Synthesis of some N-[4-(benzothiazole-2yl) phenyl]-2-aryloxyacetamide derivatives and their anticancer activities

In this study, some N-[4-(Benzothiazole-2-yl) phenyl]-2-aryloxyacetamide derivatives were prepared by reacting N-[4-(benzothiazole-2yl)phenyl]-2-chloroacetamide and different substituent phenol or thiophenol derivatives. The anticancer activities of the compounds obtained were investigated. It was observed that some of the compounds, namely 25 and 38, showed notable anticancer activity.     

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.     

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 of 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole derivatives and their effects on neuronal cell death

Novel 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole analogs were synthesized by either of the following two pathways: (1) a sequence of Knoevenagel condensation of oxindole with (4-dimethylamino)cinnamaldehyde–hydrogenation, or (2) alkylation of oxindole dianion with [(4-dimethylamino)phenyl]alkyl halides. Subsequent alkylation at C-3 and/or N-1 of the oxindole skeleton by anion-based methods provided additional substituted derivatives for structure-activity relationship studies. Their effects on neuronal cell death induced by oxidative stress were evaluated by lactate dehydrogenase assay. Compounds with the alkyl chain length of 2–4 significantly suppressed the neuronal cell death. No significant change occurred in the activity by substitution with less-polar groups. The stereochemistry at C-3 of the oxindole core was also irrelevant for the neuroprotective effects of these compounds.     

Synthesis and antibacterial activity of N-[2-[5-(methylthio)thiophen-2-yl]-2-oxoethyl] and N-[2-[5-(methylthio)thiophen-2-yl]-2-(oxyimino)ethyl]piperazinylquinolone derivatives

A number of N-substituted piperazinylquinolone derivatives were synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative bacteria. Preliminary results indicated that most compounds tested in this study demonstrated comparable or better activity against Staphylococcus aureus and Staphylococcus epidermidis than their parent piperazinylquinolones as reference drugs. Among these derivatives, ciprofloxacin derivative 5a, containing N-[2-[5-(methylthio)thiophen-2-yl]-2-oxoethyl] residue, showed significant improvement of potency against staphylococci, maintaining Gram-negative coverage.     

Synthesis of 8-substituted-4-(2/4-substituted phenyl)-2H-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2-thiones and their anticonvulsant,anti-nociceptive,and toxicity evaluation in mice

A number of new 8-substituted-4-(2/4-substituted phenyl)-2H-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2-thiones (4a–t) were synthesized and evaluated for their anticonvulsant, anti-nociceptive, hepatotoxic, and neurotoxic properties. The titled compounds (4a–t) were obtained by cyclization of N-{[6-substituted-1,3-benzothiazol-2-yl)amino]carbonothioyl}-2/4-substituted benzamides (3a–t) by refluxing in n-butanol. All the newly synthesized compounds were screened for their anticonvulsant activity in a mouse seizure model and were compared with the standard drug phenytoin. Compounds 4a, 4c, 4f, and 4l showed complete protection after time periods of 0.5?h and 4?h. Some of the selected compounds were evaluated for their neurotoxic and hepatotoxic effects, and none of these showed any sign of neurotoxicity or hepatotoxicity. Compounds 4a–t were also evaluated for their anti-nociceptive activity by a thermal stimulus technique using diclofenac as standard. Compounds 4o, 4q, and 4t displayed highly potent analgesic activity with p?<?0.01.     

Synthesis of new N-(2-(trifluoromethyl)pyridin-4-yl)anthranilic acid derivatives and their evaluation as anticancer agents

The N-(2-(trifluoromethyl)pyridin-4-yl)anthranilic acid 6 and a series of its ester and amide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cells. Ester derivatives 13 and 18 exhibited potent growth inhibitory activity with GI(50) values at nanomolar concentrations. Among amide derivatives, N-anthraniloylglycinate 19 shown moderate inhibitory activity in the full panel cancer cell line screening.     

Synthesis of some imidazolyl-thioacetyl-pyrazolinone derivatives and their antinociceptive and anticancer activities

In this study, some 4-(1,5-diarylimidazol-2-yl)thioacetyl-1-phenyl-2,3-dimethyl-3-pyrazoline-5-one derivatives were prepared by reacting 4-(2-chloroacetyl)-1-phenyl-2,3-dimethyl-3-pyrazoline-5-one and 2-mercapto-1, 5-diarylimidazole derivatives. The antinociceptive and anticancer activities of the compounds obtained were investigated. It was observed that some of the compounds, 2a, 2d, 2g, and 2j, showed remarkable antinociceptive activity, and one of the compounds, 2i, showed weak anticancer activity.     

Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives

A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents.     

Anthelmintic and antibacterial screening of a new series of N-[4-(4-nitrophenoxy)phenyl]-4-(substituted)-1,3-thiazol-2-amines

A series of N-[4-(4-nitrophenoxy)phenyl]-4-(substituted)-1,3-thiazol-2-amines was synthesized. Structural elucidation was accomplished by ¹H NMR, ¹³C NMR, IR, and elemental analyses of synthesized compounds. The title compounds were derived from 4-(4-nitrophenoxy)phenyl thiourea, which is the key intermediate in the synthesis of nitroscanate, an anthelmintic drug. Among the synthesized compounds, N-[4-(4-nitrophenoxy)phenyl]-4-(4-fluorophenyl)-1,3-thiazol-2-amine and N-[4-(4-nitrophenoxy)phenyl]-4-(4-methoxyphenyl)-1,3-thiazol-2-amine exhibited potent anthelmintic and antibacterial activities.     

Synthesis and anti-tumor activities of N'-benzylidene-2-(4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetohydrazone derivatives

A compound with a cyclic thienopyrimidine moiety and an aceto-hydrazone moiety in its chemical structure was discovered in a cell-based screening to have noticeable cytotoxicity on several tumor cell lines. A total of 38 derivatives of this compound were synthesized at five steps with high yields. These compounds were tested in standard MTT assays, and several compounds exhibited improved cytotoxic activities. The most potent compounds have IC(50) values of 10-20 μM on A549, HeLa, and MBA-MD-231 tumor cells. Flow cytometry analysis of several active compounds and subsequent examination of caspase activation indicate that they induce caspase-dependent apoptosis in tumor cells. In addition, these compounds do not have obvious effect on a normal cell line HEK-293T, demonstrating the desired selectivity against tumor cells. Results from a fluorescence polarization-based in vitro binding assay indicate that this class of compounds does not significantly interrupt the interactions between Mcl-1 and Bid. Their cytotoxicity is achieved presumably through other mechanisms.     

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.     

Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2- pyridylmethoxy)benzamide (AZD7254)

Aberrant hedgehog (Hh) pathway signaling is implicated in multiple cancer types and targeting the Smoothened (SMO) receptor, a key protein of the Hh pathway, has proven effective in treating metastasized basal cell carcinoma. Our lead optimization effort focused on a series of heteroarylamides. We observed that a methyl substitution ortho to the heteroaryl groups on an aniline core significantly improved the potency of this series of compounds. These findings predated the availability of SMO crystal structure in 2013. Here we retrospectively applied quantum mechanics calculations to demonstrate the o-Me substitution favors the bioactive conformation by inducing a dihedral twist between the heteroaryl rings and the core aniline. The o-Me also makes favorable hydrophobic interactions with key residue side chains in the binding pocket. From this effort, two compounds (AZD8542 and AZD7254) showed excellent pharmacokinetics across multiple preclinical species and demonstrated in vivo activity in abrogating the Hh paracrine pathway as well as anti- tumor effects.     

Synthesis and anticonvulsant activity of some 2-(2-{1-[substituted phenyl]ethylidene}hydrazinyl)-4-(4-methoxy-phenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile

A series of dihydro-pyrimidine-5-carbonitrile derivatives (3–16) were synthesized and evaluated for their anticonvulsant activity against MES and scPTZ models. Motor impairment screening was carried out by rotarod test method and CNS depressant effect was determined by Porsolt’s force swim pool method. Compounds 4 and 9 having p-substituted bromo and m-substituted nitro groups, respectively, were found to be most active showing activity both in MES and scPTZ screen at lower doses of 30 mgkg^?1 at 0.5?h and 100 mgkg^?1 at 4?h. In the rotarod motor impairment screen, compound 4 did not show any motor impairment even at the maximum dose of 300 mgkg^?1; however, compound 9 showed motor impairment at 300 mgkg^?1 dose after 4.0?h. The compounds were also tested for their CNS depression effect. The compounds 4 and 9 showed 41.38 and 43.44% increase in immobility time with respect to control. The pharmacophore hypothesis also fits best for compounds 4 and 9.     

N-[2-(4-benzoyl-1-piperazinyl)phenyl]-2-(4-chlorophenoxy) acetamide is a novel inhibitor of resorptive bone loss in mice

The dynamic balance between bone formation and bone resorption is vital for the retention of bone mass. The abnormal activation of osteoclasts, unique cells that degrade the bone matrix, may result in many bone diseases such as osteoporosis. Osteoporosis, a bone metabolism disease, occurs when extreme osteoclast-mediated bone resorption outstrips osteoblast-related bone synthesis. Therefore, it is of great interest to identify agents that can regulate the activity of osteoclasts and prevent bone loss-induced bone diseases. In this study, we found that N-[2-(4-benzoyl-1-piperazinyl)phenyl]-2-(4-chlorophenoxy) acetamide (PPOAC-Bz) exerted a strong inhibitory effect on osteoclastogenesis. PPOAC-Bz altered the mRNA expressions of several osteoclast-specific marker genes and blocked the formation of mature osteoclasts, suppressing F-actin belt formation and bone resorption activity in vitro. In addition, PPOAC-Bz prevented OVX-induced bone loss in vivo. These findings highlighted the potential of PPOAC-Bz as a prospective drug for the treatment of osteolytic disorders.     

Synthesis, structure analysis, and antibacterial activity of some novel 10-substituted 2-(4-piperidyl/phenyl)-5,5-dioxo[1,2,4]triazolo[1,5-b][1,2,4]benzothiadiazine derivatives

A new series of 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b]-[1,2,4]benzothiadiazine arylsulfonamide derivatives (10a-j and 13a-f) was synthesized. The structures of these compounds were confirmed on the basis of spectral data, elemental analysis, X-ray analysis, and quantum chemical calculations. These compounds were evaluated for their efficacy as antibacterial agents against various Gram-positive and Gram-negative strains of bacteria. Amongst these compounds 10f and 10i were the most active compounds against Escherichia coli and 13e against E. coli as well as Bacillus subtilis. Moreover, other compounds also showed potent inhibitory activity in comparison to the standard drugs.     

Synthesis and pharmacological evaluation of substituted 5-[4-[2-(6,7-dimethyl-1,2,3,4-tetrahydro-2-oxo-4-quinoxalinyl)ethoxy]phenyl]methylene]thiazolidine-2,4-dione derivatives as potent euglycemic and hypolipidemic agents

A series of substituted 5-[4-[2-(6,7-dimethyl-1,2,3,4-tetrahydro-2-oxo-4-quinoxalinyl)ethoxy]phenyl]methylene]thiazolidine-2,4-diones were synthesized and their euglycemic and hypolipidemic activities were investigated in Wistar male rats. Based on the in vivo data in rats, compound 4a was identified as a potent euglycemic and hypolipidemic agent.     

Synthesis and antimycobacterial activity of 4-[5-(substituted phenyl)-4, 5-dihydro-3-isoxazolyl]-2-methylphenols

Compounds based on the isoxazoline moiety were screened for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37R (MTB), and INH (isoniazid) resistant Mycobacterium tuberculosis (INHR-MTB) using the agar dilution method and bactec 460. Among the synthesized compounds, 4-[5-(4-bromophenyl)-4,5-dihydro-3-isoxazolyl]-2-methylphenol (4l) was found to be the most active agent against MTB and INHR-MTB with minimum inhibitory concentration of 0.62 microM. When compared to INH, compound (4l) was 1.12 fold and 3.0 fold more active against MTB and INHR-MTB, respectively.     

Synthesis and antimycobacterial activity of 4-[5-(substituted phenyl)-4, 5-dihydro-3-isoxazolyl]-2-methylphenols

Compounds based on the isoxazoline moiety were screened for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37R (MTB), and INH (isoniazid) resistant Mycobacterium tuberculosis (INHR-MTB) using the agar dilution method and bactec 460. Among the synthesized compounds, 4-[5-(4-bromophenyl)-4,5-dihydro-3-isoxazolyl]-2-methylphenol (4l) was found to be the most active agent against MTB and INHR-MTB with minimum inhibitory concentration of 0.62 μM. When compared to INH, compound (4l) was 1.12 fold and 3.0 fold more active against MTB and INHR-MTB, respectively.