Novel antitumor agent family of 1H-benzo[c,d]indol-2-one with flexible basic side chains: synthesis and biological evaluation

A series of mono-1H-benzo[c,d]indol-2-one with different amine side chains and bis-1H-benzo[c,d]indol-2-one as novel family of DNA intercalators were designed and synthesized, the contributions of aromatic chromophores and amine side chains for DNA binding properties, for example, intercalation and electrostatic binding, respectively, were evaluated. Among them, A3 tailed with N,N-dimethylamino-ethyl-ethane-1,2-diamine showed selective anti-tumor activities against cell lines A549 and P388 with IC(50) 0.428microm and 1.69microm.     

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.     

Radiosynthesis of [11C]BBAC and [11C]BBPC as potential PET tracers for orexin2 receptors

Radiosynthesis of [N-methyl-(11)C](S)-N-([1,1'-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide ([(11)C]BBAC or [(11)C]3) and [N-methyl-(11)C] (S)-N-([1,1'-biphenyl]-2-yl)-1-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)propanoyl)pyrrolidine-2-carboxamide ([(11)C]BBPC or [(11)C]-4), two potential PET tracers for orexin2 receptors are described. Syntheses of non-radioactive standards 3, 4 and corresponding desmethyl precursors 1, 2 were achieved from common intermediate (S)-2-([1,1'-biphenyl]-2-yl)-1-(pyrrolidin-2-yl)ethanone. Methylation using [(11)C]CH(3)OTf in the presence of base in acetone afforded [(11)C]3 and [(11)C]4 in 30±5% yield (EOS) with >99 % radiochemical purities with a specific activity ranged from 2.5±0.5 Ci/μmol (EOB). The logP of [(11)C]3 and [(11)C]4 were determined as 3.4 and 2.8, respectively. The total synthesis time was 30 min from EOB. However, PET scans performed in a rhesus monkey did not show tracer retention or appropriate brain uptake. Hence [(11)C]3 and [(11)C]4 cannot be used as PET tracers for imaging orexin2 receptors.     

Synthesis and evaluation of 2-[2-(phenylthiomethyl)-1H-benzo[d] imidazol-1-yl)acetohydrazide derivatives as antitumor agents

A novel class of acetylhydrazone derivatives (5a-x) containing 2-(phenylthiomethyl)-1H-benzo-[d]-imidazole moieties are synthesizer, and their antitumor activities against A549, HCT116, HepG2, PC-9, and A375 were determined by the MTT assay. Among them are N-(2,4-dihydroxybenzylidene)-2-(2-(phenylthiomethyl)-1H-benzo[d]-imidazol-1-yl)acetohydrazide (5a) and N-(5-bromo-2-hydroxy-benzylidene)-2-(2-(phenylthiomethyl)-1H-benzo[d]-imidazol-1-yl)acetohydrazide (5d) which displayed excellent cancer inhibitory activity against the tested cancer cells (IC(50) 4-17 μM), compared with 5-FU and SU11248. The others have moderate to weak inhibitory activity against the tested cancer cell lines.     

Practical stereoselective synthesis of (2,3,4, 5-tetrahydro-1H-benzo[b]azepin-5-yl)acetic acid

Highly enantioselective asymmetric hydrogenation of readily accessible olefins, (E)- and (Z)-[1-(toluene-4-sulfonyl)-1,2,3, 4-tetrahydro-1H-benzo[b]azepin-5-ylidene]acetic acid (4a and 4b, respectively) and [1-(toluene-4-sulfonyl)-2, 3-dihydro-1H-benzo[b]azepin-5-yl]acetic acid (4c), is presented as an efficient and straightforward route to (R)-[1-(toluene-4-sulfonyl)-2,3,4, 5-tetrahydro-1H-benzo[b]azepin-5-yl]acetic acid [(R)-1] which is a key intermediate for the synthesis of non-peptide AVP V2-agonist. Hydrogenation of carboxylic acid 4c gave (R)-1 in quantitative yield and 85% ee using Ru(OAc)2[(S)-H8-BINAP], a Ru(II) complex of a partially hydrogenated BINAP (H8-BINAP), as a catalyst. When (R)-1 of 76% ee was transformed into the corresponding isopropylamide 6, pure enantiomer (R)-6 was obtained in 75% yield by recrystallization from MeOH.     

Novel 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids: discovery and hit-to-lead evolution of a selective CRTh2 receptor antagonist chemotype

Hit-to-lead evolution of 2-(2-((2-(4-chlorophenoxy)ethyl)thio)-1H-benzo[d]imidazol-1-yl)acetic acid (1), discovered in a high-throughput screening campaign as a novel chemotype of CRTh2 receptor antagonist, is presented. SAR development as well as in vitro and in vivo DMPK properties of selected representatives of substituted 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids are discussed.     

Existence of both neuropeptide Y, Y1 and Y2 receptors in pig spleen: evidence using subtype-selective antagonists in vivo

The effects of the first selective, non-peptide, NPY Y2 receptor antagonist (S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamid (BIIE0246) were studied on splenic vascular responses evoked in the pig in vivo. BIIE0246 abolished the splenic vasoconstrictor response to the NPY Y2 receptor agonist N-acetyl[Leu25Leu31]NPY(24-36), but did not affect the response to the NPY Y1 receptor agonist [Leu31Pro34]NPY, which in turn was abolished by the selective NPY Y1 receptor antagonist (2R)-5-([amino(imino)methyl]amino)-2-[(2,2-diphenylacetyl)amino]-N-[(IR)-1-(4-hydroxyphenyl)ethyl]-pentanamide (H 409/22). Furthermore, the PYY-evoked splenic vasoconstrictor response was partially antagonized by BIIE0246 and subsequently almost abolished by the addition of H 409/22. It is concluded that BIIE0246 exerts selective (vs the NPY Y1 receptor) NPY Y2 receptor antagonism, and thus represents an interesting tool for classification of NPY receptors, in vivo. In addition, evidence for NPY Y2 receptor mediated vasoconstriction was presented. Furthermore, both NPY Y1 and Y2 receptors are involved in the splenic vasoconstrictor response to PYY.     

Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists

Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC(50)=3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC(50)=5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists.     

(S)-N-[1-(4-cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide is a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons

(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-2) was identified as a potent and efficacious KCNQ2 opener. This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine.     

Synthesis of some novel pyrazolo[3,4-d]pyrimidine derivatives as potential antimicrobial agents

The reaction of 4-hydrazino-8-(trifluoromethyl)quinoline (2) with ethoxymethylenecyanoacetate afforded ethyl 5-amino-1-[8-(trifluoromethyl)quinolin-4-yl]-1H-pyrazole-4-carboxylate (3) and that with ethoxymethylenemalononitrile afforded 5-amino-1-[8-(trifluoromethyl)quinolin-4-yl]-1H-pyrazole-4-carbonitrile (5). Compounds 3 and 5 were hydrolyzed to get 5-amino-1-[8-(trifluoromethyl)quinolin-4-yl]-1H-pyrazole-4-carboxylic acid and then reacted with acetic anhydride to afford 6-methyl-1-[8-(trifluoromethyl)quinolin-4-yl]pyrazolo[3,4-d]oxazin-4-one (6), which was condensed with different aromatic amines to give a series of 5-substituted 6-methyl-1-[8-(trifluoromethyl)quinolin-4-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones (7). Compounds 3 and 5 also reacted with formamide, urea, and thiourea affording the corresponding pyrazolo[3,4-d]pyrimidines (8-13), respectively. Structures of the products have been determined by chemical reactions and spectral studies. All compounds of the series have been screened for their antibacterial and antifungal activity studies. The results are summarized in Tables 1 and 2.     

Synthesis and D(2)-like binding affinity of new derivatives of N-(1-ethyl-2-pyrrolidinylmethyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxamide and related 4H-[1]benzothiopyrano[4,3-b]pyrrole and 5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole-3-carboxamide analogues

Various new derivatives and structural analogues of N-(1-ethyl-2-pyrrolidinylmethyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxamide (2a), a representative term of a series of 2-aminomethylpyrrolidinyl derived 4,5-dihydrobenzo[g]indolcarboxamides with good D(2)-like affinity, were synthesized and evaluated for their ability to bind to dopamine D(2)-like receptors in vitro. The structural contribution to D(2)-like receptor binding of the 4,5-dihydrobenzo[g]indole portion of the molecule was examined. From these studies, compound 2k, 2-chloro-N-(1-ethyl-2-pyrrolidinylmethyl)-5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole-3-carboxamide, was found to possess a potent affinity for D(2)-like receptors. Behavioural tests in rats have shown that this compound reduces the hyperactivity induced by amphetamine, a property shared by all antipsychotic drugs, at a dose which failed to induce catalepsy, an effect which is predictive of extrapyramidal side effects in humans. The other compounds demonstrated moderate (2c, 2h, and 2j) or no affinity for D(2)-like receptors.     

Triazolbenzo[d]thiazoles: Efficient synthesis and biological evaluation as neuroprotective agents

A number of (1H-1,2,3-triazol-1-yl)benzo[d]thiazoles were synthesized utilizing a versatile Cu-catalyzed azide-alkyne click reaction (CuAAC) on tautomeric benzo[4,5]thiazolo[3,2-d]tetrazole (1) and 2-azidobenzo[d]thiazole (2) starting materials. Moreover, one of the resulting products of this investigation, triazolbenzo[d]thiazole 22, was found to possess significant neuroprotective activity in human neuroblastoma (SH-SY5Y) cells.     

Benzimidazole bearing oxadiazole and triazolo-thiadiazoles nucleus: Design and synthesis as anticancer agents

Two new series of benzimidazole bearing oxadiazole[1-(1H-benzo[d]imidazol-2-yl)-3-(5-substituted-1,3,4-oxadiazol-2-yl)propan-1-ones (4a-l)] and triazolo-thiadiazoles[1-(1H-benzo[d]imidazol-2-yl)-3-(6-(substituted)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)propan-1-one (7a-e)] have been synthesized successfully from4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide (3) with an aim to produce promising anticancer agents. In vitro anticancer activities of synthesized compounds were screened at the National Cancer Institute (NCI), USA, according to their applied protocol against full NCI 60 human cell lines panel; results showed good to remarkable anticancer activity. Among them, compound (4j, NCS: 761980) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100μM) with GI(50) values ranging from 0.49 to 48.0μM and found superior for the non-small cell lung cancer cell lines like HOP-92 (GI(50) 0.49, TGI 19.9,LC(50) >100 and Log(10)GI(50) -6.30, Log(10)TGI -4.70, Log(10)LC(50) >-4.00).     

Discovery and initial SAR of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-ones as inhibitors of insulin-like growth factor 1-receptor (IGF-1R)

The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.     

Analogs of 4-(3-bromo-8-methyl-10-methoxy-6,11-dihydro-5H-benzo[5,6]-cyclo hepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N-oxide as inhibitors of farnesyl protein transferase.

A series of 3-substituted analogs 3 of 4-(3-bromo-8-methyl-10-methoxy-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2 b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N-oxide 2 was prepared and evaluated as FPT inhibitors. The objective of this study was to identify other substituents at C3 in this series of FPT inhibitors that would have the FPT potency enhancement similar to that found for a C3 bromo substituent. The 3-methyl analog 17b was found to be tenfold less active than 2, and other C3 substituents having more steric bulk were found to cause a further reduction in activity.     

Benzimidazol-1-yl-1-phenylpropanone Analogs as Potent Antimicrobial Agents: Rational Design and Synthesis

Designed, synthesized a sequence of novel benzimidazol-1-yl-1-phenylpropanone hybrids and assessed for in vitro antimicrobial potential counter to several bacterial strains. Computational Methodology was carried out for designing of the target molecules and structures were confirmed by spectroscopic analysis. Amid the 12 integrated derivatives, (3-(2-((3-fluorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6g ) and 3-(2-((4-fluorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6k ) were found to acquire excellent antibacterial activity against all bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus), whereas derivative 3-(2-((2-fluorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6c ), was potent against Escherichia coli, Bacillus subtilis, Staphylococcus aureus and displayed moderate action against P. aeruginosa. Derivatives with NO₂ substituent at 3^rd and 4^th position, 3-(2-((3-nitroobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6h ) and 3-(2-((4-nitroobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6 l ) respectively declared good to moderate results against all bacterial strains. Further, 3-(2-((3-chlorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6f ) and 3-(2-((4-chlorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6j ) were found to be more competent against both fungal strains (C. albicans, A. niger). Serial two-fold dilution method was used for the entire study and standard drugs utilized were ciprofloxacin and clotrimazole. MIC values (μg/ml) of novel synthesized analogs were reported in comparison to standard drugs for antibacterial and antifungal actions. Molecular docking studies showed that designed molecules dynamically bound with effective area of the receptor (DNA gyrase B, Clotrimazole complex of cytochrome P 45046A1) and in vitro results were in accord with in silico studies.     

Synthesis, antitumour activity and structure-activity relationships of 5H-benzo[b]carbazoles

A series of novel 5H-benzo[b]carbazoles related to the ellipticines was obtained from the reactions of p-benzoquinones with 2-aminomethylene-1-indanones. Most of the compounds were evaluated for their antitumour activity in the National Cancer Institute's in vitro human tumour cell line screening panel. Among them, particularly derivative 15c bearing a p-quinone methide moiety in ring C of the heterocycle was found to show in vitro activity comparable to clinically well established anticancer agents such as amsacrine or mitomycin C. Compounds 9d, 9e and 12k showed increased potency to distinct cell lines like the leukemia or melanoma subpanel of cell lines. Based on the test results, structure-activity relationships for this series of compounds were developed. For instance, it was found that a quinonoid substructure in ring C leads to a noticeable increase in activity. The same observation was made for a 2-hydroxyl substituent at the ring system. 2-Acetoxy and 2-methoxy derivatives as well as 2-unsubstituted 5H-benzo[b]carbazoles either had a decreased potency or were found to be inactive. A COMPARE analysis with some of these compounds showed poor or no correlation with anticancer drugs of the NCI's standard agents database indicating a novel mechanism of action. Additionally, UV-vis titrations in the series of 5H-benzo[b]carbazoles indicated interactions with calf thymus DNA only for the highly active quinone methide 15c.     

Potent, exceptionally selective, orally bioavailable inhibitors of TNF-alpha Converting Enzyme (TACE): novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents

Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.     

Synthesis and biological evaluation of 5-arylamino-1H-benzo[d]imidazole-4,7-diones as inhibitor of endothelial cell proliferation

5-Arylamino-1H-benzo[d]imidazole-4,7-diones were synthesized and tested for their inhibitory activities on the proliferation of human umbilical vein endothelial cells (HUVECs) and the smooth muscle cells (SMCs). Among them, several 1H-benzo[d]imidazole-4,7-diones exhibited the selective antiproliferative activity on the HUVECs. Further mechanistic study revealed that the inhibitory effect of one representative 1H-benzo[d]imidazole-4,7-dione 2b on HUVEC proliferation was mediated by the activation of p38 signaling pathway in the HUVECs.     

Reaction of glycosyl isothiocynates with 3-indolylaminomethyl-ketone hydrochloride

Reaction of glycosyl isothiocyanate la-c with 3-indolylaminomethylketone hydrochloride(2) yielded glycosylthiourea derivatives 3a-c. Cyclodehydration of 3a-c with acetic anhydride afforded 5-(indol-3-yl)-2-[N-per-O-acetyl-D-glycopyranosyl)amino]thiazoles 4a-c. Deacetylation of 4a-c gave 5-(indol-3-yl)-2-[N-(D-glycopyranosyl) amino] thiazoles 5a-c.