R. L. Khosa

Design, synthesis and biological evaluation of 1,3,4-oxadiazole derivatives.

3D QSAR analysis for the 21 molecules of 1,3,4-oxadiazoles was carried out by using k-Nearest Neighbor Molecular Field Analysis (kNN-MFA) combined with various selection procedures. 30 3D QSAR models were generated; one of these models was selected on the basis of q(2) and pred_r(2) values. The selected Model has training set of 17 molecules and test set of 4 molecules with validation (q(2)) and cross validation (pred_r(2)) values of 0.6969 and 0.6148 respectively. Title compounds of 1,3,4-oxadiazole derivatives were synthesized by the ring closure reactions of various acylhydrazides with carbon disulphide (4a-e) and with aromatic acids in POCl(3) (5a-e). After structural elucidation, all the synthesized compounds were evaluated for their antimicrobial activity against Escherichia coli, Staphylococcus aureus and Staphylococcus epidermidis.

Docking-based virtual screening of Schiff’s bases of GABA: a prospective to novel GABA-AT inhibitors

The accurate prediction of the binding modes between the ligand and protein is of fundamental importance in modern structure-based drug design. In this study, computational ligand docking methodology, AutoDock 4.0, based on Lamarckian genetic algorithm was employed for virtual screens of a compound library with 233 entries (Schiff’s bases of γ-amino butyric acid) for novel and selective inhibitors of the enzyme γ-amino butyrate aminotransferase (GABA-AT), a potential anticonvulsant drug target. Considering free energy of binding and inhibition constant (KI) as a criteria of evaluation, a total of 43 compounds were predicted to be potential inhibitors of GABA-AT and 11 compounds displayed greater binding affinities than γ-vinyl GABA, Vigabatrin, a well-known GABA-AT inhibitor. Compound SBG164, a dibenzylideneacetone analog; compound SBG195, a 1-methylanthraquinone analog; and compound SBG110, a fenchone analog were the most potent in inhibiting the GABA-AT, in silico. Putative interactions between GABA-AT and inhibitors were identified by inspection of docking-predicted poses. This understanding of protein–ligand interaction and value of KI imparts impetus to the rapid development of prospective GABA-AT inhibitor. It also helps to eliminate the number of false positives and negatives.

In silico validation and structure activity relationship study of a series of pyridine-3-carbohydrazide derivatives as potential anticonvulsants in generalized and partial seizures.

A series of twelve compounds (Compounds RNH1-RNH12) of acid hydrazones of pyridine-3-carbohydrazide or nicotinic acid hydrazide was synthesized and evaluated for anticonvulsant activity by MES, scPTZ, minimal clonic seizure and corneal kindling seizure test. Neurotoxicity was also determined for these compounds by rotarod test. Results showed that halogen substitution at meta and para position of phenyl ring exhibited better protection than ortho substitution. Compounds RNH4 and RNH12, were found to be the active analogs displaying 6Hz ED50 of 75.4 and 14.77 mg/kg while the corresponding MES ED50 values were 113.4 and 29.3 mg/kg respectively. In addition, compound RNH12 also showed scPTZ ED50 of 54.2 mg/kg. In the series, compound RNH12 with trifluoromethoxy substituted phenyl ring was the most potent analog exhibiting protection in all four animal models of epilepsy. Molecular docking study has also shown significant binding interactions of these two compounds with 1OHV, 2A1H and 1PBQ receptors. Thus, N-[(meta or para halogen substituted) benzylidene] pyridine-3-carbohydrazides could be used as lead compounds in anticonvulsant drug design and discovery.

Heterocyclic Secretase Inhibitors for the Treatment of Alzheimer’s Disease: An Overview

Alzheimers disease (AD), the most common neurodegenerative disorder and demands to find a way for prevention and delayed onset. The development of therapeutics for AD is based on the amyloid cascade hypothesis (vaccines, β- and γ-Secretase inhibitors), or targeting tau and neurofibrillary tangle formation, neuroinflammation, etc. Cholinesterase, BACE-1, amyloid-β 1-42, γ and β-Secretase, Phosphodiesterase type IV (PDE4) inhibitors are the reported treatment strategies. Among these, the γ- and β-Secretase inhibitors can be clustered in several heterocyclic classes (imidazoles, thiazoles, indoles, benzaldehydes, pyrimidine, etc), with subsequent description of the structure-activity relationships, and extended to the pharmacological profile in order to evaluate their drug-likeness, with special attention to toxicity and bioavailability. This article discusses the approaches proposed by several research groups working on the synthesis of enzyme inhibitors, based on modelling studies and the way these findings were used to obtain new drugs for the treatment of AD.

Designing of Selective γ-Secretase Inhibitory Benzenesulfonamides through Comparative In Vitro and In Silico Analysis

BACKGROUND In Alzheimers disease (AD), the gene mutations have been identified in the amyloid precursor protein (APP), the presenilin-1 (PS1) and -2 (PS2) genes. APP is a transmembrane protein which gets cleaved by α- and β- secretase enzymes and releases Aβ peptides which forms senile plaques in brain tissue. It contributes for local inflammatory response, subsequent oxidative stress, biochemical changes and neuronal death. Targeting the development of Aβ aggregates in the senile plaques is an important strategy in the treatment of AD. To facilitate the normal processing of APP, some of the reported approaches are stimulation of α- secretase activity or the modulation/inhibition of the β- and γ-secretase complex. METHODS The mechanism of γ-secretase inhibition is targeted based on the QSAR and molecular docking methods. The series based on 3-chloro-2-hydroxymethylbenzenesulfonamide was selected for in silico ligand-based modeling. Significant correlations, between their γ-Secretase inhibitory profile and 2D-descriptors, were obtained through multiple linear regression (MLR) computational procedure. RESULTS During QSAR nalysis, calculated molar refractivity (CMR) and surface tension (ST) were found to be contributing parameters along with halogen substituent at a particular position. Applicability analysis revealed that the suggested models have acceptable predictability (rpred2 = 0.827). CONCLUSION The inferences drawn from MLR were utilized to prepare a data set of fourteen substituted benzenesulfonamides (N1-N14). The in silico studies provides strong impetus towards systematic application of such methods during lead identification and optimization.

N-Substituted Aryl Sulphonamides as Potential Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

INTRODUCTION A novel series of multifunctional anti-Alzheimers agents based on Nsubstituted aryl sulphonamides were designed and synthesized. During in vivo moderate to good anti- Alzheimers Disease (AD) activity was observed as correlated by the modulation of some selected biochemical markers of AD as well as during behavioral assessment. METHODS Among the series, some compounds have shown multi-functional potency by inhibition of Acetylcholinesterase (AChE), Scopolamine induced oxidative stress and were found comparable to the standard drug. Successful modulation of biochemical markers of oxidative stress in AD, displays neuroprotective properties and did not exert any significant toxicity. RESULTS AND CONCLUSION Thus, the present study has evidently shown that these series of compounds have potential to be optimized as anti-AD agents with multi-functional properties. The aryl sulphonamide nucleus might serve as a promising lead candidate for developing novel anti-AD drug.