Design, Synthesis, and Biological Evaluation of quinoxaline bearing tetrahydropyridine derivatives as anticancer, antioxidant, and anti-tubercular agents.

BACKGROUND: Quinoxaline and Tetrahydropyridine derivatives showed various biological properties. The combination of these two scaffolds may contribute to good biological activity and may give novel and efficacious bioactive candidates. OBJECTIVE: The present study aimed to identify bioactive agents with quinoxaline bearing tetrahydropyridine derivatives possessing anticancer, antioxidant, and anti-tubercular agents. METHOD: A series of novel quinoxaline bearing tetrahydropyridine derivatives have been designed and synthesized in good yields. The synthetic protocol involves three-component Povarov reactions of 6-amino quinoxaline, propenyl guaethol, and substituted aldehydes using BF3•OEt2 as catalyst. The newly synthesized molecules were evaluated for their anticancer activity against four cell lines, i.e. A-549, MCF-7, PC-3, and HepG2. RESULTS: The results from in vitro assay indicated that compound 4a proved to be as potent as the standard drug adriamycin against all cell lines with GI50 values <10 µg/ml. Compounds 4b, 4f, and 4i exhibited good cytotoxicity against A-549 cell line. All synthesized molecules were evaluated for their antioxidant activity and the results revealed that the compounds 4a, 4b, and 4i showed promising antioxidant activities against DPPH and H2O2 scavenging. In addition, the anti-mycobacterial activity of the synthesized compounds against MTB H37Rv strain was determined using MABA method. The results indicate that the compounds 4a, 4b, 4g, and 4i showed better anti-mycobacterial activity than the standard drugs pyrazinamide, ciprofloxacin and streptomycin with MIC value 1.6 µg/ml. Furthermore, molecular docking studies and ADME properties showed good pharmacokinetic profile and drug-likeness properties. CONCLUSION: These studies showed that a series of novel quinoxaline bearing tetrahydropyridine derivatives exhibit anticancer, anti-mycobacterial, and antioxidant activities.

Design, synthesis and evaluation of dihydropyranoindole derivatives as potential cholinesterase inhibitors against Alzheimer's disease.

A series of novel dihydropyranoindole derivatives containing sulphonamide group were designed, synthesized and evaluated for in-vitro anti-cholinesterase activity. The result showed that all the compounds exhibited potent acetylcholinesterase (AChE) activity (IC50 = 0.41-8.79 µM) while demonstrated moderate to good activity for butyrylcholinesterase (BuChE) (IC50 = 1.17-30.17 µM). The tested compounds exhibited selectivity towards AChE over BuChE. Compound 5o was most potent towards both AChE (IC50 = 0.41 µM) and BuChE (IC50 = 1.17 µM) when compared to standard galantamine and rivastigmine. Enzyme kinetics and molecular docking studies revealed that compound 5o shows mixed type inhibition and binds to peripheral anionic site (PAS) and the catalytic sites (CAS) of both the enzymes. Furthermore, cell viability studies were also performed against N2a cells along with neuroprotection studies against H2O2 in the same cell line. Antioxidant studies using DPPH radical and H2O2 were also performed which revealed that all compounds possessed some antioxidant activity. Also, DNA damage protection assay for compound 5o was performed implying that compound 5o was protective in nature. ADME studies were also performed which demonstrated good pharmacokinetics. These findings indicated that dihydropyranoindole derivatives could be possible drug lead in the search for new multifunctional AD drugs.

Design, synthesis and evaluation of pyrazole bearing α-aminophosphonate derivatives as potential acetylcholinesterase inhibitors against Alzheimer's disease.

A series of novel scaffold of N-substituted pyrazole derived α-aminophosphonates were designed, synthesized and evaluated for their anti-cholinesterase activity. Porcine pancreatic lipase (PPL) was used as a catalyst for the organic transformation. Compounds 4ah and 4bh proved to be more potent than the standard drug tacrine, rivastigmine and galantamine for AChE inhibition activity with IC50 value between 0.055 ± 0.143 µM and 0.017 ± 0.02 µM respectively. BuChE activity of the synthesized derivatives possessed moderate to weak inhibition potency. 4bhshows a comparable activity to Rivastigmine against BuChE (IC50 = 6.331 ± 0.17). The compounds did not show any cytotoxicity against HEK-293 cells when compared to standard drugs. Cell viability assay using N2a cell showed compounds 4ah and 4bh showed comparable results to positive control rivastigmine. In addition, these compounds showed promising antioxidant activities against DPPH and H2O2 scavenging. Both 4ah and 4bh showed mixed-type inhibition which supported by molecular docking studies by acting as a dual site inhibitor. The predicted ADME showed good pharmacokinetics as predicted by QikProp. DNA cleavage studies and DNA protection assay of active compounds were also performed. 4bh did not show any damage to DNA and was protective in nature.