M. K. Prashanth

Synthesis, characterization, antidepressant and antioxidant activity of novel piperamides bearing piperidine and piperazine analogues.

A series of piperamide derivatives (8a-j) was synthesized with various substituted piperidine and piperazine compounds. The prepared compounds were evaluated for antibacterial activity against gram-positive and gram-negative bacteria and antifungal activity by disc diffusion method. The antioxidant activity of the compounds was evaluated by DPPH and superoxide radical scavenging method and antidepressant activity using forced swim and tail suspension behavioral despair tests in mice. The compounds 8a, 8b and 8c were investigated for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory property. Some of the test compounds were active in forced swim test (FST) and tail suspension test (TST). Compounds 8a and 8b showed a significant effect, when compared to standard drug, clorgyline.

Synthesis, anticonvulsant, antioxidant and binding interaction of novel N-substituted methylquinazoline-2,4(1H, 3H)-dione derivatives to bovine serum albumin: A structure-activity relationship study.

A novel class of N-substituted glycosmicine derivatives was synthesized, and their anticonvulsant, antioxidant activity and interaction with bovine serum albumin (BSA) were evaluated. The synthesized compounds 4a-j were examined for anticonvulsant activity by maximal electroshock induced seizures (MESs) test and their neurotoxic effects were determined by rotorod test in mice. The structure-activity relationships (SARs) of these compounds were also investigated. Compounds 4d, 4g, 4i and 4j were found to have good protective effect from seizure. The in vitro antioxidant activity was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging assay. The interaction between novel N-substituted methylquinazoline-2,4(1H,3H)-dione (NMQ) and BSA was analyzed by fluorescence and ultraviolet spectroscopy at 304K under simulative physiological conditions. BSA fluorescence quenched by NMQ is discussed according to the Stern-Volmer equation. The binding constant and binding sites of NMQ with BSA were calculated. According to Forster non-radiation energy transfer theory, the binding distance (r) between NMQ and BSA was calculated.

Synthesis of some new glutamine linked 2,3-disubstituted quinazolinone derivatives as potent antimicrobial and antioxidant agents

A series of novel glutamine linked 2,3-disubstituted quinazolinone conjugates was synthesized from methyl anthranilate and different substituted acids and acid chlorides. The compounds 5a–l were prepared in good yields. All compounds were screened for their antibacterial activity against Gram-positive and Gram-negative bacteria and for antifungal activity against Candida albicans and Aspergillus flavus using paper disk diffusion technique. The minimum inhibitory concentrations of the compounds were also determined by agar streak dilution method. The compound 5b was found to exhibit the most potent in vitro anti-microbial activity. When tested for their antioxidant activity, compounds 5i and 5l showed potent radical scavenging activity, while compound 5g had moderate effect against 2,2-diphenyl-1-picrylhydrazyl, hydroxyl, nitric oxide, and superoxide radical scavenging assays. These results suggest that, the three quinazolinone analogs (5g, 5i, and 5l) could be considered as useful templates for future development to obtain more potent antioxidant agents.

Synthesis and pharmacological evaluation of novel 1'-[2-(difluoromethoxy)benzyl]-2'H,5'H-spiro[8-azabicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-diones and their derivatives.

A series of novel 1′‐[2‐(difluoromethoxy)benzyl]‐2′H,5′H‐spiro[8‐azabicyclo[3.2.1]octane‐3,4′‐imidazolidine]‐2′,5′‐dione substituted hydantoins (5–32) were synthesized using an appropriate synthetic route and characterized by elemental analysis and spectral data. The novel molecules were screened for anticonvulsant activity in mice by maximal electroshock (MES) and subcutaneous pentylenetetrazol (ScPTZ)‐induced seizure tests. The neurotoxicity was assessed using the rotarod method. Compounds 9, 10, 18, 30, and 31 exhibited anticonvulsant potency against MES seizure and in the ScPTZ model, with lesser neurotoxicity. Some title compounds showed lesser central nervous system depression compared to phenytoin.

Synthesis and evaluation of 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives as potential anticonvulsants.

New 3‐[(2,4‐dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile derivatives 8–37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure–activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11, 18, 31, and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two‐electron donor.

Synthesis and antioxidant activity of novel quinazolinones functionalized with urea/thiourea/thiazole derivatives as 5-lipoxygenase inhibitors.

In the present study, a series of novel quinazolinones functionalized with urea/thiourea/thiazole derivs. was synthesized and evaluated for their antioxidant and 5-lipoxygenase (5-LOX) inhibition activities. The newly synthesized compds. were characterized using 1H NMR, 13C NMR, IR, Mass spectra and elemental anal. The antioxidant activities of the title compds. were evaluated using DPPH, superoxide, hydroxyl and nitric oxide radical scavenging assay in vitro. It is revealed from the antioxidant screening results that the compds. 3e, 5f and 6c manifested profound antioxidant potential. The synthesized compds. were screened for their 5-LOX inhibitory activity. Overall, 3e, 5f and 6c showed promising antioxidant and 5f showed 5-LOX inhibitory activity and may be used as the lead compds. in the future study. [on SciFinder(R)]

ANTIDEPRESSANT DRUGS: HIGHLY SENSITIVE AND VALIDATED SPECTROPHOTOMETRIC TECHNIQUE

A simple, rapid, selective and highly sensitive spectrophotometric method is described for the quantitative determination of the tricyclic antidepressant drugs, desipramine hydrochloride (DPH), clomipramine hydrochloride (CPH) and imipramine hydrochloride (IMH) in pure and in pharmaceutical preparations. The proposed method is based on the bromination of above drugs with known excess of bromine. The unreacted bromine is determined based on its ability to bleach the dye Eiochrome blue black R quantitatively at 530 nm for all the three drugs obeying Beer’s law in the range, 0.0 – 8, 0.0 – 10 and 0.0 – 9.0 µg ml-1 for DPH, CPH and IMH, respectively. The molar absorptivity values were found to be 1.61 × 104, 1.62 × 104 and1.57 × 104 l mol-1cm-1, respectively with the corresponding Sandell’s sensitivity values 0.0187, 0.0216 and 0.0202 µg cm-2. The limits of detection and (LOD) and quantification (LOQ) are also reported for the developed method. Intra- and inter-day precision and accuracy of the method were established according to the current ICH guidelines. Applications of the procedure to the analysis of various pharmaceutical preparations gave reproducible and accurate results. Further, the validity of the procedure was confirmed by applying the standard addition technique and the results were evaluated in terms of Student’s t-test and variance ratio F-test to find out the significance of proposed method over the reference method.

Synthesis and structure–activity relationship studies on novel 8-amino-3-[2-(4-fluorophenoxy)ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione derivatives as anticonvulsant agents

A series of novel 8-amino-3-[2-(4-fluorophenoxy)ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione derivatives 7–36 was synthesized and their pharmacological activity was determined with the objective to better understand their structure–activity relationship for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) test and their neurotoxic effects were determined by rotarod test. Majority of the compounds were active in MES tests. Compounds 24, 27, and 34 showed a significant and protective effect on seizure, when compared with standard drug phenytoin. The compounds having amide bond showed moderate protective effect on MES induced seizures compared to sulfonamide.

Development and Validation of Reverse Phase HPLC Method for the Determination of Midazolam in Human Plasma

Abstract: A simple, rapid, sensitive and specific high performance liquid chromatograpic (HPLC-UV) method was developed and fully validated for the quantification of midazolam in human plasma. Alprazolam was used as an internal standard. The analyte was extracted from human plasma samples by liquid-phase extraction technique. Analyte was chromatographed on a Zorbax XDB C18 column (3.5 µm, 4.6 x 100 mm i.d. from Agilent Technologies) by using a mixture of 0.05 M Na3PO4 (pH-4): toluene: acetonitrile (40:40:20, v/v/v) as the mobile phase at a flow-rate of 0.9 ml min−1 and the chromatogram was monitored with UV detection at 220 nm. The calibration curve obtained was linear (r2=0.99) over the concentration range of 2-200 ng ml−1. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. Extraction recoveries of MDZ from plasma were 85.73, 91.93 and 93.68 % at 5, 84 and 148 ng ml−1 respectively. The mean recovery of the internal standard was found to be 102.8 % at the spiked concentration of 1 µg ml−1. The method was validated and can be successfully applied for routine analyses.