Tabassum Hossain

Expedient Synthesis of Biologically Potent Aryloxycoumarins and (Aryloxyimino)ethylcoumarins via Copper(II)-Promoted Chan–Lam Coupling Reaction

Abstract A convenient protocol for the efficient synthesis of aryloxycoumarins and (aryloxyimino)ethylcoumarins is described. The synthetic route developed involves the Cu-promoted C-O and N-O coupling reactions from readily available hydroxycoumarin and (hydroxyimino)ethylcoumarin derivatives in the presence of the catalytic system Cu(OAc)2/Et3N. By applying this condition, a series of arylboronic acids have been successfully reacted to afford the coupled products in fair to good yields. GRAPHICAL ABSTRACT

Exploring molecular structural requirement for AChE inhibition through multi-chemometric and dynamics simulation analyses

The acetylcholinesterase enzyme (AChE) plays an important role in central and peripheral nervous systems. Acetylcholine (ACh) acts through the regulation of AChE activity, which can play a key role in accelerating senile amyloid β-peptide (Aβ) plaque deposition. Therefore, inhibition of the AChE enzyme can be used as a key principle to prevent ACh depletion. The present study has been emphasized to explore both ligand- and structure-based 3D QSAR, HQSAR, pharmacophore, molecular docking and simulation studies on a set of structurally diverse inhibitors to optimize prime structural features responsible for selective binding to AChE, and vis-à-vis inhibiting enzyme activity. The pharmacophore model showed the importance of HB acceptor and donor, positive ionization and hydrophobic features of the molecule for effective binding. Structure-based docking and simulation studies adjudged the significance of features obtained from ligand-based 3D QSAR, CoMFA (Q2 = .608, = .700), CoMSIA (Q2 = .632, = .734), HQSAR (Q2 = .850, = .693) and pharmacophore (Q2 = .839, ROCscore = .769) models. The aim of the present study is to identify the essential structural and physicochemical profiles of molecules that can provide therapeutic benefits with less toxicity. Structurally diverse compounds have been used for the study, and the generated models showed the large applicability domain.

Molecular modeling on structure-function analysis of human progesterone receptor modulators.

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): nTr=100, R2pred=0.702; test set (Ts): nTs=30, R2pred=0.705, R2m=0.635; validation set (Vs): nVs=40, R2pred=0.715, R2m=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: nTr=26, Q2=0.927; Ts: nTs=60, R2pred=0.613, R2m=0.545; Vs: nVs=84, R2pred=0.611, R2m=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A.

NMDA-Chemometric analyses to explore essential structural and physicochemical requirement of small molecules to inhibit NMDA functionality

To optimize a nanostructured lipid carriers system (NLC) for the per-oral delivery of valsartan (Val), a model BCS class II drug, in an attempt to enhance its therapeutic performance by increasing both solubility and dissolution. Val-loaded NLCs were prepared using ultrasonic melt-emulsification method. Number of formulation factors including the type of oil/lipid, Val to lipid ratio, and surfactant ratio were investigated. The prepared NLC were evaluated for their particle size and shape, polydispersity index, zeta potential, and drug entrapment efficiency. The in vitro drug release profiles were evaluated using a dialysis bags with cut-off 12KD. The prepared NLCs showed average sizes between 423.99±12.73 and 805.53±39.5 nm, and polydispersity index in the range of 0.287 to 0.361. The zeta-potential values were between -3.34 and -10.59 mV. The entrapment efficiency was not very high between 27.3 to 75.04%. The scanning electron images showed almost spherical shapes with sizes lower than those obtained by light scattering. The in vitro release followed a bi-phasic pattern with an initial rapid Val release followed by a slow release varying according to the composition. Two formulations F2 and F4 showed complete drug release within the first two hours. The optimum surfactant ratio was 37.5% by weight of the total lipid. NLC successfully enhanced the Val release rate and dissolution with high potential to enhance its bioavailability.Results: Of 1435 citation reviewed, 22 studies published in 26 papers were appraised. These studies mainly focused on factors affecting patients reporting of ADRs. None of these studies conducted at North America. Sixteen out of 22 reviewed studies described barriers to the reporting process included: Poor awareness of ADR reporting systems; difficulties with reporting procedure and forms; lack of feedback to ADRs submitted by the patients; confusion as to who reports ADRs and to whom they are reported; poor economic status; ADRs resolved; and prior negative reporting experience. Another 11 out of the 22 reviews studies described the motives for reporting ADRs by patients and those included: prevent others from similar ADRs; inform regulatory bodies, drug manufacturer, HCPs, and public; improve drug safety and medication leaflet and enhance scientific knowledge; improve HCP practices; failure of HCPs to report their ADRs; asked to report ADRs by HCPs; it was serious ADRs; and desire for personal feedback and want more information about the ADRs.W are unfortunately subject to an optimistic bias when we evaluate how, and to what extent, drugs and other medical therapies will become available and accessible to patients on the global level in which pharmaceutical enterprises operate. In developed countries, the pricing and affordability of medicines is a controversial issue that highlights health and economic inequalities, and great challenges for the future. According to the New York Times article Lawmakers Look for Ways to Provide Relief for Rising Cost of Generic Drugs (November 24th 2014), “the cost of many generic medications has increased so much over the past year that prices for many common generic drugs in the USA have surpassed those of their brandname equivalents in other developed countries”. The issue of unaffordable healthcare is more challenging with technological advances and the demographic growth of the geriatric population, including those with cancer and cardiac disease. Legislation can be instrumental in the creation of equitable solutions. The EU member state’s management of healthcare access and drug entry; the implementation of regulatory requirements aimed at ensuring quality, safety, and efficacy of medicines and vaccines for human use; and the European Transparency Directive (Council Directive 89/105) which defines procedural requirements for pricing and reimbursement of medicinal products will be discussed. These issues must be taken into account since few of the hundreds of drugs in clinical development ever reach the stage of final approval, having failed to produce the anticipated results expected by the investigators. These trials can take up to 20 years to complete, and several billion dollars to reach the stage of approval or denial by the regulatory agency involved. When failing to demonstrate viability, preexisting expenditures are allowed to be passed onto the price the pharmaceutical company charges patients. In the cancer industry for example, most new drugs require the patient or insurance company to pay 50-100,000 dollars for a course of treatment which may not offer more than several months of improvement in the clinical response. It is essential that the legislators in each of the countries where the drug is to be introduced be able to negotiate a fee arrangement where the patient will not be denied treatment and the drug company be compensated reasonably for development costs.Copyright:

Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies.

Glycogen synthase kinase-3β (GSK-3β) is a promising target for therapeutic invasion of Alzheimers disease (AD). The kinase enzyme plays major role in pathological process for the formation of β-amyloid plaques and neurofibrillary tangles in AD. In the present study, structure-based pharmacophore and ligand-based 3D QSAR, HQSAR and pharmacophore mapping studies have been emphasized to explore the possible structural requirement of this potential kinase inhibitors using a structurally diverse set of compounds. The developed models were validated with the interaction study at the catalytic cleft. The 3D QSAR studies yield robust models of CoMFA R(2) = 0.965, se = 0.212, Q(2) = 0.525, R(2)pred = 0.709, r(2)m = 0.579 and CoMSIA: R(2) = 0.935, se = 0.289, Q(2) = 0.581, R(2)pred = 0.723, r(2)m = 0.935, that explain the importance of steric, electrostatic, hydrogen bond (HB) acceptor of the molecule for inhibition of GSK-3β. The HQSAR study (R(2) = 0.871, se = 0.400, Q(2) = 0.639, R(2)pred = 0.721, r(2)m = 0.664) indicated the fragments of the molecular fingerprints that might be important for inhibition. Both structure- and ligand-based pharmacophore mapping proposed that acceptor and donor features of the molecule are essential for receptor-ligand interactions. Molecular diversity provides an opportunity on wide range of applicability for the GSK-3β inhibitors, and depicts information on the structural and properties requirement for effective binding at the active site selectivity that minimize the side effects with therapeutic benefits.

MM AChEI-Molecular modeling studies for exploring structural requirement of acetylcholinesterase inhibitors

Background and Aims: Human serum albumin (HSA) is one of the most abundant proteins in the circulatory system and plays a crucial role in the transport of different drugs, metabolites, and fatty acids. Therefore, a drug binding to serum albumin is an important parameter to determine pharmacokinetic and pharmacodynamics properties for chemical substances in the human body. However, despite the numerous attempts to characterize the HSA binding sites involved in this process, none of them have employed linear interaction energy method to predict binding affinities and compare them to the experimentally determined ones. Here, we performed classical molecular dynamics (MD) simulations on general anesthetic propofol bound to HSA to describe the drug binding affinity using linear interaction energy method.BACKGROUND/AIM Inhibition of arachidonic acid metabolism by curcumin has been suggested to be a key mechanism for its anti-carcinogenic action. Recently, we reported on the synthesis of curcumin analogues and their evaluation as selective COX1 inhibitors. Two compounds (HP109/HP102) were selected for evaluation of their anti-proliferative and pro-apoptotic potential in Jurkat T-cells. MATERIALS AND METHODS Jurkat T-cells were stimulated with phorbol 12-myristate 13-acetate/phytohemagglutinin (PMA/PHA) in the absence and presence of different concentrations of curcumin or HP109/HP102. Interleukin 2 (IL2) production and IL2 promoter activity were analyzed by enzyme-linked immunosorbent assay and a luciferase reporter assay, respectively. Proliferation and cell viability were monitored by 2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide assay, annexin -V/7-amino-actinomycin D staining and western blotting. RESULTS HP102 was about 10-times more effective in blocking IL2 synthesis compared to curcumin. Enhanced effects of HP102 were also observed in reducing the proliferation rate and cell viability. In contrast to HP102, HP109 did not exhibit enhanced effects compared to curcumin. CONCLUSION The curcumin analog HP102 had strongly improved the anti-proliferative and pro-apoptotic potential in Jurkat T-cells compared to curcumin.T aza-Cope rearrangements are examples of heteroatom versions of the Cope rearrangement, which is a [3, 3]-sigmatropic rearrangement that shifts single and double bonds between two allylic fragments. The most common and synthetically useful strategy couples the cationic 2-aza-Cope rearrangement with a Mannich cyclization. This tandem reaction is well fit for pyrrolidine compound array generations. The aza-Cope-Mannichtandem reaction is characterized by mild reaction conditions, diastereoselectivity, and a wide synthetic versatility. It provides easy access to acyl-substituted pyrrolidines, a structure commonly found in natural products such as alkaloids, and has been used in the synthesis of a number of them, notably strychnine and crinine. With cyclic amino alcohols substrates, this transformation leads to ring-enlarged pyrrolidine annulated products. Because of the restricted conformational freedom in the transition state, this variant of the aza-CopeMannich reaction occurs without loss of enantiomeric purity of the starting amino alcohol and usuallyleads to an excellent stereoselectivity. In a recent work, the author and his team have reported a case of a highly stereo-controlled synthesis of trans-fused octahydrocyclohepta[b]pyrrol-4(1H)-ones via the aza-Cope-Mannich rearrangement in either the racemic and enantiopure forms. In order to enlarge the medicinal chemistry reaction portfolio, we have evaluated the possibility of extending this technology for the synthesis of more complex ring systems such as 5, 7-fused heterocyclic systems and their pyrrolidine-based derivatives. There are 2 major drawbacks for these methods. The first one is the necessity of developing a robust synthetic method for the production of the starting amino alcohols to be used as substrates for the aza-Cope-Mannich reactions. The second drawback is linked to the correct stereoselectivity assessment. These drawback factors can be tackled by adjusting a synthetic methodology used for the synthesis of trans octahydropyrrolo[2, 3-c]azepin-4(5H)-ones, previously developed, which can be applied to this case just with minor modifications. The amine 6 was effectively synthesized in five steps with excellent overall yield of 60%. All steps were very handy to perform. Due to the robustness of the synthetic method developed and to its easy scalability, we manage to achieve the desired compound in gram quantities (>10g). In order to generate the required heterocyclic ketones, we have investigated the azaCope -Mannich reaction conditions of the starting alcohol and the formaldehyde by using a set of different solvents. This ultimately allowed us to synthesize a separable mixture of transand cis-products, with one isomer predominance. This work demonstrate the synthetic flexibility of our previous methodic and how well it can be used, just by minor variations, for the synthesis of complex cis and trans fused heterocyclic systems such the octahydropyrrolo[2, 3-c]azepin-4(5H)-ones.R developments in cancer biology have identified the existence of a sub-population of cells—cancer stem cells—that are immune to most traditional therapies (e.g., chemotherapy and radiotherapy) and have the ability to repair their damaged DNA. Here, we show the resistance of hepatocarcinoma stem cells and glioblastoma multiform stem cells to both radiation and therapy. Also, we show the efficiency of the conjugated iron oxide nanoparticles for the in vivo disruption of Notch signaling by the gamma secretase inhibitor DAPT [N-(N-((3,5-Difluorophenacetyl))-L-alanyl)-S-phenylglycerin t-butyl ester. By introducing these targeted conjugated nanoparticles, detection, targeting, and destruction of the Hepatocarcinoma and glioblastoma stem cells was achieved. An efficient alternative treatment for the incurable disease of cancer could be provided.T is a di-copper oxidative enzyme widely present in plants, mushroom, bacteria and humans. It remains the most efficient way to down-regulate melanin production and improve melanin-biosynthesis disorders. In humans, tyrosinase inhibitors were developed to be used as dermocosmetics for management of melanogensis. In this regard, a large number of tyrosinase inhibitors are reported in literature, but only very few of them have reached the human use.I of significant scientific progress and growth of modern drugs, at least 30 million people throughout the world still suffer from the diseases related to metabolic syndrome. Peroxisome proliferator-activated receptors (PPARα, δ, and γ) play important roles in the regulation of metabolism, inflammation, and cell differentiation. Considering the importance of the regulating receptor, most studies have been focused on developing PPARγ modulators for reducing the complications associated with type-2 diabetes mellitus (T2DM). But only few studies were performed to explore the role of γ-receptor subtype. In present work, multi-chemometric techniques, such as ligand-based pharmacophore, e-pharmacophore, hologram based quantitative structural activity relationship (HQSAR), de novo design and stepwise virtual screening with MM-GBSA analysis have been performed for exploring potent and selective PPARγ modulators. The two different types of pharmacophore models infer that compounds bearing three aromatic rings are crucial for PPARγ agonistic activity. The HQSAR model adjudged the importance of the aromatic rings, benzene and substituted indole nucleus along with carbonyl functional group for the optimal activity of the molecules. After drug-likeness screening by Lipinski filter, traditional Chinese medicine database and de novo designed molecules were mapped for hits identification. From the docking and MMGB-SA study of the hit molecules, it is observed that 14 molecules, having dockscore <5, showed similar interactions with the amino acid residues at the active site of PPARγ as that of the co-crystallized ligands rosiglitazone. The chemometric studies provide key information on activity pattern for development of potent and selective PPARγ modulators is schematically represented.T oxidative deamination mechanism of monoamine oxidase B is studied by means of density functional theory calculations. This enzyme catalyzes the oxidative deamination of neurotransmitters to yield a half-reduced flavine and a protonated imine byproduct. The quantum chemical cluster approach is employed to characterize transition states of two good substrates such as phenethylamine, benzylamine, and its para-nitro substituted counterpart which is a poor substrate for which experimental catalytic kinetic constants are available. Our results strongly suggest that this isoform can act using both mechanisms, contrary with what has been speculated for this enzyme. Also, the observed experimental kcat values reflect the preference that this isoform has for one mechanism over the other (polar nucleophilic vs. hydride transfer). According to our results, the better stabilized transition state, regarding their reactant complexes, determine the most probable mechanism for this isoform.