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Alzheimer's disease (AD) is the most common form of dementia, a general term for memory loss and other cognitive abilities. This disorder is well associated with an impairment in cholinergic transmission. Therefore, cholinesterase inhibition leads to revert of putative deficit in acetylcholine levels in AD and thus might reverse the memory impairment characteristics. A series of compounds were rationally designed by taking donepezil as a lead molecule by using molecular modeling studies. All the designed compounds were analyzed by calculating their dock scores to check their probable binding affinities within the active site of acetylcholinesterase enzyme. Among all the compounds, six compounds showed significant dock score within the active site of enzyme which suggest that these molecules could effectively block the catalytic activity of enzyme. Compounds with nitro groups on the terminal benzyl moiety were found to be most prominent ones and could act as hit lead for the further development of acetylcholinesterase inhibitors. In silico study of all the compounds were also performed by using computational Marvin Sketch software which describes the compliance of all the designed compounds with the Lipinski rule of five. Furthermore, potent compounds were synthesized and characterized by using 1H & 13C NMR and MASS spectroscopic techniques were sent for further biological evaluations.

Background Topoisomerases are a set of nuclear enzymes that play a vital role in handling of topological consequences of DNA during various genetic activities necessary for vitality of cell. Inhibition of these enzymes consequently leads to the blockage of ligation step of the cell cycle which generates single and double strand breakage in DNA strand. Introduction of these breaks subsequently leads to programmed cell death (Apoptosis). Objective In the past several years, topoisomerases have become one of the most expedient and strategic molecular targets for anticancer drugs and numerous patents have been filed and published on topoisomerase inhibitors. This review compiles the patent literature up to 2016 embracing topo I and II inhibitors as well as dual inhibitors which are structurally adjacent to camptothecin (CPT), natural products such as lamellarins and synthetic trisubstituted pyridines. The present assemblage can be extremely advantageous for the medicinal chemists who are in crave for the development of potential anticancer agents targeting topoisomerases. Conclusion Recent patents indicated that some of the nitrogen containing heteroaromatic compounds have immense potential to inhibit topoisomerase enzyme. In particular, fused N-Heterocycles can be anticipated for their promising therapeutic potential alone or in combination with other anticancer agents. Naphthyridinone and indenoisoquinoline derivatives, described in the preceding sections of this review, are endowed with significant potency against topoisomerase I which clearly indicates the need of preclinical and clinical studies to place them in forefront as potential future drug candidates.

Aims: The current study is focused on the design and synthesis of 4-aryl/heteroaryl-4H-fused pyrans as anti-proliferative agents. All the synthesized molecules were screened against a panel of human carcinoma cell lines. Description: Significant inhibition was exhibited by the compounds against HCT-116 (Colon) and PC-3 (Prostate) cell lines while A-549 (Lung) cell lines, MiaPaCa-2 (Pancreatic) cell lines and HL-60 (Leukemia Cancer) cell lines were almost resistant to the exposure of the test compounds. Compound FP-(v)n displayed noteworthy cytotoxicity towards HCT-116 malignant cells with the IC50 value of 0.67 µM. It induces apoptosis as revealed by several biological endpoints like apoptotic body formation, through DAPI staining, phase contrast microscopy and mitochondrial membrane potential loss. Moreover FP-(v)n is a potent apoptotic inducer confirmed by cell cycle arrest and ROS generation. The cell phase distribution studies indicate an augment from 4.94 % (control sample) to 39.68 % (sample treated with 1.5 µM compound FP-(v)n) in the apoptotic population. Compound FP-(v)n inhibits the tumor growth in Ehrlich ascites carcinoma (EAC), Ehrlich Tumor (ET, solid) and sarcoma-180 (solid) mice models. Additionally, it was established to be non-toxic at maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Conclusion: The current study provides an insight into anti-cancer potential of FP-(v)n, which might be valuable in the treatment of tumor.

The present study involves the design of a series of 3-aryl-9-acetyl-pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76 μM. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41 μM against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.

A Hybrid drug which comprises the incorporation of two drug pharmacophores in one single molecule are basically designed to interact with multiple targets or to amplify its effect through action on another bio target as one single molecule or to counterbalance the known side effects associated with the other hybrid part(.) The present review article offers a detailed account of the design strategies employed for the synthesis of anticancer agents via molecular hybridization techniques. Over the years, the researchers have employed this technique to discover some promising chemical architectures displaying significant anticancer profiles. Molecular hybridization as a tool has been particularly utilized for targeting tubulin protein as exemplified through the number of research papers. The microtubule inhibitors such as taxol, colchicine, chalcones, combretasatin, phenstatins and vinca alkaloids have been utilized as one of the functionality of the hybrids and promising results have been obtained in most of the cases with some of the tubulin based hybrids exhibiting anticancer activity at nanomolar level. Linkage with steroids as biological carrier vector for anticancer drugs and the inclusion of pyrrolo [2,1-c] [1,4]benzodiazepines (PBDs), a family of DNA interactive antitumor antibiotics derived from Streptomyces species in hybrid structure based drug design has also emerged as a potential strategy. Various heteroaryl based hybrids in particular isatin and coumarins have also been designed and reported to posses' remarkable inhibitory potential. Apart from presenting the design strategies, the article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of the hybrids.

A series of naphthopyrans was synthesized employing silica supported fluoroboric acid under solvent free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesised compounds were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have also been presented. Among the synthesised compounds, NP-17, NP-19, NP-20, NP-23, NP-24, NP-25 and NP-26 were the active inhibitors with an IC50 ranging from 4 to 17 μM. Compound NP-19 with a thiophenyl ring at position 1 emerged as the most potent xanthine oxidase inhibitor (IC50=4 μM) in comparison to allopurinol (IC50=11.10 μM) and febuxostat (IC50=0.025 μM). The basis of significant inhibition of xanthine oxidase by NP-19 was rationalized by its molecular docking at MTE binding site of xanthine oxidase.

A library of 3,4,6,7-tetrahydro-3,3,6,6-tetramethyl-9,10-diphenylacridine-1,8-dione derivatives were synthesized via microwave-assisted three-component reaction employing silica supported sulphuric acid under solvent free conditions and tested for in vitro cholesterol esterase inhibitory activity. All synthesized compounds exhibited moderate to good inhibition of cholesterol esterase enzyme. Among all the synthesized acridinedione derivatives, compound HSM-1a showed the most promising activity with IC50 value of 1.53 µM against cholesterol esterase enzyme. Enzyme kinetic studies carried out for HSM-1a, revealed its mixed-type inhibition approach. Molecular protein–ligand docking studies were also performed to figure out the key binding interactions of HSM-1a with the amino acid residues of the enzyme’s active site. Furthermore, acquiescence of some potent compounds to the Lipinski rule was also determined.

Kinases control a diverse set of cellular processes comprising of reversible phosphorylation of proteins. Protein kinases play a pivotal role in human tumor cell proliferation, migration and survival of neoplasia. In the recent past, purine based molecules have emerged as significantly potent kinase inhibitors. In view of their promising potential for the inhibition of kinases, this review article focuses on purines which have progressed as kinase inhibitors during the last five years. A detailed account of the design strategies employed for the synthesis of purine analogs exerting inhibitory effects on diverse kinases has been presented. Apart from presenting the design strategies, the article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of the purine analogs for kinase inhibition. The interactions with the amino acid residues responsible for kinase inhibitory potential of purine based molecules have also been discussed. In this assemblage, purine based protein kinase inhibitors patented in the past have also been summarized in the tabular form. This compilation will be of great interest for the researchers working in the area of protein kinase inhibitors.

A series of twenty-two compounds of thiazole-5-carboxylic acid derivatives was rationally designed and synthesized. All the compounds were characterized by using 1H & 13C NMR and tested against xanthine oxidase enzyme by spectrophotometric assay. Majority of the compounds were found active against the enzyme amongst which GK-20 with an IC50 value of 0.45 μM was found to be most potent. Structure-activity relationship obtained from the biological results revealed that the di-substituted compounds as Ring B were more potent than that of mono- substituted derivatives. Para-substitution on Ring B is crucial for the xanthine oxidase inhibitory potential. Enzyme kinetic studies further revealed their mixed type inhibition behaviour. Moreover, the binding pattern of the most potent compound GK-20 within the febuxostat binding site of the enzyme was further analyzed by using docking studies which revealed that it sufficiently block the catalytic active site which prevents the substrate to bind.

Kinases control a diverse set of cellular processes comprising of reversible phosphorylation of proteins. Protein kinases play a pivotal role in human tumor cell proliferation, migration and survival of neoplasia. In the recent past, purine based molecules have emerged as significantly potent kinase inhibitors. In view of their promising potential for the inhibition of kinases, this review article focuses on purines which have progressed as kinase inhibitors during the last five years. A detailed account of the design strategies employed for the synthesis of purine analogs exerting inhibitory effects on diverse kinases has been presented. Apart from presenting the design strategies, the article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of the purine analogs for kinase inhibition. The interactions with the amino acid residues responsible for kinase inhibitory potential of purine based molecules have also been discussed. In this assemblage, purine based protein kinase inhibitors patented in the past have also been summarized in the tabular form. This compilation will be of great interest for the researchers working in the area of protein kinase inhibitors.

The present study involves the design and synthesis of naphthoflavones as antiproliferative agents. The strategy presents naphthoflavones as hybrids of naphthyl based chalcones and flavones. A panel of human cancer cell lines were employed for the cytotoxicity studies. DK-13 exhibited significant cytoxicity against MiaPaCa-2 cell lines with IC50 value of 1.93 μM and 5.63 μM against MCF-7 cell lines. The compound DK-13 was found to induce apoptosis evidenced through phase contrast microscopy, DAPI staining, and mitochondrial membrane potential loss. The cell phase distribution studies indicated an increase from 11.26 % (control sample) to 55.19 % (sample treated with 20 μM compound DK-13) in the apoptotic population.

Keeping in view the recent success of molecular hybridization technique in drug design, 2,4-diarylpyrano[3,2-c]chromen-5(4H)-ones as conjugates of coumarins and chalcones have been designed and synthesized in the present study. The catalytic efficiency of various Lewis acids for the synthesis of designed conjugates under neat conditions was investigated, and SiO2 (200–400 mesh)-ZnCl2 was optimized as the best catalyst among the tested ones. The conjugates were evaluated for in-vitro xanthine oxidase activity. The results of the in-vitro assay were quite promising as some conjugates were endowed with remarkable inhibitory potential against the enzyme. HV-8, 11 and 12 were found to be high-potent inhibitors with HV-11 (the most potent inhibitor) possessing an IC50 value of 2.21 µM. The most active conjugate HV-11 was evaluated for the type of inhibition and was found to be a mixed type inhibitor. The compliance of some selected conjugates to the Lipinski rule was also calculated.

4,6-diarylpyrimidones as constrained chalcone analogues have been synthesised in the present study. The synthesised compounds were evaluated against a panel of human cancer cell lines. Striking selectivity was displayed by the compounds against MiaPaCa (Pancreatic) cell lines while PC-3 (prostate) and A-549 (lung) cell lines were almost resistant to the exposure of the test compounds. Compound SK – 25 exhibited remarkable cytotoxicity against MiaPaca-2 cell line with an IC 50 value of 1.95 µM and was found to induce apoptosis evidenced through phase contrast microscopy, DAPI staining and mitochondrial membrane potential loss. The cell phase distribution studies indicated that the apoptotic population increased from 1.79% in control sample to 30.33 % in sample treated with 20 µM compound SK-25.

A Hybrid drug which comprises the incorporation of two drug pharmacophores in one single molecule are basically designed to interact with multiple targets or to amplify its effect through action on another bio target as one single molecule or to counterbalance the known side effects associated with the other hybrid part(.) The present review article offers a detailed account of the design strategies employed for the synthesis of anticancer agents via molecular hybridization techniques. Over the years, the researchers have employed this technique to discover some promising chemical architectures displaying significant anticancer profiles. Molecular hybridization as a tool has been particularly utilized for targeting tubulin protein as exemplified through the number of research papers. The microtubule inhibitors such as taxol, colchicine, chalcones, combretasatin, phenstatins and vinca alkaloids have been utilized as one of the functionality of the hybrids and promising results have been obtained in most of the cases with some of the tubulin based hybrids exhibiting anticancer activity at nanomolar level. Linkage with steroids as biological carrier vector for anticancer drugs and the inclusion of pyrrolo [2,1-c] [1,4]benzodiazepines (PBDs), a family of DNA interactive antitumor antibiotics derived from Streptomyces species in hybrid structure based drug design has also emerged as a potential strategy. Various heteroaryl based hybrids in particular isatin and coumarins have also been designed and reported to posses' remarkable inhibitory potential. Apart from presenting the design strategies, the article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of the hybrids.

The screening of the in vitro xanthine oxidase inhibitory potential of the title compounds (IV) shows that compound (IVj) is a potential inhibitor of xanthine oxidase.

In view of reported xanthine oxidase inhibitory potential of naphthopyrans and flavones, naphthoflavones as hybrids of the two were designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity in the present study. The results of the assay revealed that the naphthoflavones possess promising inhibitory potential against the enzyme with IC50 values ranging from 0.62 to 41.2 μM. Structure activity relationship indicated that the nature and placement of substituents on the phenyl ring at 2nd position remarkably influences the inhibitory activity. Substitution of halo and nitro groups at ortho and para position of the phenyl ring (2nd position) remarkably favored the activity. NF-4 with p-fluoro phenyl ring was the most potent inhibitor with IC50 value of 0.62 μM. Enzyme kinetics study was also performed to investigate the inhibition mechanism and it was found that the naphthoflavones displayed mixed type inhibition. The basis of significant inhibition of xanthine oxidase by NF-4 was rationalized by molecular modeling studies.

The petroleum ether (PE), chloroform (CH), ethanol (ETH) and water extracts of E. arvense stems were evaluated for anti-anxiety activity in mice using elevated plus maze model. Ketamine induced hypnosis and actophotometer was used to evaluate sedative effect with various extracts in mice. The results were compared with standard drug diazepam. The ethanolic extract of E. arvense (50 and 100 mg/kg) significantly increased the time-spent and the percentage of the open arm entries in the elevated plus-maze model which was comparable to diazepam. Ethanolic extract (100 mg/kg) prolonged the ketamine-induced total sleeping time and decreased the locomotor activity in mice. The results suggest that the ethanolic extract of E. arvense seems to possess anxiolytic effect with lower sedative activity than that of diazepam. The results could be attributed to the flavonoid content of the ethanolic extract.