Design, synthesis and biological evaluation of novel antipyrine based α-aminophosphonates as anti-Alzheimer and anti-inflammatory agent.

Herein, a series of novel antipyrine based α-aminophosphonates derivatives were synthesized and characterized. The synthesized derivatives were subjected for in vitro cholinesterase inhibition, enzyme kinetic studies, protein denaturation assay, proteinase inhibitory assay and cell viability assay. For cholinesterase inhibition, the results inferred that the test compounds possess better AChE activity (0.46 to 6.67 µM) than BuChE (2.395 to 12.47 µM). Compound 4j inhibited both AChE and BuChE (IC50 = 0.475 ± 0.12 µM and 2.95 ± 0.16 µM, respectively), implying that it serves as a dual AChE/BuChE inhibitor. Also, kinetic studies revealed that compound 4j exhibits mixed-type inhibition against both AChE and BuChE, with Ki values of 3.003 µM and 5.750 µM, respectively. Further, protein denaturation and proteinase inhibitory assays were used to test in vitro anti-inflammatory potential. It was found that compound 4o exhibited highest activity against protein denaturation (IC50 = 42.64 ± 0.19 µM) and proteinase inhibition (IC50 = 37.57 ± 0.19 µM) when compared to diclofenac. In addition, cell viability assay revealed that active compounds possess no cytotoxicity against N2a cell and RAW 264.7 macrophages. Finally, molecular docking experiments for AChE, BuChE, and COX-2 were conducted to better understand the binding modes of active compounds.Communicated by Ramaswamy H. Sarma.

Synthesis of carbazole based α-aminophosphonate derivatives: design, molecular docking and in vitro cholinesterase activity.

A series of novel carbazole based α-aminophosphonate derivatives were synthesized under solvent-free condition, characterized and evaluated for their cholinesterase inhibition, enzyme kinetic inhibition, in-vitro cell viability using N2a cells, neuroprotective studies against H2O2-induced stress using N2a cells and antioxidant studies using DPPH radical activity. Test compounds displayed better AChE activity (0.475 to 7.781 µM) than BuChE (3.306 to 21.32 µM). Compound 4j was most potent derivative against AChE as well as BuChE with IC50=0.475 ± 0.12 µM and IC50=3.306 ± 0.21 µM respectively. Kinetic inhibition studies indicate that compound 4j exhibits mixed type inhibition against both enzymes which was supported by molecular docking studies. Cell viability studies showed that compounds did not induce any cytotoxic effect against N2a cells using MTT assay. Also, compound 4j, 4 s and 4r were subjected to H2O2-induced stress using N2a cells and were found to be protective in nature. ADME predictions were carried out to understand the pharmacokinetics behaviour.Communicated by Ramaswamy H. Sarma.

Synthesis, characterization, in vitro cholinesterase and hRBCs hemolysis assay and computational evaluation of novel 2,3,4,5-tetrahydrobenzothiazepine appended α-aminophosphonates.

A series of novel 2,3,4,5-tetrahydrobenzothiazepine appended α-aminophosphonate derivatives were synthesized by subjecting 2,3-dihydrobenzothiazepine to Pudovik reaction using diethyl phosphite. Tested derivatives exhibited better AChE inhibition (0.86-12.85 µM) when compared to BuChE (3.13-19.36 µM). Derivative 5f (IC50 = 0.86 ± 0.08 µM), 5g (IC50 = 1.05 ± 0.06 µM) and 5d (IC50 = 1.64 ± 0.06 µM) exhibited higher AChE inhibitory activity as compared to standard drug galantamine (IC50 = 2.15 ± 0.05 µM). Similarly, derivative 5e (IC50 = 3.13 ± 0.11 µM) and 5f (IC50 = 3.64 ± 0.06 µM) demonstrated comparable BuChE inhibitory activity to reference drug galantamine (IC50 = 3.86 ± 0.03 µM). Further, enzyme kinetic studies were carried out for the most active molecule i.e. derivative 5f (for AChE) and derivative 5e (for BuChE) and the results imply that derivatives 5f and 5e show mixed-type inhibition with Ki values of 1.779 µM and 3.851 µM respectively. Enzyme reversibility inhibition studies demonstrated that all the tested derivatives possess reversible inhibitor characteristics. In addition, % hemolysis studies were carried out using human red blood cells (hRBCs) and the results demonstrated that the synthesized derivatives were biocompatible in nature as they impart very less cytotoxicity to hRBCs (CC50 > 1000 µg/mL). Also, cell viability studies for tested derivatives revealed no cytotoxicity in N2a cells. Moreover, molecular docking studies revealed that derivative 5e and 5f bind to the PAS and CAS of the AChE. ADME predictions suggested that synthesized derivatives have high possibility of being drug-like.

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.

Forced eruption without orthodontic brackets using fiber reinforced composite prostheses: a case report.

Maintenance of periodontal health is one of the most important factors governing success of the restoration and longevity of teeth. For proper maintenance of periodontal health, the biologic width functions as a protective barrier against the entrance of microorganisms in to the internal medium of the periodontal ligament and osseous connective tissue. This clinical case describes a technique to reestablish the biologic width surrounding a fractured central incisor by forced eruption without orthodontic brackets, using fibre reinforced composite prostheses. Main advantages of using fibre reinforced composite prostheses are aesthetic maintenance during the treatment period, no need for occlusal adjustments, simplicity, low cost, and stability.

Rehabilitation of anterior edentulous space by glass fiber reinforced composite removable partial denture during preadolescent period: a case report.

The loss of anterior teeth can be hurtful to the patient both psychologically and socially. In adolescent patients, temporary replacement of the teeth can minimize these concerns. Many approaches have been described for this temporary replacement. This article presents an alternative approach for oral rehabilitation of the preadolescent male who has edentulous space including median palatine suture in the anterior maxilla. High expectations regarding esthetics by the patient were successfully met by utilizing a glass fiber reinforced composite temporary removable partial denture. Restoration remained intact, with no discoloration or deterioration at 12 months recall.

Analyses of prosthetic episodes in trans-tibial amputees.

The prosthetic episodes, i.e. actual processes of provision, identifying number of prostheses, their maintenance, repairs and replacements were analysed for 104 trans-tibial amputees aged 16 and over, over a 10 year period. The purpose of this investigation was to identify how frequently a new prosthesis is actually required for this group of amputees and what are their maintenance requirements. Variations of requirement between the amputee groups of aged 16-60 and over 60 years are also addressed. In the 10 years period of the study the amputees needed an average of 5.04 new prostheses, 6.25 refits, 2.28 major repairs and 17.04 day repairs. The younger amputees, i.e. below the age of 60 years, required significantly more new prostheses (p=0.003), more refit of sockets (p=0.0012) and more day repairs (p=0.01). Traumatic amputees below the age of 60 years needed significantly more day repairs compared to the non-traumatic amputees in the older age group (p=0.003).