Saurabh K. Sinha

Synthesis, evaluation and molecular dynamics study of some new 4-aminopyridine semicarbazones as an antiamnesic and cognition enhancing agents

Some new semicarbazones of 4-aminopyridine were synthesized and evaluated for antiamnesic, cognition enhancing and anticholinesterase activities. The results illustrated a significant cognition enhancing effect on elevated plus maze model with a significant reversal of scopolamine-induced amnesia. A significant inhibition in acetycholinesterase (AChE) activity by all the synthesized compounds in specific brain regions that is, prefrontal cortex, hippocampus and hypothalamus was observed. Compound 4APi exhibited significant antiamnesic and cognition enhancing activity which was comparable with standard drug donepezil. Its enzyme kinetic study revealed a non-competitive inhibition of AChE and a competitive inhibition of butyrylcholinesterase (BChE). Docking studies predicted the binding modes of these compounds in AChE active site, which were further processed for molecular dynamics simulation for calculating binding free energies using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA). All the computational study confirmed their consensual interaction with AChE justifying the experimental outcome.

Synthesis and evaluation of some new 4-aminopyridine derivatives as a potent antiamnesic and cognition enhancing drugs

Abstract4-Aminopyridine (4AP) potentiates acetylcholine (ACh) release by blocking potassium channel in axon terminal and can be used in the treatment of Alzheimer’s type of dementia and cognitive disorder. It is reported that ACh is well related with memory and learning. On the basis of these fact, we decided to synthesis and evaluate some new Schiff bases of 4AP (SBAPs) for their putative cognition enhancing, antiamnesic, and anticholinesterase activity. The synthesized and purified SBAPs were characterized by elemental analysis, UV, FTIR, 1H-, and 13C-NMR. SBAPs facilitated the learning on elevated plus maze model and they also significantly reversed the scopolamine-induced amnesia on the same model. The effect of SBAPs on learning and memory was qualitatively similar to standard nootropic drug piracetam used. The SBAPs were found to inhibit acetylcholinesterase enzyme significantly in specific brain regions prefrontal cortex, hippocampus, and hypothalamus. Thus, SBAPs derivatives showed cognitive and antiamnesic activities in the model tested and these effects may probably be due to their anticholinesterase activity.

Synthesis and evaluation of novel analogues of mangiferin as potent antipyretic

OBJECTIVE To screen different analogues of mangiferin pharmacologically for antipyretic activity. METHODS The naturally occurring xanthone glycoside mangiferin was isolated by column chromatography from the ethanolic extract of stem bark of Mangifera indica. Mangiferin was further converted to 5-(N-phenylamino methyleno) mangiferin, 5-(N-p-chlorophenylamino methyleno) mangiferin, 5-(N-2-methyl phenylamino methyleno) mangiferin, 5-(N-p-methoxy phenylamino methyleno) mangiferin, 5-(N, N-diphenylamino methyleno) mangiferin, 5-(N-α-napthylamino methyleno) mangiferin and 5-(N-4-methyl phenylamino methyleno) mangiferin analogues. The synthesized compounds were further screened for antipyretic activity along with mangiferin at a dose level of 100 and 200 mg/kg. Mangiferin and its analogues were characterized by melting point andR(f)value determination and through spectral technique like UV, IR, and NMR spectral analysis. RESULTS The antipyretic activity of mangiferin as well as all analogues was found to be more significant in at higher dose ie. 200 mg/kg which was depicted through a decrease in rectal temperature up to 3 h. CONCLUSIONS The antipyretic activity of mangiferin and its analogues may be attributed to inhibition in synthesis of TNF-α and anti-oxidant activity associated with amelioration of inflammatory actions of cytokines.

Development and validation of a HPLC method for the simultaneous estimation of amlodipin and telmisartan in pharmaceutical dosage form

Abstract Objective To develope and validate a simple and rapid isocratic reversed-phase highperformance liquid chromatographic method (RP-HPLC) for the simultaneous estimation of amlodipin and telmisartan in combined dosage form. Methods The chromatographic separation was achieved by using mobile phase acetonitrile and 0.05M sodium dihydrogen phosphate buffer (60:40) adjusted to pH 6.0, a C-18 column, perfectsil target ODS3 (150 mm × 4.6 mm i.d. , 5 μm). The mobile phase was pumped at a flow rate of 0.8 mL/min and the eluents were monitered at 254 nm. Results Retention times were 4.0 min and 8.2 min for amlodipine and telmisartan respectively. The method was validated in terms of accuracy, precision, linearity, range, specificity, limit of detection and limit of quantitation. Linearity for amlodipine besylate and telmisartan was established in the range of 5-30 and 10-60 μg/mL, respectively. The recoveries for the two compounds were above 96%. Conclusions This method was found to be efficient, accurate, precise, specific and economic and is suitable for routine quality control analyses.

Lamotrigine–dextran conjugates-synthesis, characterization, and biological evaluation

Synthesis of lamotrigine–dextran conjugates is done by oxidation of dextran using sodium periodate (NaIO4), where the aldehyde groups formed were coupled with the amino (–NH2) group of lamotrigine and reduced to secondary imine groups. Characterization of synthesized conjugates was done by using ultraviolet, infrared, nuclear magnetic resonance spectroscopy. Viscometer was used to determine molecular weight, and degree of substitution was estimated by complete hydrolysis of conjugates in borate buffer, which was found to be 8%. Buffer solutions with different pH, i.e., 1.2, 7.4, and 9.0 were used to perform the in vitro hydrolysis study and the amount of conjugates released was estimated by high performance liquid chromatography. The study showed that the rate of hydrolysis increases with increase in pH. The anticonvulsant and hepatotoxicity screening of the synthesized conjugates in different rat models showed that lamotrigine–dextran conjugates proved to be potentially safer than parent lamotrigine formulations.

Dextran carrier macromolecules for colon-specific delivery of 5-aminosalicylic acid

Present manuscript describes the sustained and targeted delivery of 5-aminosalicylic acid to the distal ileum and proximal colon, using dextran (40 kDa) as a carrier for targeting 5-aminosalicylic acid at the colonic site by attaching p-aminobenzoic acid and benzoic acid as linkers. Prepared conjugate were characterized by UV, HPLC, FT-IR, and 1H NMR. The degree of substitution was estimated by complete hydrolysis of conjugates in borate buffer and in vitro hydrolysis study of conjugates was performed in different biological media. It was observed that 5-aminosalicylic acid alone have produced high incidence of gastric ulcer with high ulcer index whereas lower ulcer index was found for the dextran conjugates of 5-aminosalicylic acid. The release pattern of conjugates in 3% w/v rat caecal content was confirmed the colon specificity of 5-aminosalicylic acid conjugates.

Antimicrobial evaluation of mangiferin and its synthesized analogues

Abstract Objective To isolate the mangiferin from Mangifera indica (M. indica) and assess the antimicrobial activity of different analogues synthesized from mangiferin. Methods Mangiferin was isolated by column chromatography from the ethanolic extract of stem bark of M. indica. Mangiferin was further converted to 5-(N-phenylamino methyleno) mangiferin, 5-(N-p-chlorophenylamino methyleno) mangiferin, 5-(N-2-methyl phenylamino methyleno) mangiferin, 5-(N-p-methoxy phenylamino methyleno) mangiferin, 5-(N, N-diphenylamino methyleno) mangiferin, 5-(N-α-napthylamino methyleno) mangiferin and 5-(N-4-methyl phenylamino methyleno) mangiferin. Mangiferin and its analogues were characterized by melting point and Rf value determination and through spectral technique like UV, IR, and NMR spectral analysis. The antimicrobial effect of mangiferin and its derivatives was studied according to the disc diffusion method. Results The solutions of mangiferin and its derivatives in polyethylene glycol-400 showed an activity with regard to four bacterial species-Bacillus pumilus (B. pumilus), Bacillus cereus (B. cereus) and Salmonella virchow (S. virchow) and two fungal species-Thermoascus aurantiacus (T. aurantiacus) and Aspergillus flavus (A. flavus). Conclusion The present study confirms the antimicrobial activity of different analogues of mangiferin which could be further processed for the development of a potential antimicrobial agent.

Design, synthesis and evaluation of novel thiazolidinedione derivatives as anti-hyperglycemic and anti-hyperlipidemic agents

A novel series of thiazolidine-2,4-diones was designed, synthesized and investigated for anti-diabetic activity. The (2,4-dioxo-1,3-thiazolidin-5-yl)methylphenylbenzamide derivatives contain an amide linkage between the central aryl ring and the hydrophobic tail. Structures of the compounds were confirmed by spectroscopic techniques fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance and elemental (C, H, N) analysis. The synthesized compounds were evaluated for their in-vivo pharmacological activity (blood glucose and triglyceride lowering activity), where compounds thiazolidinediones-C and thiazolidinediones-E showed significant effects, comparable to the standard pioglitazone. Computational studies positively substantiated the nature and interaction of the designed compounds with peroxisome proliferator-activated receptor gamma.

Design, synthesis and evaluation of some N-methylenebenzenamine derivatives as selective acetylcholinesterase (AChE) inhibitor and antioxidant to enhance learning and memory.

Series of some 3,5-dimethoxy-N-methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N-methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in vitro DPPH (2,2-diphenyl-1-picryl-hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4. The in vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory.

Design, synthesis and evaluation of some new 4-aminopyridine derivatives in learning and memory.

Some new anilide and imide derivatives of 4-aminopyridine (4AP) were synthesized and evaluated against antiamnesic, cognition enhancing and anticholinesterase activity through their respective in vitro and in vivo models. These newly synthesized derivatives have illustrated an enhanced cognition effect on elevated plus maze model and also demonstrated a significant reversal in scopolamine-induced amnesia in same model. The IC50 value of synthesized compounds showed maximum activity of 4APMb compared to standard drug donepezil and other derivatives, whereas its enzyme kinetic study revealed a non-competitive inhibition of acetycholinesterase (AChE) and a competetive inhibition of butyrylcholinesterase (BChE). Significant inhibitions in AChE activity by all the synthesized compounds were found in specific brain regions that is prefrontal cortex, hippocampus and hypothalamus. The docking study confirmed their consensual interaction with AChE, showed an affinity and binding with the key peripheral anionic site residues Trp-286, Tyr-124 and Tyr-341 of AChE.