Synthesis of Functionalized Isoxazolines as New Acetylcholinesterase and Tyrosinase Inhibitors and Antioxidant Agents

In the search for new leads capable of interacting with multiple targets involved in NDD pathogenesis, a series of pyrazine-linked isoxazoline scaffolds were designed, synthesized and evaluated for their acetylcholinesterase and tyrosinase inhibitory potency and antioxidant activity. Isoxazolines 4a, 4d and 4h exhibited better molecular interaction with cholinesterases, tyrosinases and peroxiredoxin enzymes. Isoxazolines 4a, 4d and 4h interacted with acetylcholinesterase with the highest docking score of −9.083, −8.68 and −7.87 kcal/mol, respectively. Compound 4h ranked top when interacting with butyrylcholinesterase with a docking score of −7.926 kcal/mol, followed by 4a (−6.327 kcal/mol). 4a exhibited a robust interaction with 1HD2 with a docking score of −3.103 kcal/mol followed by 4d and 4h. 4a, 4d and 4h exhibited better docking scores of −5.47 kcal/mol, −4.63 kcal/mol and −5.157 kcal/mol with the enzyme tyrosinase. Based on the in-silico data, we have proceeded further to synthesis and in-vitro studies. Chalcones were synthesized by the Claisen-Schmidt reaction, which was cyclised to isoxazolines by the cycloaddition of hydroxylamine HCl. FTIR, 1HNMR, 13CNMR, and mass spectral studies further characterized the compounds. The prediction of pharmacokinetic parameters also supports the study, and all the compounds passed the screening. In-vitro studies were performed to evaluate acetylcholinesterase and tyrosinase inhibition. Compound 4h displayed excellent action against acetylcholinesterases and tyrosinase enzymes. Hydrogen peroxide assay determined the antioxidant effect, which found that 4h and 4d compounds exhibited higher strength as peroxide scavengers. Thus, the study shows that pyrazine-based isoxazolines with electron-withdrawing groups can be used as leads to develop a drug of choice for NDD, as it has excellent acetylcholinesterase and tyrosinase inhibitory action and tremendous peroxide scavenging effect.</p

Pharmacophore Modeling, 3D QSAR, Molecular Dynamics Studies and Virtual Screening on Pyrazolopyrimidines as anti-Breast Cancer Agents

Various targets, such as estrogen receptor (ER), mammalian target ofrapamycin(mTOR), epidermal growth factor receptor (EGFR), androgen receptor (AR) andpoly adenosine diphosphate-ribose polymerase (PARP), are focused on the treatment of breast cancer. In this study, in silico tools such as pharmacophore modeling, 3D QSAR study, molecular docking, binding free energy determination and molecular dynamics were executed on a series of pyrazolopyrimidines derivatives. The pharmacophore modeling of forty-one anticancer derivatives was generated, and atom-based 3D QSAR was applied. Molecular docking, dynamics, binding energy and high-throughput virtual screening (HTVS) were conducted by the software Schrodinger. The best five featured pharmacophore hypotheses AHRRR_1 with a maximum survival score of 5.533 was subjected to rigorous scoring function analysis and 3D QSAR studies. Docking studies and binding free energy were carried out on 41 inhibitors for their anti-breast cancer activity against human estrogen, progesterone receptor, EGFR kinase and mammalian target of rapamycin mTOR. Molecular dynamics simulation of the docked complex-34/4WKQ validated the stability of this complex. HTVS was performed to determine the virtual hits with the best-fitted model AHRRR_1. New EGFR kinase inhibitors were designed based on the active compound templates. Molecular docking was carried out on virtual hits, and newly designed compounds and dynamics studies revealed that the binding modes obtained after MD simulation were more or less similar to that acquired post docking mode. Promiscuity assessments demonstrated that designed compounds would be specific rather than a promiscuous one. Based on these findings, we have designed four novel compounds as anti-breast inhibitors, with potent binding affinity and desirable ADME properties.</p

Synthesis, Molecular Docking and Molecular Dynamic Studies of Thiazolidineones as Acetylcholinesterase and Butyrylcholinesterase Inhibitors

Neurodegenerative diseases are chronic, progressive, age-related, and characterized by the loss of function of neurons caused by the accumulation of free radicals and oxidative stress. Although the prevalence of neuro disorders is rising, therapeutic efficacy is still limited due to various variables, including the blood-brain barrier. Hence, to identify molecules targeting different enzymes like acetylcholinesterase, butyrylcholinesterase and peroxiredoxins, a series of thiazolidineone derivatives were designed and synthesized. Schiff base was synthesized and cyclised with thioglycolic acid to yield thiazolidineones (T1-T10). Structural characterization was performed by IR, Mass and 1H NMR spectral studies and then subjected to in silico analysis against acetylcholinesterase (6O4W) and butyrylcholinesterase (1P0P). Compound T-9 (–10.10 kcal/mol) and T-8 (–7.65 kcal/mol) have shown excellent binding with 6O4W and 1P0P, respectively, compared with other derivatives. In addition, the compounds were checked for antioxidant activity by analyzing the interactions with peroxiredoxins (1URM), and compound T-4 was active. According to the physicochemical and ADME properties of Qikprop, synthesized compounds can be considered druglike molecules. In vitro, acetylcholinesterase inhibitory activity reveals compound T-8 as the most potent AChE inhibitor. In vitro, antioxidant activity found that compound T-4 has significant antioxidant activity. The compound T-8, with better docking scores and decisive acetylcholinesterase inhibitory action, was further explored to validate the molecular interactions through molecular dynamics studies. It was observed that compounds with the benzyl sulfonyl group (T-6 to T-10) showed higher AChE inhibitory potency than derivatives with phenyl substituents in place of the benzyl sulfonyl group (T-1 to T-5). Therefore, it is inferred that the sulfonyl group and substituents at the para position are essential for the higher inhibitory activity of compounds. Thus, there is plenty of scope for further study in developing these as promising lead compounds.</p