New indenopyrazole linked oxadiazole conjugates as anti-pancreatic cancer agents: Design, synthesis, in silico studies including 3D-QSAR analysis.

To continue the quest of newer anticancer agents, herein a novel class of 1,4-Dihydroindenopyrazole linked oxadiazole conjugates 9(a-r) was designed, synthesized and experimented for their anti-proliferative activities against four different cancer cell lines (human) such as MDA MB-231 (breast), PANC-1 (pancreatic), MCF-7 (breast), and Caco-2 (Colorectal) by using MTT assay. Among the series compound 9h and 9 m demonstrated significant potency against the PANC-1 (human pancreatic cancer cells) with IC50 value 7.4 µM and 4.3 µM respectively. While compound 9 m was found to be equipotent to standard Gomitabine (IC50 = 4.2 µM). The detailed biological assays revealed S phase cell cycle arrest and their ability to propagate apoptosis by activating caspase 3 and 9 enzymes which was confirmed by Annexin-FITC assay and caspase assay. Moreover, docking study suggested their binding modes and interactions with caspase-3. In addition, in silico studies revealed that they exhibit good pharmacokinetics and drug likeliness properties. Furthermore, 3D-QSAR was carried out to achieve a pharmacophoric model with CoMFA (q2 = 0.631, r2 = 0.977) and CoMSIA (q2 = 0.686, r2 = 0.954) on PANC-1 cancer cells which were established, generated and validated to be reliable models for further design and optimization of newer molecules with enhanced anticancer activity.

Anti-hyperglycemic and genotoxic studies of 1-O-methyl chrysophanol, a new anthraquinone isolated from Amycolatopsis thermoflava strain SFMA-103.

The compound 1-O-methyl chrysophanol (OMC) which belongs to a class of hydroxyanthraquinones was isolated from Amycolatopsis thermoflava strain SFMA-103 and studied for their anti-diabetic properties. OMC was evaluated as an anti-diabetic agent based on in silico studies which initially predicted the binding energy with α-amylase (-188.81 KJ mol-1) and with α-glucosidase (70.53 KJ mol-1). Further, these results were validated based on enzyme inhibition assays where OMC demonstrated enzyme inhibitory activity towards α-amylase (IC50 3.4 mg mL-1) and α-glucosidase (IC50 38.49 µg mL-1). To confirm the anti-diabetic activity, in vivo studies (oral dose in Wistar rats) revealed that OMC inhibited significantly the increase in glucose concentration at 100 mg/kg as compared to starch control (p < 0.05). Further, to understand the safety of OMC as a therapeutic agent, the genotoxic analysis was performed in both in vitro Chinese Hamster Ovary cells (250, 500, and 1000 µM/mL) and in vivo Swiss albino mice (250, 500, and 1000 mg/kg). In vitro results showed that OMC concentration of up to 250 µM/mL did not elicit significant changes in CAs, MI, and MN counts in CHO cells. Similarly, in mice experiments (i.p. injection), no significant changes in CAs, MI, and MN induction were observed till 500 mg/kg of OMC when compared with chrysophanic acid (Cy) (200 mg/kg). In addition, mice that received the lowest dose of OMC (250 mg/kg) did not show any histological changes in liver, kidney, and heart. The study concluded that five times higher therapeutic dose (100 mg/kg) of OMC can be utilized against hyperglycemia with no genotoxic effects.

Synthesis, antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives.

In recent years, indole-indazolyl hydrazide-hydrazone derivatives with strong cell growth inhibition and apoptosis induction characteristics are being strongly screened for their cancer chemo-preventive potential. In the present study, N-methyl and N,N-dimethyl bis(indolyl)hydrazide-hydrazone analog derivatives were designed, synthesized and allowed to evaluate for their anti-proliferative and apoptosis induction potential against cervical (HeLa), breast (MCF-7 and MDA-MB-231) and lung (A549) cancer cell lines relative to normal HEK293 cells. The MTT assay in conjunction with mitochondrial potential assays and the trypan blue dye exclusion were employed to ascertain the effects of the derivatives on the cancer cells. Further, mechanistic studies were conducted on compound 14a to understand the biochemical mechanisms and functional interactions with various signaling pathways triggered in HeLa and MCF-7 cells. Compound 14a induced apoptosis via caspase independent pathway through the participation of mitogen-activated protein kinases (MAPK) such as extracellular signal related kinase (ERK) and p38 as well as p53 pathways. It originates the activation of pro-apoptotic proteins such as Bak and Mcl-1s and also strongly induced the generation of reactive oxygen species. In downstream signaling pathway, activated p53 protein interacted with MAPK pathways, including SAPK/c-Jun N-terminal protein kinase (JNK), p38 and ERK kinases resulting in apoptotic cell death. The involvement of MAPK cascades such as p38, ERK and p38 on compound 14a induced apoptotic cell death was evidenced by the fact that the inclusion of specific inhibitors of p38, ERK1/2 and JNK MAPK (SB2035809, PD98059 and SP600125) prevented the compound 14a towards induced apoptosis. The results clearly showed that MAP kinase cascades were crucial for apoptotic response in compound 14a induced cellular killing and were dependent on p53 activity. Based on the results, compound 14a was identified as a promising candidate for cancer therapeutics and these findings furnish a basis for further in vivo experiments on anti-proliferative activity.

Synthesis and biological evaluation of pyrazole linked benzothiazole-ß-naphthol derivatives as topoisomerase I inhibitors with DNA binding ability.

A series of new pyrazole linked benzothiazole-ß-naphthol derivatives were designed and synthesized using a simple, efficient and ecofriendly route under catalyst-free conditions in good to excellent yields. These derivatives were evaluated for their cytotoxicity on selected human cancer cell lines. Among those, the derivatives 4j, 4k and 4l exhibited considerable cytotoxicity with IC50 values ranging between 4.63 and 5.54 µM against human cervical cancer cells (HeLa). Structure activity relationship was elucidated by varying different substituents on benzothiazoles and pyrazoles. Further, flow cytometric analysis revealed that these derivatives induced cell cycle arrest in G2/M phase and spectroscopic studies such as UV-visible, fluorescence and circular dichroism studies showed that these derivatives exhibited good DNA binding affinity. Additionally, these derivatives can effectively inhibit the topoisomerase I activity. Viscosity studies and molecular docking studies demonstrated that the derivatives bind with the minor groove of the DNA.

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.

1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential anticancer agents.

A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 ∼6-10µM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60-70% at 10µM) that was supported by the docking studies (PLP score 87-94) in silico.

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.

Biological evaluation of 3-hydroxybenzyl alcohol, an extrolite produced by Aspergillus nidulans strain KZR-132.

AIMS: The aim of the study was to purify and characterize a bioactive compound from Aspergillus nidulans strain KZR-132 and its biological evaluation. METHODS AND RESULTS: A bioactive extolite was purified from A. nidulans strain KZR-132, and its chemical structure was elucidated as 3-hydroxylbenzyl alcohol (3-HBA) based on 1 H and 13 C NMR, FT-IR and mass spectroscopic analysis. The antimicrobial efficacy of 3-HBA was established against Gram-positive, Gram-negative bacteria and different Candida strains. It also showed promising antibiofilm activity against various tested microbial strains. Reactive oxygen species induced by 3-HBA treatment on different Candida strains killed most of the cells and showed necrotic effect. It also exhibited dose-dependent antioxidant and anti-inflammatory activities. CONCLUSIONS: This bioactive extrolite produced by A. nidulans isolated from a niche habitat was demonstrated to possess significant biotechnological and pharmacological potential since it exhibited broad-spectrum antimicrobial and antibiofilm activities which are reported for the first time. SIGNIFICANCE AND IMPACT OF THE STUDY: The overall study demonstrates that 3-HBA produced by A. nidulansKZR-132 is a promising bioactive metabolite and possibly can function as a pharmacologically suitable broad-spectrum antimicrobial drug candidate against various dreaded human-related bacterial and fungal pathogens.

Synthesis, characterization, antimicrobial and biofilm inhibitory studies of new esterquats.

Novel esterquats (monoesterquats and diesterquats) were synthesized from 11-bromo undecanoic acid (11-BUA) and different alkyl amines. The prepared compounds were characterized by FT-IR, (1)H NMR, (13)C NMR and mass spectral analysis. 11-BUA was converted into methyl 11-bromo undecanoate which was further converted into amine ester (amine monoester and diester) by reacting with different aliphatic amines (hexyl, dodecyl, octadecyl, dioctyl and dicyclohexyl amine). Finally, the obtained amine esters were converted into esterquats (monoesterquat and diesterquat) by reacting with methyl iodide followed by ion exchange to afford chloride counter ion esterquats (5a-h). The synthesized esterquat products were studied for their antimicrobial and biofilm inhibitory activities. Among all the compounds, amine ester 3a and esterquat 5d showed potent antimicrobial activity towards pathogenic Gram-positive bacterial strains with minimum inhibitory concentration (MIC) values in the range of 3.9-15.6 µg mL(-1) and 1.9-7.8 µg mL(-1), respectively. The esterquat 5d also showed promising antifungal activity against Candida albicans MTCC 3017, Candida albicans MTCC 4748 and Candida aaseri MTCC 1962 strains with MIC value of 7.8 µg mL(-1) which was identical to standard Miconazole. The compounds which exhibited antimicrobial activity were also effective in anti-biofilm activity and it was found that compound 5d exhibited excellent biofilm inhibitory activity with IC50 value of 0.9 µg mL(-1) against Staphylococcus aureus MLS16 MTCC 2940.

Synthesis of novel ethyl 1-ethyl-6-fluoro-7-(fatty amido)-1,4-dihydro-4-oxoquinoline-3-carboxylate derivatives and their biological evaluation.

A series of novel ethyl 1-ethyl-6-fluoro-7-(fatty amido)-1,4-dihydro-4-oxoquinoline-3-carboxylate derivatives were prepared through multistep synthesis. The key step in the synthesis was to obtain the C-7 fatty amide derivative. The azide was selectively formed at C-7 position using sodium azide at 60°C. Subsequently, the azide was reduced under mild conditions using zinc and ammonium chloride to form the corresponding amine. The synthesized derivatives were further subjected to biological evaluation studies like cytotoxicity against a panel of cancer cell lines such as DU145, A549, SKOV3, MCF7 and normal lung cells, IMR-90 as well as with antimicrobial and antioxidant activities. It was observed that the carboxylated quinolone derivatives with hexanoic (8a), octanoic (8b), lauric (8d) and myristic (8e) moieties exhibited promising cytotoxicity against all the tested cancer cell lines. The results also suggested that hexanoic acid-based fatty amide carboxylated quinolone derivative (8a) exhibited promising activity against both bacterial and fungal strains and significant antibacterial activity was observed against Staphylococcus aureus MTCC 96 (MIC value of 3.9µg/mL). The compound 8a also showed excellent anti-biofilm activity against Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121 with MIC values of 2.1 and 4.6µg/mL, respectively.

A diastereoselective synthesis of tetrahydro- and dihydro-pyrido[2,3-c]coumarin derivatives via a one-pot three-component Povarov reaction catalyzed by bismuth(III) chloride.

A diastereoselective synthesis of tetrahydro- and dihydro-pyrido[2,3-c]coumarin derivatives has been achieved via a one-pot three-component aza-Diels-Alder reaction of aromatic aldehydes, 3-aminocoumarin and dienophiles catalyzed by BiCl3. NOE studies proved that exo-isomers were obtained in all cases with high selectivity. The reaction proceeded at room temperature providing good yields of products as well as applicability on a wide range of substrates. Among all the synthesized derivatives, compounds 4i and 4k showed promising DPPH radical scavenging activity as compared to other tested derivatives.

Synthesis, DNA binding affinity and anticancer activity of novel 4H-benzo[g][1,2,3]triazolo[5,1-c][1,4]oxazocines.

A new class of tricyclic heterocycles 4H-benzo[g][1,2,3]triazolo[5,1-c][1,4]oxazocines was synthesized through a Knoevenagel condensation/azide-alkyne cycloaddition reaction cascade in one-pot operation. These eight membered ring containing heterocycles exhibited moderately high anticancer activity against four cancer cell lines; human cervix cancer cell line (HeLa), human prostate cancer cell line (DU145), human breast cancer cell line (MCF-7) and human breast adenocarcinoma epithelial cell line (MDA-MB-231). Our results indicate that these compounds have a weak cytotoxic effect on normal human mammary epithelial cell line (MCF-10A). Cell cycle and apoptosis assay indicate that they inhibit the cell cycle at the G2/M phase and induce apoptosis. Through the RED100 assay, it is evident that they have potential to inhibit pBR 322 plasmid DNA cleavage by BamH1. UV-visible, fluorescence titration and viscosity studies suggested that these compounds possess DNA binding affinity.

Synthesis of novel amide functionalized 2H-chromene derivatives by Ritter amidation of primary alcohol using HBF4·OEt2 as a mild and versatile reagent and evaluation of their antimicrobial and anti-biofilm activities.

A series of novel amide functionalized 2H-chromene derivatives 3 were prepared starting from ethyl-2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate 1 via sodium borohydride reduction followed by Ritter amidation using HBF4·OEt2 as a mild and versatile reagent. All the products 3 were screened for antimicrobial activity against various Gram-positive, Gram-negative bacteria and fungal strain. The promising derivatives such as 3f, 3g, 3k, 3l, 3m, 3n and 3o were further screened for minimum bactericidal concentration and bio-film inhibition activity and identified the potential ones. Among all the promising, compound 3g was more potent for antimicrobial, MBC and anti bio-film activities. The structure verses activity relationship of 3g revealed that the presence of two bromine atoms at sixth and R position promotes high activity.

One-pot catalyst free synthesis of novel kojic acid tagged 2-aryl/alkyl substituted-4H-chromenes and evaluation of their antimicrobial and anti-biofilm activities.

A number of 3-hydroxy-6-(hydroxymethyl)-2-(2-phenyl-4H-chromen-4-yl)-4H-pyran-4-ones (3) have been synthesized in a one pot catalyst free reaction of 2-hydroxy chalcone (1) with kojic acid (2) in toluene at reflux temperature and evaluated for antimicrobial and anti-biofilm activities. Compounds 3a, 3e, 3f, 3l showed potent antimicrobial activity against Staphylococcus aureus MLS-16 MTCC 2940, Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739, whereas 3b and 3k exhibited excellent activity against Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739, while 3g showed promising activity against Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739. On the other hand, compounds 3a, 3b and 3l showed very good anti-biofilm activity and 3g showed moderate activity against Bacillus subtilis MTCC 121. Whereas, compounds 3a and 3f showed moderate activity against Escherichia coli MTCC 739, while compounds 3a, 3b, 3k and 3l displayed similar activity against Staphylococcus aureus MLS-16 MTCC 2940.

Design of new hybrid template by linking quinoline, triazole and dihydroquinoline pharmacophoric groups: A greener approach to novel polyazaheterocycles as cytotoxic agents.

A new hybrid template designed by linking three pharmacophoric groups, for example, quinoline, triazole and dihydroquinoline moieties have been used for the generation of a library of molecules as potential cytotoxic agents. Synthesis of these polyazaheterocycles were carried out by using a strategy that involved one-pot sequential azidation and CuAAC in water under mild conditions. A number of 1,4-disubstituted 1,2,3-triazoles possessing quinolinylmethylene at N-1 and 1,2-dihydroquinolinyl methylene at C-4 as different substituents were synthesized and evaluated for their cytotoxic effects against various cancer cells. Some of them showed encouraging activities against lung cancer cells and one of them showed inhibition of PDE4 indicating the potential medicinal value of these novel polyazaheterocycles.

Regioselective synthesis, antimicrobial evaluation and theoretical studies of 2-styryl quinolines.

2-Styryl quinolines (9a-l) have been synthesized regioselectively from 2-methyl-quinoline by using NaOAc in water acetic acid binary solvents and evaluated for their antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the compounds 12 and 8 were found to be active against both bacterial strains. Compounds 9b, 9f, 9g, 9i, 9j and 9k were the most active among the series exhibiting MIC values ranging between 1.9 and 31.2 µg ml(-1) against different bacterial strains. Compounds 9j and 9k were found to be as potent as the standard drug ciprofloxacin against Micrococcus luteus, Klebsiella planticola and Staphylococcus aureus. In addition, the compounds showed bactericidal activity; compound 9j was found to be better than ciprofloxacin, with an MBC value of 0.9 µg ml(-1) against both M. luteus and K. planticola. The compounds also inhibited biofilm formation, and compound 9j was found to be equipotent to erythromycin against M. luteus and S. aureus MLS16. Further, theoretical studies such as those on druggable properties and PMI plot have been carried out.

Stereoselective total synthesis of a novel regiomer of herbarumin I and its cytotoxic and antimicrobial activities.

Stereoselective synthesis of a novel regiomer of the natural nonenolide, herbarumin I has been accomplished. The synthesis involves the coupling of the alcohol and acid fragments of the molecule using Yamaguchi protocol followed by intramolecular ring closing metathesis. The cytotoxic and antimicrobial properties of the synthetic regiomer have been studied.

Green synthesis of Kocuran-functionalized silver glyconanoparticles for use as antibiofilm coatings on silicone urethral catheters.

Microbial infections due to biofilm formation on medical implants are serious complications arising after surgery which can be prevented by using antimicrobial coatings on biomaterial surfaces. We developed a simple, rapid and green chemistry approach for synthesis of silver glyconanoparticles (AgNPs) using Kocuran, an exopolysaccharide produced by Kocuria rosea strain BS-1. Kocuran-capped AgNPs exhibited a characteristic surface plasmon resonance (SPR) peak around 435 nm. They were mono-dispersed, spherical with an average particle size of 12 nm. XRD and SAED studies suggested that AgNPs were crystalline in nature. AgNPs had a zeta potential of -33.9 mV and were anionic charged. They showed colloidal stability at different pH (6 to 10), temperatures (30 °C to 100 °C), in NaCl, NaNO3 and BSA solutions. Kocuran-capped AgNPs exhibited effective antimicrobial activity against Staphylococcus aureus and Escherichia coli and cell death was mainly due to hydroxyl radical induction and depletion of NADH. They also inhibited the biofilm development by S. aureus and E. coli and confocal scanning laser microscopic images revealed the damage of intact cell architecture. In vitro evaluation of Kocuran-capped silver glyconanoparticles on human gingival fibroblasts demonstrated good cell proliferation as compared to commercial AgNPs suggesting that they are biocompatible and non-toxic in nature. This is a first report on Kocuran-functionalized AgNPs exhibiting potential antibacterial and antiadhesive properties for use as antimicrobial coatings against bacterial adhesion and biofilm formation on silicone urethral catheters.

A new strategy for the synthesis of crucigasterin A, and cytotoxic activity of this compound and its related analogues.

Stereoselective total synthesis of bioactive marine natural product crucigasterin A has been accomplished from commercially available and inexpensive L-(-)-malic acid as a starting material. Julia olefination and chelation controlled Grignard additions are the key steps involved in the present synthesis. Cytotoxic properties of crucigasterin A and its related analogues crucigasterins B and D have been evaluated. Crucigasterin A showed promising activities against both the human cervical cancer cell line and human breast adenocarcinoma cell line.

Synthesis of new chromeno-annulated cis-fused pyrano[4,3-c]isoxazole derivatives via intramolecular nitrone cycloaddition and their cytotoxicity evaluation.

New cis-fused chromeno pyrano[4,3-c]isoxazole derivatives have been synthesized by intramolecular [1,3]-cycloaddition of the nitrones generated in situ from hydroxylamine derivatives and 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones using PEG-400 as a reaction medium under catalyst-free conditions good to excellent yields. The structures were established by spectroscopic data and further confirmed by X-ray diffraction analysis. The results showed that compounds 4b, 4c, 4d, 4e and 4k exhibit very potent antiproliferative activity against MDA-MB-231 breast cancer cells. Compounds 4a, 4c, 4e, 4i and 4k displayed potent inhibitory activity against human MCF-7 breast cancer cell lines. Compounds 4h and 4i exhibited significant anti-proliferative activity against human cervical cancer cell line, HeLa. While 4b, 4d and 4j were active against human lung cancer cell line, A549. In addition, Compound 4j was found to be the most promising against A549 (Lung cancer) with IC50 value of 0.194 µM.