up to 512 μg/mL in mammalian erythrocytes was observed.     

Synthesis and antiprotozoal activity of novel 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives

A series of 19 new 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives was synthesized starting from the properly substituted 1,2-phenylendiamine. These compounds have hydrogen or methyl at position 1; while hydrogen, chlorine, ethoxy or methoxycarbonyl group is at position 5 and/or 6. The novel compounds were tested against protozoa Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Experimental evaluations revealed strong activity for all tested compounds, having IC₅₀ values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.     

Synthesis and anticonvulsant activity of new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones

Twenty-two new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. Several compounds were tested additionally in the 6-Hz psychomotor seizure model. The neurotoxicity was determined applying the rotarod test. Excluding one compound, all other molecules were found to be effective in at least one seizure model. The most active were 1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (14), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylpyrrolidine-2,5-dione (17), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3,3-dimethylpyrrolidine-2,5-dione (23) and 3,3-dimethyl-1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (26). These compounds showed high activity in the 6-Hz psychomotor seizure test as well as were active in the maximal electroshock and subcutaneous pentylenetetrazole (14 and 23) screens. Initial SAR studies for anticonvulsant activity have been discussed.     

Synthesis and anti-inflammatory activity of some [4,6-(4-substituted aryl)-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetic acid derivatives

A series of [4,6-(substituted aryl)-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetic acid (4a-r) has been synthesized by the base catalyzed condensation of beta-aroylpropionic acid, thiourea with aldehyde in ethanol. Structures of the new compound were established on the basis of (1)H NMR and IR spectral data. Anti-inflammatory activity in vivo were evaluated and compared with standard drug diclofenac sodium. Some compounds have shown moderate activity.     

Synthesis and in vitro antibacterial activity of 3-[N-methyl-N-(3-methyl-1,3-thiazolium-2-yl)aminolmethyl cephalosporin derivatives

The new cephalosporins having N-linked quarternary ammonium salt at C-3 position were prepared from the reaction of 2-methylimino-3-methyl-1,3-thiazoline derivatives with cephalosporins. Also antimicrobial activities of those compounds were determined.     

Synthesis,anticancer and antioxidant activities of some novel N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives

A series of N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives were synthesized by treating N-(benzoxazol-2-yl)hydrazinecarboxamide with different isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral analyses. All the synthesized derivatives (Va-l) were screened for anticancer and antioxidant activities. The results showed the anticancer activity of test compounds against HeLa, IMR-32 and MCF-7 cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. All the synthetic compounds produced a dose-dependant inhibition of growth of the cells. The IC₅₀ values of some compounds were comparable with standard anticancer agent, cisplatin. All the title compounds effectively scavenged the free radical, α,α-diphenyl-β-picryl hydrazyl. The test compounds having substitution with different halides (electron withdrawing groups) at C5 position showed more potent anticancer and antioxidant activities than those at C7 position. These results indicate that C5-substituted derivatives may be useful for developing antioxidant agents that play a protective role in many pathological conditions such as cancer, diabetes and so on.     

Synthesis, anticancer and antioxidant activities of some novel N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives

A series of N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives were synthesized by treating N-(benzoxazol-2-yl)hydrazinecarboxamide with different isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral analyses. All the synthesized derivatives (Va-l) were screened for anticancer and antioxidant activities. The results showed the anticancer activity of test compounds against HeLa, IMR-32 and MCF-7 cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. All the synthetic compounds produced a dose-dependant inhibition of growth of the cells. The IC(50) values of some compounds were comparable with standard anticancer agent, cisplatin. All the title compounds effectively scavenged the free radical, α,α-diphenyl-β-picryl hydrazyl. The test compounds having substitution with different halides (electron withdrawing groups) at C5 position showed more potent anticancer and antioxidant activities than those at C7 position. These results indicate that C5-substituted derivatives may be useful for developing antioxidant agents that play a protective role in many pathological conditions such as cancer, diabetes and so on.     

Identification and synthesis of N-(thiophen-2-yl) benzamide derivatives as BRAFV600E inhibitors

The V600E BRAF kinase mutation, which activates the downstream MAPK signaling pathway, commonly occurs in about 8% of all human malignancies and about 50% of all melanomas. In this study, we employed virtual screening and chemical synthesis to identify a series of N-(thiophen-2-yl) benzamide derivatives as potent BRAF^V600E inhibitors. Structure–activity relationship studies of these derivatives revealed that compounds b40 and b47 are the two most potent BRAF^V600E inhibitors in this series.