Synthesis and screening of novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines as antiproliferative and tubulin polymerization inhibitors.

Colchicine binding site represent a crucial target for the anticancer drug development especially in view of emerging drug resistance from the currently available chemotherapeutics. A total of 16 novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines were synthesized and screened for antiproliferative and tubulin polymerization inhibition potential. The synthesized compounds were evaluated against MCF-7, HeLa and HT-29 cancer cell lines and normal cell line HEK-293 T. In the series, 2­aryl group with 4­bromophenyl substitution displayed IC50 values of 6.37 µM, 17.43 µM, 6.76 µM and 4­chlorophenyl substitution displayed IC50 values of 2.16 µM, 8.53 µM, 10.42 µM against MCF-7, HELA and HT29 cancer cell lines, respectively. In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, both the lead compounds were found to induce mitochondria mediated apoptosis and lead molecule with 4­chlorophenyl substitution displayed significant tubulin polymerization inhibition activity. In the computation studies, lead molecule displayed significant binding affinites in the colchicine domain and showed good thermodynamic stability during 100 ns MD simulation studies. 4-N-Heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines showed appreciable drug like characteristics and can be developed as potent anticancer agents.

Virtual screening and molecular dynamics simulation approach for the identification of potential multi-target directed ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurological disorder characterized by memory loss and cognitive impairment. The currently available single-targeting drugs have miserably failed in the treatment of AD, and multi-target directed ligands (MTDLs) are being explored as an alternative treatment strategy. Cholinesterase and monoamine oxidase enzymes are reported to play a crucial role in the pathology of AD, and multipotent ligands targeting these two enzymes simultaneously are under various phases of design and development. Recent studies have revealed that computational approaches are robust and trusted tools for identifying novel therapeutics. The current research work is focused on the development of potential multi-target directed ligands that simultaneously inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) enzymes employing a structure-based virtual screening (SBVS) approach. The ASINEX database was screened after applying pan assay interference and drug-likeness filter to identify novel molecules using three docking precision criteria; High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP). Additionally, binding free energy calculations, ADME, and molecular dynamic simulations were employed to get structural insights into the mechanism of protein-ligand binding and pharmacokinetic properties. Three lead molecules viz. AOP19078710, BAS00314308 and BDD26909696 were successfully identified with binding scores of -10.565, -10.543 & -8.066 kcal/mol against AChE and -11.019, -12.357 & -10.068 kcal/mol against MAO-B, better score as compared to the standard inhibitors. In the near future, these molecules will be synthesized and evaluated through in vitro and in vivo assays for their inhibition potential against AChE and MAO-B enzymes.

Exploring anticancer properties of the phytoconstituents and comparative analysis of their chemical space parameters with USFDA-approved synthetic anticancer agents.

The present review article thoroughly analyses natural products and their derived phytoconstituents as a rich source of plausible anticancer drugs. The study thoroughly explores the chemical components derived from various natural sources, thus emphasizing their unique structural characteristics and therapeutic potential as an anticancer agent. The review contains the critical chemical constituents' in-depth molecular mechanisms, their source's chemical structures and the categories. The review also comprises an exhaustive and comprehensive analysis of different chemical spacing parameters of the anticancer agents derived from natural products. It compares them with USFDA-approved synthetic anticancer drugs up to 2020, thus providing a meaningful understanding of the relationship between natural and synthetic compounds portraying the anticancer assets. The review also delves more deeply into the chemical analysis of the heterocyclic moieties from the natural product arena, illustrating the anticancer mechanisms. The present article is, therefore, expected to serve as a valuable resource for natural product and medicinal chemists, encouraging and promoting an integrated approach to exploit the potential of natural products in drug discovery development and translational research, which have a prerequisite of bench to bedside approach. The work could guide researchers toward innovative approaches for the ever-evolving field of anticancer drug discovery.

Iodine-PEG as a unique combination for the metal-free synthesis of flavonoids through iodonium-triiodide ion-pair complexation.

An efficient metal-free single-step protocol has been developed for the direct synthesis of flavones from 2-hydroxyacetophenone and substituted benzaldehydes. This chemical transformation is exclusively promoted by the iodonium-triiodide ion couple formed through iodine and PEG-400 complexation. The triiodide anion not only helps in the abstraction of a proton from the acetophenone but also promotes the cyclization of intermediate chalcone to the corresponding flavones. The flavones were obtained in very high yields without using any toxic metal catalysts or harsh reaction conditions. The reaction mechanism was established through a series of test reactions and entrapping of reaction intermediates. The developed protocol provides direct access to flavones in high yields under milder reaction conditions with great substrate compatibility, including hydroxylated derivatives.

In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model.

Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid ß aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 µM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 µM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aß1-42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 µM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 µM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aß1-42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.

Benzotriazole Substituted 2-Phenylquinazolines as Anticancer Agents: Synthesis, Screening, Antiproliferative and Tubulin Polymerization Inhibition Activity.

AIMS: Development of anticancer agents targeting tubulin protein. BACKGROUND: Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. OBJECTIVE: Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. METHODS: A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. RESULTS: ARV-2 with IC50 values of 3.16 µM, 5.31 µM, 10.6 µM against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. CONCLUSION: The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents.

Caesium carbonate promoted regioselective O-functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions and mechanistic insight.

A facile one-step catalyst free methodology has been developed for the regioselective functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions. Selectivity towards the O-regioisomer was achieved by using Cs2CO3 in DMF without use of any coupling reagents. A total of 14 regioselective O-alkylated 4,6-diphenylpyrimidines were synthesized in 81-91% yield. In the DFT studies it was observed that the transition state for the formation of the O-regioisomer is more favourable with Cs2CO3 as compared to K2CO3. Furthermore, this methodology was extended to increase the O/N ratio for the alkylation of 2-phenylquinazolin-4(3H)-one derivatives.

Multi-Target-Directed Ligands as an Effective Strategy for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurological disorder and multiple pathological factors are believed to be involved in the genesis and progression of the disease. A number of hypothesis including Acetylcholinesterase, Monoamine oxidase, ß- Amyloid, Tau protein etc. have been proposed for the initiation and progression of the disease. At present, acetylcholine esterase inhibitors and memantine (NMDAR antagonist) are the only approved therapy for the symptomatic management of AD. Most of these single-target drugs have miserably failed in the treatment or halting the progression of the disease. Multi-factorial diseases like AD require complex treatment strategies that involve simultaneous modulation of a network of interacting targets. Since last few years, Multi-Target-Directed Ligands (MTDLs) strategy, drugs that can simultaneously hit multiple targets, is being explored as an effective therapeutic approach for the treatment of AD. In the current review article, the authors have briefly described various pathogenic pathways associated with the AD. Importance of Multi-Target-Directed Ligands and their design strategies in recently reported articles have been discussed in detail. Potent leads identified through various structure-activity relationship studies and their drug like characteristics are described. Recently developed promising compounds have been summarized in the article. Some of these MTDLs with balanced activity profile against different targets have the potential to be developed as drug candidates for the treatment of AD.

Morpholine substituted quinazoline derivatives as anticancer agents against MCF-7, A549 and SHSY-5Y cancer cell lines and mechanistic studies.

A series of morpholine substituted quinazoline derivatives have been synthesized and evaluated for cytotoxic potential against A549, MCF-7 and SHSY-5Y cancer cell lines. These compounds were found to be non-toxic against HEK293 cells at 25 µM and hence display anticancer potential. In these series compounds, AK-3 and AK-10 displayed significant cytotoxic activity against all the three cell lines. AK-3 displayed IC50 values of 10.38 ± 0.27 µM, 6.44 ± 0.29 µM and 9.54 ± 0.15 µM against A549, MCF-7 and SHSY-5Y cancer cell lines. Similarly, AK-10 showed IC50 values of 8.55 ± 0.67 µM, 3.15 ± 0.23 µM and 3.36 ± 0.29 µM against A549, MCF-7 and SHSY-5Y, respectively. In the mechanistic studies, it was found that AK-3 and AK-10 inhibit the cell proliferation in the G1 phase of the cell cycle and the primary cause of death of the cells was found to be through apoptosis. Thus, morpholine based quinazoline derivatives have the potential to be developed as potent anticancer drug molecules.

Design, Synthesis, and Pharmacological Evaluation of N-Propargylated Diphenylpyrimidines as Multitarget Directed Ligands for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a multifactorial complex neural disorder, is categorized with progressive memory loss and cognitive impairment as main clinical features. The multitarget directed ligand (MTDL) strategy is explored for the treatment of multifactorial diseases such as cancer and AD. Herein, we report the synthesis and screening of 24 N-propargyl-substituted diphenylpyrimidine derivatives as MTDLs against acetylcholine/butyrylcholine esterases and monoamine oxidase enzymes. In this series, VP1 showed the most potent MAO-B inhibitory activity with an IC50 value of 0.04 ± 0.002 µM. VP15 with an IC50 value of 0.04 ± 0.003 µM and a selectivity index of 626 (over BuChE) displayed the most potent AChE inhibitory activity in this series. In the reactive oxygen species (ROS) inhibition studies, VP1 reduced intercellular ROS levels in SH-SY5Y cells by 36%. This series of compounds also exhibited potent neuroprotective potential against 6-hydroxydopamine-induced neuronal damage in SH-SY5Y cells with up to 90% recovery. In the in vivo studies in the rats, the hydrochloride salt of VP15 was orally administered and found to cross the blood-brain barrier and reach the target site. VP15·HCl significantly attenuated the spatial memory impairment and improved the cognitive deficits in the mice. This series of compounds were found to be irreversible inhibitors and showed no cytotoxicity against neuronal cells. In in silico studies, the compounds attained thermodynamically stable orientation with complete occupancy at the active site of the receptors. Thus, N-propargyl-substituted diphenylpyrimidines displayed drug-like characteristics and have the potential to be developed as MTDLs for the effective treatment of AD.

Role of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Different Disease States: Recent Updates.

Peroxisome proliferator-activated receptor (PPAR), a ligand dependant transcription factor, is a member of the nuclear receptor superfamily. PPAR exists in three isoforms i.e. PPAR alpha (PPARα), PPAR beta (PPARß), and PPAR gamma (PPARγ). These are multi-functional transcription factors and help in regulating inflammation, type 2 diabetes, lipid concentration in the body, metastasis, and tumor growth or angiogenesis. Activation of PPARγ causes inhibition of growth of cultured human breast, gastric, lung, prostate, and other cancer cells. PPARγ is mainly involved in fatty acid storage, glucose metabolism, and homeostasis and adipogenesis regulation. A large number of natural and synthetic ligands bind to PPARγ and modulate its activity. Ligands such as thiazolidinedione, troglitazone, rosiglitazone, pioglitazone effectively bind to PPARγ; however, most of these were found to display severe side effects such as hepatotoxicity, weight gain, cardiovascular complications and bladder tumor. Now the focus is shifted towards the development of dual-acting or pan PPAR ligands. The current review article describes the functions and role of PPARγ in various disease states. In addition, recently reported PPARγ ligands and pan PPAR ligands were discussed in detail. It is envisaged that the present review article may help in the development of potent PPAR ligands with no or minimal side effects.

Targeting Cancer Stem Cells Pathways for the Effective Treatment of Cancer.

Resistance to chemotherapy and relapse are major hurdles for the effective treatment of cancer. Major reason for this is a small sub population of cancer stem cells (CSCs) and its microenvironment. CSCs are critical driving force for several types of cancer, such as gastric, colon, breast and many more. Hence, for the complete eradication of cancer, it is necessary to develop therapeutic approaches that can specifically target CSCs. Chemical agents that target different proteins involved in CSC signaling pathways, either as single agent or simultaneously targeting two or more proteins have generated promising pre-clinical and clinical results. In the current review article, we have discussed various targets and cellular pathways that can be explored for the effective and complete eradication of CSCs. Some latest developments in the field of design, synthesis and screening of ligands to target cancer stem cells have been summarized in the current review article.

4,6-Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal-chelation potential. All the synthesized compounds were found to be selective and potent inhibitors of MAO-A and AChE enzymes at nanomolar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 µM, respectively. It also showed potent AChE inhibition with an IC50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with an IC50 value of 9.54 ± 0.07 nM and displayed an IC50 value of 1010 ± 70.42 nM against the MAO-A isoform. In the cytotoxic studies, these compounds were found to be nontoxic to the human neuroblastoma SH-SY5Y cells even at 25 µM concentration. All the compounds were found to be reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA- and H2O2-induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found to be stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual-acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer's disease.

Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase.

Alzheimer's disease (AD) is a multifactorial neurological disorder involving complex pathogenesis. Single target directed drugs proved ineffective and since last few years' different pharmacological strategies including multi-targeting agents are being explored for the effective drug development for AD. A total of 19 dipropargyl substituted diphenylpyrimidines have been synthesized and evaluated for the monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibition potential. All the compounds were found to be selective and reversible inhibitors of MAO-B isoform. These compounds also displayed good AChE inhibition potential with IC50 values in low micromolar range. AVB4 was found to be the most potent MAO-B inhibitor with IC50 value of 1.49 ±â€¯0.09 µM and AVB1 was found to be the most potent AChE inhibitor with IC50 value of 1.35 ±â€¯0.03 µM. In the ROS protection inhibition studies, AVB1 and AVB4 displayed weak but interesting activity in SH-SY5Y cells. In the cytotoxicity studies involving SH-SY5Y cells, both AVB1 and AVB4 were found to be non-toxic to the tissue cells. In the molecular dynamic simulation studies of 30 ns, the potent compounds were found to be quite stable in the active site of MAO-B and AChE. The results suggested that AVB1 and AVB4 are promising dual inhibitors and have the potential to be developed as anti-Alzheimer's drug.

Synthesis, Biological Evaluation and Molecular Modeling Studies of Propargyl-Containing 2,4,6-Trisubstituted Pyrimidine Derivatives as Potential Anti-Parkinson Agents.

Monoamine oxidase B (MAO-B) inhibitors are potential drug candidates for the treatment of various neurological disorders including Parkinson's disease. A total of 20 new propargyl-containing 2,4,6-trisubstituted pyrimidine derivatives were synthesized and screened for MAO inhibition using Amplex Red assays. All the synthesized compounds were found to be reversible and selective inhibitors of the MAO-B isoform at sub-micromolar concentrations. MVB3 was the most potent MAO-B inhibitor with an IC50 value of 0.38±0.02 µµ, whereas MVB6 (IC50 =0.51±0.04 µµ) and MVB16 (IC50 =0.48±0.06 µµ) were the most selective for MAO-B with a selectivity index of more than 100-fold. In cytotoxic studies, these compounds were found to be nontoxic to human neuroblastoma SH-SY5Y cells at concentrations of 25 µm. MVB6 was found to decrease the intracellular level of reactive oxygen species to 68 % at 10 µm concentration, whereas other compounds did not produce significant changes in reactive oxygen species levels. In molecular modeling studies, MVB3 displayed strong binding affinity for the MAO-B isoform with a dock score of -10.45, in agreement with the observed activity. All the compounds fitted well in the hydrophobic cavity of MAO-B. Thus, propargyl-substituted pyrimidine derivatives can be promising leads in the development of potent, selective and reversible MAO-B inhibitors for the treatment of Parkinson's disease.

Recent Developments on 1,2,4-Triazole Nucleus in Anticancer Compounds: A Review.

1,2,4-triazole is an important nucleus present in a large number of compounds. More than thirty-five compounds containing this nucleus are introduced into the market. 1,2,4-triazole nucleus is stable to metabolism and acts as an important pharmacophore by interacting at the active site of a receptor as hydrogen bond acceptor and as a donor. Due to its polar nature, the triazole nucleus can increase the solubility of the ligand and it can significantly improve the pharmacological profile of the drug. A large number of 1,2,4-triazole derivatives are reported to possess a wide range of bioactivities including anti-cancer activity. This review article describes the role of 1,2,4-triazole nucleus in different types of anti-cancer agents such as nucleoside based anti-cancer agents, kinase inhibitors, tubulin modulators, aromatase and steroid sulfatase inhibitors, methionine aminopeptidase inhibitors, tankyrase inhibitors and metal complex based anti-cancer agents. It is expected that the current review article will provide insight into various ligand-receptor interactions and help in the rational design and development of novel 1,2,4-triazole based anti-cancer drugs with improved selectivity for cancer cells.