R.L. Khosa’s research while affiliated with Bharat Institute of Technology and other places

Background In spite of current progress in treatment methods, cancer is a major source of morbidity and death rate all over the world. Traditional chemotherapeutic agents aim to divide cancerous cells, are often associated with deleterious side effects to healthy cells and tissues. Host defense peptides Cecropin A and B obtained from insects are capable to lyses various types of human cancer cells at peptide concentrations which are not fatal to normal eukaryotic cells. Methods In the present work we have designed short chain α-helical linear and cyclic peptide from cecropin A having same cationic charge, hydrophobicity and helicity. Synthesis of designed novel short chain linear (10) and cyclic compound (12) was accomplished by using solution phase method. All the coupling reactions were carried out by using dicyclohexylcarbodiimide (DCC) as the coupling reagent at room temperature in the presence of N-methylmorpholine (NMM) as the base. The Structure of newly synthesized peptidse were elucidated by 1H-NMR, 13C-NMR, FT-IR, FABMS and elemental analysis data.Cytotoxicity of synthesized compound was tested against Dalton’s Lymphoma Ascites (DLA), Ehrlich’s Ascites Carcinoma (EAC) and MCF-7 cell lines by using MTT assay and 5-FU as reference compound. Results From biological assessment,it was found that short chain cyclicpeptide12 showed high level of cytotoxic activity against DLA and EAC cell lines. Conclusion By utilizing a structure-based rational approach to anticancer peptide design from cecropin A, we were able to develop short chain linear and cyclic peptides having same charge, hydrophobicity and with improved activity. Systematically removing amino acids, we were able to retaining peptide charge and hydrophobicity/hydrophilicity in linear and cyclic peptide which results to optimize the anticancer activity against DLA and EAC cell lines.

Introduction: Epilepsy is a chronic neurological disorder, involving group of nerve cells, or neurons, in the brain. Many classes of antiepileptic drugs are being prescribed and used by the stake holders but most of them are associated with serious side effects and toxicity. There is a strong need of new antiepileptic molecules with less side effects and toxicity. Objective: A series of aryl acid hydrazones of Isonicotinic acid hydrazide (RINH1 -RINH14) were synthesized and evaluated for Anticonvulsant activity. Material and Method: Compounds (RINH1 -RINH14) were synthesized by refluxing Isonicotinic acid hydrazide with different substituted benzaldehydes/ substituted acetophenones in absolute ethanol. Melting points of all synthesized compounds were monitored by open glass-capillary tube method on Digital Melting point apparatus and are uncorrected. The synthesized compounds were tested for anticonvulsant potential using MES and scPTZ whereas neurotoxicity was determined using Rotarod model. Result and Discussion: At 100mg/kg compound RINH10 have shown 29% protection at both 0.5hr and 4.0 time interval .At 300mg/kg and 0.5 hr, compounds RINH4 and RINH10 showed 100% and 50 % protection respectively. Compounds RINH4 and RINH10 have better anti MES activity proving that halogens have prominent contribution in Anticonvulsant activity. In scPTZ screen, all synthesized Acid hydrazone (RINH1- RINH14 ) did not show any protection at 30, 100,300 mg/kg , at 0.5 hr and 4.0 hr duration .In rotorod test i.e neurotoxicity screen, compound RINH5, RINH6 , RINH10 have shown toxicity. Conclusion: The synthesized new molecules were proved to be having anticonvulsant activity with less signs of neurotoxicity.

Introduction: A novel series of multifunctional anti-Alzheimer's agents based on N-substituted aryl sulphonamides were designed and synthesized. During in vivo moderate to good anti-Alzheimer's 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 acetylchlinesterase (AChE), Scopolamine induced oxidative stress and were found comparable to the standard drug (Donepezil, 50µg/kg, i.p.). Successful modulation of biochemical markers of oxidative stress in AD, displays neuroprotective properties and did not exert any significant toxicity. Results: 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.

The present research work is targeted to develop an orally bioavailable form of Ceftriaxone using natural polysaccharide for sustaining and site specific release. The polysaccharide is linked with Ceftriaxone, a third generation cephalosporin (even effective against various flouroquinolone resistant strains) via an enzyme specific spacer dipeptide. The research work explains method for synthesis of polymeric prodrugs using natural polysaccharides and peptide spacer. The in vitro release of ceftriaxone from the polymeric prodrugs were evaluated in pH 1.2 (acidic buffer), simulated gastric fluid (pH 1.2 with pepsin), pH 7.4 (phosphate buffer) and simulated intestinal fluid (pH 7.4 with trypsin-chymotrypsin). The data showed that the release of Ceftriaxone is sustained over a period of 24 h (with a total of 69.38% drug release) at pH 1.2 while at pH 7.4 there was a sudden increase in the drug concentration (> 45% drug release within 15 min) with a total of 70.56% drug release in 24 h. The hydrolytic stability of AG (Gly-Phe-Ceftriaxone]n to pepsin was assessed in simulated gastric fluid (SGF) (pepsin) and simulated intestinal fluid (SIF) (trypsin, chymotrypsin). The amount of ceftriaxone released over a period of 24 h in the SGF was found to be 88.91%, which is less than that release in SIF, i.e., 91.44% indicating that the drug release takes place predominantly at higher pH of intestine. Also it was observed that in SGF, the drug release is sustained (T50 = 5.9) while in SIF there was a sudden increase in the drug concentration (> 66% drug release within 15 min) with a total of 91.44% drug release in 24 h. On the basis of above work Prunus amygdalus polysaccharide can be considered as a promising tool for the preparation of polymeric prodrugs. Method was found suitable for preparing prodrugs of required release profile. The prepared batches were found to release the drug within 24 hour period. Present data are supporting the utility of extracted natural polysaccharide as a polymer for developing polymeric prodrugs for oral sustained delivery of drugs.

Background: In Alzheimer's 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-hydroxymethyl-benzenesulfonamide 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.

Herbal drug therapy is the most trusted system of medicine in countries like India, where people strongly believe in Ayurveda as herbs are the part of rural Indian lifestyle. Most of the diseases which have no medicine in allopathic system can be cured successfully by using traditional medicines. Leea indica, a traditional Chinese medicinal plant is the sole member of the family Leeaceae, which is closely related to the economically important grape family, Vitaceae. It is widely distributed from Southern Asia to Northern Oceania. The plant parts are enriched with various bioactive compounds such as gallic acid, quercitrin, β-amyrin, β-sitosterol and lupeol, etc. Traditionally, it is used to treat itchy skin, fever, diarrhea, and body aches. The current review attempts to encompass the available literature on Leea indica with respect to its phytochemistry, traditional uses and gist of its various pharmacological activities.

Alzheimer's 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.

Graptophyllum pictum (L.) Griff. (Family-Acanthaceae) occupies a key role in traditional system of medicine. Since an extensive literature survey did not provide any information about studies on its standardization. Therefore, we designed the current study to establish the quality control parameters of G. pictum aerial parts. The investigation included determination of various standardization parameters such as macroscopic and microscopic studies, physicochemical parameters as well as phytochemical analysis of the crude drug. The microscopy study of aerial parts revealed that stem shows typical dicotyledonous characters with prismatic crystals of calcium oxalate in the cortical region and dorsiventral leaf. Physicochemical constants such as moisture content, ash values, fluorescence analysis, and extractive values were established. Preliminary phytochemical analysis confirmed the presence of alkaloids, flavonoids, saponins, tannins, etc. The present study suggests establishing the parameters for pharmacopoeial standardization of G. pictum.

Pandanus odoratissimus (Pandanaceae) is popular in the indigenous system of medicines like Ayurveda, Siddha, Unani and Homoeopathy. In the traditional system of medicine various plant parts such as leaves, root, flowers, and oils are used as anthelmintic, tonic, stomachic, digestive and in the treatment of jaundice and various liver disorders. The aim was to investigate the hepatoprotective activity of ethanolic extract of the root of P. odoratissimus against paracetamol (PCM) induced hepatotoxicity in rats. Hepatotoxicity was induced in male Wistar rat by PCM (2 g/kg b.w. p.o. for 7 days). The ethanolic extract of P. odoratissimus root was administered at the dose level of 200 mg/kg and 400 mg/kg b.w. orally for 7 days and silymarin (100 mg/kg b.w. p.o.) as standard drug was administered once daily for a week. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic-pyruvic transaminase, serum alkaline phosphatase, total and direct bilirubin and triglycerides. Histopathological study of rat liver was also done. Experimental findings revealed that the extract at dose level of 200 mg/kg and 400 mg/kg of b.w. showed dose dependant hepatoprotective effect against PCM induced hepatotoxicity by significantly restoring the levels of serum enzymes to normal that was comparable to that of silymarin, but the extract at dose level of 400 mg/kg was found to be more potent when compared to that of 200 mg/kg. Besides, the results obtained from histopathological study also support the study. From the results, it can be concluded that ethanolic extract of the root of P. odoratissimus afforded significant protection against PCM induced hepatotoxicity in rats.

Objective: To investigate the hepatoprotective activity of ethanolic extract of leaves of Caesalpenia crista (C. crista) against paracetamol induced hepatotoxicity in rats. Methods: Paracetamol (2 g/kg body weight) was used to induce hepatotoxicity in albino rats. Ethanolic extract of leaves of C. crista was administered at the dose levels of 200 and 400 mg/kg body weight orally for 7 d. Silymarin (100 mg/kg) was used as standard drug. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, serum alkaline phosphatase, bilirubin (total and direct), and triglycerides content. Histopathological study of rat liver was also done. Results: Administration of ethanolic extract at doses 200 mg/kg and 400 mg/kg body weight exhibited significant reduction in elevated level of serum marker enzymes, bilirubin (total and direct) and triglycerides when compared to positive control group. Conclusions: It is concluded that the ethanolic extract of C. crista leaves seems to justify the promising hepatoprotective effect on paracetamol induced liver damage in rats.