Synthesis and anti-proliferative activity of a novel 1,2,3-triazole tethered chalcone acetamide derivatives.

A new series of 1,2,3-triazole tethered chalcone acetamide derivatives (7a-c &8a-r) have been synthesized in excellent yields and their structures were determined by analytical and spectral (FT-IR, 1H NMR, 13C NMR & HRMS) studies. The newly synthesized derivatives were evaluated for their cytotoxic activity against four human cancer cell lines, such as HeLa (Human cervical cancer), A549 (Human alveolar adenocarcinoma), MCF-7 (Human breast adenocarcinoma) and SKNSH (Human brain cancer). Among them, compound 7c exhibited good anti-proliferation activity with HeLa (IC50 7.41 + 0.8 µM), SKNSH (IC50 8.68 + 1.1 µM), MCF-7 (IC50 9.76 + 1.3 µM) and MDA-MB-231, while compounds 7a and 7b showed promising anti-proliferation against above four human cancer cell lines with IC50 7.95-11.62 µM, respectively, compared with the standard drug Doxorubicin. We explored the probable key active site and binding mode interactions in HDAC8 (PDB ID:3SFH) and EHMT2 (PDB ID:3K5K) proteins. The docking results are complementary to the experimental observations.

Design, Synthesis, and in vitro antitubercular activity of 1,2,3-triazolyl-dihydroquinoline derivatives.

In the quest for new active molecules against Mycobacterium tuberculosis, a series of dihydroquinoline derivatives possessing triazolo substituents were efficiently synthesized using click chemistry. The structure of 6l was evidenced by X-ray crystallographic study. The newly synthesized compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The compounds 6a, 6g, and 6j (MIC: 3.13 µg/ml) showed promising activity when compared to the first-line drug such as ethambutol. In addition, the structure and antitubercular activity relationship were further supported by in silico molecular docking studies of the active compounds against 3IVX.PDB (crystal structure of pantothenate synthetase in complex with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid).

A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial evaluation and molecular docking studies.

A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by 1H NMR, 13C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase.

Potent ACE inhibitors from 5-hydroxy indanone derivatives.

A novel triazole derivatives(±)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b]furan-6(2H)-one (12a-j) were designed and synthesized by the reaction between racemic azide and terminal acetylenes under click chemistry reaction conditions followed by biological evaluation as angiotensin converting enzyme (ACE) inhibitors. ß-Amino alcohol derivatives of 1-indanone (15a-l) were synthesized from 5-hydroxy indanone, it was reacted with epichlorohydrin and followed by oxirane ring opening with various piperazine derivatives. Among the newly synthesized compounds 12b (IC50: 1.388024 µM), 12g (IC50: 1.220696 µM), 12j (IC50: 1.312428 µM) and 15k (IC50: 1.349671 µM) and 15l (IC50: 1.330764 µM) emerged as most active non-carboxylic acid ACE inhibitors with minimal toxicity comparable to clinical drug Lisinopril.

Iodine mediated pyrazolo-quinoline derivatives as potent anti-proliferative agents.

A novel series of substituted pyrazolo-quinoline derivatives 7pa-7qg were synthesized efficiently by using molecular iodine in DMSO and further characterized based on 1H NMR, 13C NMR, IR and HRMS spectral studies. All the synthesized derivatives were screened for their in vitro cytotoxic activity against a panel of five different cancer cell lines such as A549, HeLa, SKNSH, HepG2 and MCF7. The compounds 7pc, 7pd, and 7pj exhibited considerable to promising anti-proliferative activity with IC50 values of 3.76, 3.87 and 3.83 µM against SKNSH cancer cell line. It was revealed that the compounds 7pa and 7pg have shown very close IC50 values of 2.43 and 6.01 µM, against A549 and MCF7 cancer cell lines respectively, which compared to positive control of Doxorubicin. This is the first report on the synthesis and in vitro anti-proliferative evaluation of pyrazolo-quinoline derivatives.

Potential antimicrobial agents from triazole-functionalized 2H-benzo[b][1,4]oxazin-3(4H)-ones.

A series of substituted triazole functionalized 2H-benzo[b][1,4]oxazin-3(4H)-ones were synthesized by employing click chemistry and further characterized based on 1H NMR, 13C NMR, IR and mass spectral studies. All the synthesized derivatives were screened for their in vitro antimicrobial activities. Further, molecular docking studies were accomplished to explore the binding interactions between 1,2,3-triazol-4-yl-2H-benzo[b][1,4]oxazin-3(4H)-one and the active site of Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCS). These docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9c, 9d and 9e were identified as promising antimicrobial leads.

Design, synthesis and in vitro anti-tuberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole derivatives.

A series of novel benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole hybrids (7a-j &8a-j) have been designed and synthesized in excellent yields by Huisgen's [3+2] cyclo addition reaction of 3-(azidomethyl)-2-methyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine (5) with various alkynes 6 in presence of copper sulphate and sodium ascorbate and their structures were confirmed by IR, 1H NMR, 13C NMR and HRMS. The newly synthesized compounds 7a-j &8a-j were evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). Among the compounds tested, the compounds 7i and 8g displayed most potent activity with MIC value of 1.56 µg/mL with low cytotoxicity.

Potential anti-proliferative agents from 1,4-benzoxazinone-quinazolin-4(3H)-one templates.

A novel synthetic protocol has been developed for the synthesis of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids 7a-n by employing Pd-catalyzed CH arylation in presence of 5-10% phosphine ligand in good to excellent yields and evaluated for their anti-proliferative activity against three cancer cell lines such as A549 (lung), HeLa (cervical), MDA-MB-231 (breast). Compounds 7d, 7f, 7l and 7n exhibited promising anti-proliferative activity with GI50 values ranging from 0.37 to 2.73 µM respectively against A549, HeLa, and MDA-MB-231, while compound 7f showed significant activity against MDA-MB-231 with GI50 value 0.58 µM, 7j showed significant activity against A549 with GI50 value 0.32 µM and 7l showed significant activity against HeLa with GI50 value 0.37 µM. This is the first report on the synthesis and in vitro anti-proliferative evaluation of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids.

Design, synthesis, and in vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,3,4-oxadiazole derivatives.

A new antitubercular agents, benzo[6,7]cyclohepta[1,2-b]pyridine-1,3,4- oxadiazole hybrids (6a-o), have been designed and synthesized involving oxidative cyclization of hydrazones by use of di(acetoxy)iodobenzene, characterized by IR,1 H NMR,13 C NMR, and HRMS, and further confirmed by X-ray analysis. All the newly synthesized compounds 4a-o evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Among the compounds tested, the compounds 4o (MIC: 1.56 µg/ml) and 4l, 4m (MIC: 3.125 µg/ml) are promising lead analogues and have shown lower cytotoxicity.

A novel piperazine linked ß-amino alcohols bearing a benzosuberone scaffolds as anti-proliferative agents.

A new series of 1-((9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methoxy)-3-(4-phenylpiperzin-1-yl) propan-2-ols (6a-k) have been designed, synthesized and their structures were established by spectroscopic data (FT-IR, 1H NMR, 13C NMR, HRMS) and further confirmed by X-ray analysis. The newly synthesized compounds 6a-k were evaluated for their in vitro anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MDA-MB-231 (breast), A549 (lung) and MIAPACA (pancreatic). Among the compounds tested, the compound 6e displayed most potent activity against four cancer cell lines with GI50 values ranging from 0.010 to 0.097µM. The structure and anti-proliferative activity relationship was further supported by in silico molecular docking study of the active compounds against Colchicine binding site of ß-tubulin.

Novel benzothiazine-piperazine derivatives by peptide-coupling as potential anti-proliferative agents.

In an attempt to develop potential and selective anti-proliferative agents, a series of novel benzothiazine-piperazine derivatives 8a-i and 10a-g were synthesized by coupling of 2H-1,4-benzothiazin-3(4H)-one with various amines 7a-i and 9a-g in excellent yields and evaluated for their in vitro anti-proliferative activity against four cancer cell lines, HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). In vitro inhibitory activity indicated that compounds 8a, 8d, 8g, 10a, 10b, 10e, 10f were found to be good anti-proliferative agents. Among them the derivatives 8g, 10e and 10f were found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking was undertaken to investigate the probable binding mode and key active site interactions in HDAC8 and EHMT2 proteins. The docking results are complementary to the experimental results.

Design, synthesis and docking studies of novel 1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamide derivatives as a potential anti-proliferative agents.

A new series of 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hybrids 8a-l have been designed and synthesized using peptide coupling agents with substituted N-phenyl piperazines and piperidines with good to excellent yields. The synthesized compounds were evaluated for their in vitro anti-proliferative activity against PANC 1, HeLa and MDA-MB-231. The compounds 8d, 8e, 8f, 8g, 8h and 8k exhibited considerable anti-proliferative activity with GI50 values ranging from 0.15 to 1.4 µM. The structure and anti-proliferative activity relationship was further supported by in silico molecular docking study of the active compounds against tubulin protein.

A convenient synthesis and screening of benzosuberone bearing 1,2,3-triazoles against Mycobacterium tuberculosis.

A series of benzosuberone bearing 1,2,3-triazoles were rationally designed and alkyl/aryl groups appended on 1,2,3-triazole derivatives 5a-o were synthesized using click chemistry and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Compounds 5h (MIC: 3.125µg/mL) and 5l, 5m, 5o (MIC: 6.25µg/mL) exhibited promising hits. This is the first Letter on the synthesis and in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv of benzosuberone alkyl/aryl groups appended on 1,2,3-triazole derivatives.

Quinazolinones-Phenylquinoxaline hybrids with unsaturation/saturation linkers as novel anti-proliferative agents.

A new series of novel quinazolinones with allylphenyl quinoxaline hybrids 9a-n were efficiently synthesized in good yields by the reaction of 3-allyl-2-methylquinazolin-4(3H)-one (5a-n) with bromophenyl)quinoxaline (8) utilizing Pd catalyzed Heck-cross coupling and evaluated for anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). Compounds 9a, 9e, 9g and 9h exhibited promising anti-proliferative activity with GI50 values ranging from 0.06 to 0.2µM against four cell lines, while compounds 9e and 9k showed significant activity against HeLa and MIAPACA cell lines and compounds 9b, 9d, 9h and 9j showed selective potency against IMR32 and MDA-MB-231 cell lines. This is the first report on the synthesis and in vitro anti-proliferative evaluation of E-2-(4-substituted)-3-(3-(4-(quinoxalin-2-yl)phenyl)allyl)quinazolin-4(3H)-ones (9a-n). Docking results indicate a sign of good correlation between experimental activity and calculated binding affinity (dock score), suggesting that these compounds could act as promising DNA intercalates.

Three-component, one-pot synthesis of benzo[6,7]cyclohepta[1,2-b]pyridine derivatives under catalyst free conditions and evaluation of their anti-inflammatory activity.

An efficient three-component protocol is described for the synthesis of benzo[6,7]cyclohepta[1,2-b]pyridine derivatives using ß-chloroacroleins, 1,3-dicarbonyls and ammonium acetate under catalyst free conditions by using ethanol as reaction media. The mild reaction conditions, operational simplicity and high yields are the advantages of this protocol and the broad scope of this one-pot reaction makes this procedure promising for practical usages. All the final compounds were screened for anti-inflammatory activity. Among the compounds tested, the compounds 5a, 5b, 5c, 5d, 5f, and 5k exhibited significant inhibition of IL-1ß and MCP-1 secretion as a measure of anti-inflammatory activity.

Design and synthesis of 3-(3-((9H-carbazol-4-yl)oxy)-2-hydroxypropyl)-2-phenylquinazolin-4(3H)-one derivatives to induce ACE inhibitory activity.

In an attempt to develop a new class of cardiovascular drugs, a series of novel carbazolyloxy phenylquinazoline derivatives 9a-g have been synthesized and evaluated as angiotensin converting enzyme (ACE) inhibitors. Most of these compounds exhibited activity as significant ACE inhibitors and three compounds (9b, 9c & 9e) showed maximum inhibitory potency in enzyme based assays. To render support to the experimental results, a series of quinazolinone derivatives were docked into active site of ACE and identified the probable binding modes compared to Lisinopril. Also we have identified common pharmacophore hypothesis (AAADDRR) among the best docked conformers of most potent compounds in a series of compounds. The most potent 9b, 9c, 9e compounds shared common active site with the Lisinopril binding site and retained the key active site residue interactions. The obtained results from pharmacological and molecular modeling studies can be utilized for further optimization of identified hits for selective inhibition of ACE.

Synthesis and evaluation of benzosuberone embedded with 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole moieties as new potential anti proliferative agents.

As an aspect of our ongoing research in search of new anti proliferative agents, a series of novel analogs of benzosuberone embedded with 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole moieties were synthesized in excellent yields (82-93%). All the newly synthesized compounds were characterized by (1)H NMR, (13)C NMR, ESI/LC-MS, HRMS and evaluated for their in vitro anti proliferative activity against four human cancer cell lines (cervical, breast, pancreatic and alveolar). Among the synthesized compounds, 4b, 6a, 7d and 7l showed potent anti proliferative activity with GI50 values range of 0.079-0.957µM against four human cancer cell lines. However, it was revealed that the compound 7d have shown very close GI50 value 0.079µM as compared with positive control of colchicine against cervical cancer cell line.

Luotonin-A based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa cells.

A series of novel quinazolinone hybrids were synthesized by employing click chemistry and evaluated for anti-proliferative activities against MCF-7, HeLa and K562 cell lines. Among these cell lines, HeLa cells were found to respond effectively to these quinazolinone hybrids with IC50 values ranging from 5.94 to 16.45 µM. Some of the hybrids (4q, 4r, 4e, 4k, 4t, 4w) with promising anti-cancer activity were further investigated for their effects on the cell cycle distribution. FACS analysis revealed the G1 cell cycle arrest nature of these hybrids. Further to assess the senescence inducing ability of these compounds, a senescence associated ß-gal assay was performed. The senescence inducing nature of these compounds was supported by the effect of hybrid (4q) on p16 promoter activity, the marker for senescence. Moreover, cells treated with most effective compound (4q) show up-regulation of p53, p21 and down-regulation of HDAC-1, HDAC-2, HDAC-5 and EZH2 mRNA levels. Docking results suggest that, the triazole nitrogen showed Zn(+2) mediated interactions with the histidine residue of HDACs.

Synthesis and antimicrobial activity of novel benzoxazine sulfonamide derivatives.

A new series of benzoxazine-6-sulfonamide derivatives were synthesized in excellent yields and the resulting compounds were evaluated for their antimicrobial activities. All the synthesized compounds were assessed for their antibacterial and antifungal activities. Among them 1a, 1b, 1c, 1e, 1h, 2c, 2d, 2e, 2g, 2h, 2i, 2j, 2k and 2l showed low inhibitory concentration (MIC of 31.25 and 62.5 µg/mL) against Gram-positive bacteria, Gram-negative bacteria and fungi, which are comparable to the inhibitory effect of standard drugs.

Rational design, synthesis and anti-proliferative evaluation of novel 1,4-benzoxazine-[1,2,3]triazole hybrids.

A series of novel 1,2,3-triazole-1,4-benzoxazine hybrids 5a-n were efficiently synthesized employing click chemistry approach and evaluated for anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). Compounds 5n and 5g exhibited promising anti-proliferative activity with GI50 values ranging from 1.2 to 2.5 µM and 0.1-1.1 µM respectively against all cell lines, like HeLa, MDA-MB-231, MIAPACA and IMR32, while compound 5l showed significant activity against MDA-MB-231 and IMR32 with GI50 values ranging from 1.1 and 1.4 µM. This is the first report on the synthesis and in vitro anti-proliferative evaluation of 1,2,3-triazole-1,4-benzoxazine hybrids.