QSAR, Molecular Docking, MD Simulation and MMGBSA Calculations Approaches to Recognize Concealed Pharmacophoric Features Requisite for the Optimization of ALK Tyrosine Kinase Inhibitors as Anticancer Leads.

ALK tyrosine kinase ALK TK is an important target in the development of anticancer drugs. In the present work, we have performed a QSAR analysis on a dataset of 224 molecules in order to quickly predict anticancer activity on query compounds. Double cross validation assigns an upward plunge to the genetic algorithm−multi linear regression (GA-MLR) based on robust univariate and multivariate QSAR models with high statistical performance reflected in various parameters like, fitting parameters; R2 = 0.69−0.87, F = 403.46−292.11, etc., internal validation parameters; Q2LOO = 0.69−0.86, Q2LMO = 0.69−0.86, CCCcv = 0.82−0.93, etc., or external validation parameters Q2F1 = 0.64−0.82, Q2F2 = 0.63−0.82, Q2F3 = 0.65−0.81, R2ext = 0.65−0.83 including RMSEtr < RMSEcv. The present QSAR evaluation successfully identified certain distinct structural features responsible for ALK TK inhibitory potency, such as planar Nitrogen within four bonds from the Nitrogen atom, Fluorine atom within five bonds beside the non-ring Oxygen atom, lipophilic atoms within two bonds from the ring Carbon atoms. Molecular docking, MD simulation, and MMGBSA computation results are in consensus with and complementary to the QSAR evaluations. As a result, the current study assists medicinal chemists in prioritizing compounds for experimental detection of anticancer activity, as well as their optimization towards more potent ALK tyrosine kinase inhibitor.

Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer's treatment.

Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Aß) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Aß and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC50: 4.16 ± 0.063 µM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Aß aggregation at 0.5, 10 and 20 µM doses. Approximately, 50% of AChE-induced Aß aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.

Indene-Derived Hydrazides Targeting Acetylcholinesterase Enzyme in Alzheimer's: Design, Synthesis, and Biological Evaluation.

As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer's disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule SD-30, having hydrogen bond donor (HBD) at para-position, showed maximum AChE inhibition potential (IC50 13.86 ± 0.163 µM) in the indene series. Further, the SD-30 showed maximum BuChE inhibition potential (IC50 = 48.55 ± 0.136 µM) with a selectivity ratio of 3.50 and reasonable antioxidant properties compared to ascorbic acid (using DPPH assay). SD-30 (at a dose level: of 10 µM, 20 µM) effectively inhibited AChE-induced Aß aggregation and showed no significant toxicity up to 30 mM against SH-SY5Y cell lines.

Phytochemical investigation and evaluation of in vitro free radical scavenging activity of Tabernaemontana divaricata Linn.

We evaluate the in vitro free radical scavenging activity of the leaves of Tabernaemontana divaricata Linn. Petroleum ether, ethanol and aqueous extracts of T. divaricata were prepared with successive extraction in a soxhlet apparatus. Each extract was selected to study the free radical scavenging activity by superoxide scavenging assay method. It was found that the aqueous extract contained carbohydrates, glycosides, amino acids, flavonoids, tannins, alkaloids, and steroids, and the ethanolic extract contained glycosides, amino acids, flavonoids, tannins, alkaloids and steroids. The ethanolic extract of T. divaricata showed 58.7 +/- 0.62% inhibition in the superoxide scavenging model. The aqueous extract also showed almost similar activity (54.9 +/- 0.53% compared to the ethanolic extract), while petroleum ether extract showed poor inhibition of superoxide scavenging activity. All extracts showed the dose- and time-dependent inhibition of the superoxide scavenging activity.