Pharmacological exploration of traditional plants for the treatment of neurodegenerative disorders.

Alzheimer's disease (AD) is clinically characterized as memory deficits, altered behavior and impaired cognitive functions. The most important risk factor for AD is aging and mounting. Evidences suggested in different studies that traditionally used plants in Asia, China, and Europe significantly affect aging and AD involved neurodegeneration pathways. Research into ethnobotanicals for impaired memory and cognition has been burgeoned in last decades. The inclusion and exclusion criteria for the plant selection were based on reputed herbs recommended for treatment of neurological disorders and their scientific validation to cure neurodegenerative disorders. A range of traditional plants imparts effects via acetylcholinesterase activity, ß-amyloid peptide formation in plaques, neurotrophic factors and through antioxidant activity. On one side preclinical investigations identified promising drug candidates for AD, on the other side, clinical evidences are still pending. Presently, according to WHO, around more than 80% world population relay on natural remedies to cure their health related issues. Plants contain rich source of primary and secondary metabolites for improving health problems. Pharmaceutical industry is facing intriguing challenges like elevated cost and unendurable risk management due to the high burden of neurodegenerative disorders. A significant shift of drug discovery is being witnessed from synthetic moieties to herbal formulation.

Synthesis, computational studies, tyrosinase inhibitory kinetics and antimelanogenic activity of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives.

The over expression of melanogenic enzymes like tyrosinase caused many hyperpigmentaion disorders. The present work describes the synthesis of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives 3a-e and 5a-e as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives 3a-e and 5a-e was determined and it was found that derivative 5c possesses excellent activity with IC50 = 0.0089 µM compared to standard kojic acid (IC50 = 16.69 µM). The presence of hydroxyl groups at the ortho and the para position of cinnamic acid phenyl ring in compound 5c plays a vital role in tyrosinase inhibitory activity. The compound 5d also exhibited good activity (IC50 = 8.26 µM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound 5c is a competitive inhibitor while 5d is a mixed-type inhibitor. The mode of binding for compounds 5c and 5d with tyrosinase enzyme was also assessed and it was found that both derivatives irreversibly bind with target enzyme. The molecular docking and molecular dynamic simulation studies were also performed to find the position of attachment of synthesized compounds at tyrosinase enzyme (PDB ID 2Y9X). The results showed that all of the synthesized compounds bind well with the active binding sites and most potent derivative 5c formed stable complex with target protein. The cytotoxicity results showed that compound 5c is safe at a dose of 12 µg/mL against murine melanoma (B16F10) cells. The same dose of 5c was selected to determine antimelanogenic activity; the results showed that it produced antimelenogenic effects in murine melanoma (B16F10) cells. Based on our investigations, it was proposed that compound 5c may serve as a lead structure to design more potent antimelanogenic agents.

SHORT COMMUNICATION-Anticancer activity of Ziziphus mauritiana roots against human breast cancer cell line.

This study was designed to evaluate the anticancer activity of Ziziphus mauritiana roots. The dichloromethane and methanol extracts were prepared and anticancer activity was investigated the by using MTT assay. Human breast cancer cell line (MCF-7) was used in this study. 50µg/ml of dichloromethane extract of the roots of plant exhibited significant anticancer activity (70%) against the breast cancer cell line with IC50 20.34±0.9 using doxorubicin as standard. The study indicated that Ziziphus mauritiana has anticancer activity against MCF-7 cell line.

Erupt of malaria, dengue and chikungunya in Pakistan: Recent insights about prevalence, diagnosis and treatment.

Malaria, dengue and chikungunya are the most rampant mosquito-borne infections predominantly in Pakistan. They pose a serious threat and cause a havoc for the victims owing to the life threatening signs and symptoms marked with elevated morbidity and mortality rate. It seems hard to discriminate due to common indications, consequently, deserves appropriate diagnosis prior elevated toll of death. Present article encompasses depth insights about their prevalence, diagnosis and clinical manifestation if erupt in the pandemic. However, host-vector-host cycle is the root cause of transmission and diverse mosquito species confer dissimilar infections. Indeed these infections are seasonal but other factors like flood, open irrigation channels, immense agricultural land, rich fauna and water reservoirs can't be overlooked. Dire need was felt to acknowledge and aware the public about local transmission, vector control, entomologic, research resources, diagnosis and advancement in healthcare system to alleviate them absolutely in future.

Evaluation of different Pakistani medicinal plants for inhibitory potential against Echis carinatus induced Phospholipase A2 toxicity.

Medicinal plants of Pakistan are known for their curative properties against snake bite as rural people have been using natural herbs for such injuries for hundreds to thousands of years. People of rural areas of Pakistan are prone to snakebite, and on the whole death due to snakebite has been increasing worldwide. The objective of this study was to test the neutralizing potential of 17 Pakistani medicinal plant extracts against phospholipase A2 activity in Echis carinatus venom. Plant material was extracted by simple maceration and fractionation of active plant extracts. Venom was collected by manual massage of the venom glands. The PLA2 enzymatic assay was performed to map out the venomous activity of Echis carinatus envenomation. Snake venom released fatty acids at different concentrations (0.1-5 mg/ml) of venom in a dose-dependent manner. Reduction of pH by 01 correlated with 133 µmol of fatty acids released at 5mg/ml of venom. All plants extract inhibited PLA2 activity, however, Curcuma longa, Citrullus colocynthis and Rubia cordifolia inhibited maximum of PLA2 activity (⁓78%) comparable to the standard antidote (p>0.5). Medicinal plants possess secondary metabolites and many active compounds that may have neutralizing or inhibiting properties against the PLA2 activity of Echis venom. Further studies such as compound analysis could provide an alternative against snakebites injuries resulting from Echis carinatus venom.

ACETYL CHOLINESTERASE AND BUTYRYL CHOLINESTERASE INhIBITORY ACTIVITIES OF ZALEYA PENTANDRA.

The aim of this study was to reveal acetyl cholinesterase (AchE) and butyryl cholinesterase (BchE) inhibitory activities of Zaleya pentandra. The aerial parts of the plant were air, freeze-dried and powdered. The extraction was carried out with methanol at room temperature for 24 h. The extract was concentrated on rotavapor and fractioned by column chromatography. The isolation and purification afforded amorphous solid which was subjected to physical, chemical and spectroscopic techniques i.e., UV, IR, H-NMR, "C-NMR and HREI-MS for the structure elucidation of the isolated compound. The compound was concluded as "Pentandradione" a novel compound. AchE and BchE inhibitory activities were estimated. The result showed that the isolated extract possessed significant activity against butyryl cholinesterase as compared to standard eserine while the extract lacks acetyl cholinesterase inhibitory activity.

PLANTAGO OVATA: A COMPREHENSIVE REVIEW ON CULTIVATION, BIOCHEMICAL, PHARMACEUTICAL AND PHARMACOLOGICAL ASPECTS.

The basic aspire of current study was to review different aspects of Plantago ovata together with its cultivation, growth, biochemistry, pharmaceutical and pharmacological attributes. Plantago ovata belongs to family Plantaginaceae. It is an annual herb, indigenous to Mediterranean region especially Southern Europe, North Africa and West Asia. Different electronic databases (Medline, Science Direct, Springer link, Pubmed, Google and Google Scholar) were analyzed for the literature on medicinal properties of Plantago ovata. The literature analysis has revealed that Plantago ovata has been endowed with diverse pharmaceutical and pharmacological activities. It is widely used in numerous medicines owing to its both pharmaceutical properties such as mucilage, superdisintegrant, gelling agent, suspending agent as well as pharmacological actions like anti-diarrheal, anti-constipation, wound healer, hypocholestrolemic and hypoglycemic. Thus, Plantago ovata can be employed in the manufacture of a number of pharmaceutical products as well as a safe and efficacious ethnobotanical remedy in several health problems.

Development and evaluation of novel antihypertensive orodispersible tablets.

Objective of present study was to enhance patient compliance in pediatrics and geriatrics patients of Hypertension. To achieve this target, innovative orodispersible tablets of atenolol and atorvastatin was developed to produce instant action by rapidly disintegrating into oral cavity. Three different techniques like direct compression, effervescent and sublimation methods were used to prepare these tablets (Five batches of tablets by each method) by using two superdisintegrants like Sodium starch glycolate and pregelatinized starch alone and in combination. Pre-formulation studies including rheological analysis (Bulk density, tapped density, Angle of repose, Carr's compressibility index, Hausner's ratio), compatibility studies such as Fourier transform infrared spectrophotometry (FTIR) and Differential scanning colorimetry (DSC), Post-compression and stability studies were also performed. Finally, results were statistically evaluated by the applying one way ANOVA test and mean. It was concluded that the formulation F8 containing Sodium starch glycolate 2% and pregelatinized starch 6% found best regarding disintegration time, wetting volume, wetting time, release studies etc. The order in which drug release was quicker is Pregelatinized starch plus Sodium starch glycolate > Pregelatinized starch > Sodium starch glycolate (primojel). It was concluded that sublimation method was the best among three methods used for orodispersible tablets formulations.

Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen-Antioxidant Mutual Prodrugs.

Dexibuprofen-antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a-c were obtained by reacting its -COOH group with chloroacetyl derivatives 3a-c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a-c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a-c interacts with the residues present in active binding sites of target protein. The stability of drug-target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.

GENUS RUELLIA: PHARMACOLOGICAL AND PHYTOCHEMICAL IMPORTANCE IN ETHNOPHARMACOLOGY.

Ruellia is a genus of flowering plants commonly known as Ruellias or Wild Petunias which belongs to the family Acanthaceae. It contains about 250 genera and 2500 species. Most of these are shrubs, or twining vines; some are epiphytes. Only a few species are distributed in temperate regions. They are distributed in Indonesia and Malaysia, Africa, Brazil, Central America and Pakistan. Some of these are used as medicinal plants. Many species of the genus has antinociceptive, antioxidant, analgesic, antispasmolytic, antiulcer, antidiabetic and anti-inflammatory properties. The phytochemicals constituents: glycosides, alkaloids, flavonoids and triterpenoids are present. The genus has been traditionally claimed to be used for the treatment of flu, asthma, fever, bronchitis, high blood pressure, eczema, and diabetes. The objective of this review article is to summarize all the pharmacological and phytochemical evaluations or investigations to find area of gap and endorse this genus a step towards commercial drug. Hence, further work required is to isolate and characterize the active compounds responsible for these activities in this plant and bring this genus plants to commercial health market to serve community with their potential benefits.

Neurological Manifestations of Chronic Methadone Maintenance Therapy: A Case Report and Literature Review.

Methadone is a long-acting opioid medication that is used as maintenance therapy for heroin addiction. We present a case of a patient on methadone maintenance therapy for chronic back pain who developed neurological complications. The patient presented with mental status changes and choreiform movements. Workup revealed lesions involving the subcortical white matter and basal ganglia. Choreiform movements improved after the initiation of treatment with topiramate, clonazepam, and risperidone. This combination was chosen as several prior case reports published significant benefit and improvement in choreiform movements with the mentioned regimen.

Anti-5'-Nucleotidases (5'-ND) and Acetylcholinesterase (AChE) Activities of Medicinal Plants to Combat Echis carinatus Venom-Induced Toxicities.

Echis carinatus is one of the highly venomous snakes of Pakistan that is responsible for numerous cases of envenomation and deaths. In Pakistan, medicinal plants are commonly used traditionally for snakebite treatment because of their low cost and easy availability in comparison with antivenom. The current research is aimed at evaluating the inhibitory activity of Pakistani medicinal plants against acetylcholinesterase and 5'-nucleotidases present in Echis carinatus venom. Acetylcholinesterase and 5'-nucleotidase enzymatic assays were performed at different venom concentrations to check the activity of these enzymes. Methanolic extracts from different parts of plants were used for in vitro determination of their inhibitory activity against 5'-nucleotidases in snake venom. Active methanolic extracts were subsequently fractioned using different solvents, and these fractions were also assessed for their anti-5'-nucleotidase activity. Results of this study exhibited that Eugenia jambolana Willd. ex O. Berg, Rubia cordifolia L., Trichodesma indicum (L.) R. Br., Calotropis procera (Wild.) R. Br., Curcuma longa L., and Fagonia arabica L. were able to significantly (p > 0.5) neutralize the 5'-nucleotidase activity by 88%, 86%, 86%, 85%, 83.7%, and 83%, respectively, compared with a standard antidote (snake venom antiserum). Thus, this study indicates that these plants possess the potential to neutralize one of the toxic enzymatic components of Echis carinatus venom and hence can help to augment the future efforts of developing alternative therapy for the management of snakebites.

Effect of herbal formulation intake on health indices in albino Wistar rat model.

Dyslipidemia management activity of ginger-, garlic-, and lemon-based herbal mixture was tested as paste and herbal extract in hypercholesterolemic adult male albino rats. Atherogenic diet-induced hypercholesterolemia in rats was treated by supplementing the diet with 2.5% herbal paste (4.2 g/kg b.w.) or 2.5 ml oral gavage (20 ml/kg b.w.) of liquid herbal extract daily for 42 days. Hematological and serological outcomes of herbal formulation feeding were compared with the cholesterol-fed positive control and normal control. The results suggest the significant (p < .05) inhibitory properties of herbal paste and liquid extracts against dyslipidemia showing 31%-37%, 62%-68%, and 40%-56% lower levels of total cholesterol, triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), respectively. Treating cholesterol-fed animals with herbal paste and extract significantly (p < .05) increased total protein (5-5.5 g/dl) and serum albumin (3.7-4.2 g/dl) concentration as compared to the normal control. Contrary to significant hypocholesterolemic activity, higher serum total bilirubin levels, that is, 0.70 mg/dl, were observed in rats subchronically exposed to herbal paste and liquid extracts. Nonsignificant (p > .05) impact of herbal formula feeding was observed on hematological indices except lymphocyte counts, that is, 93% in rats fed on herbal paste. The results validate conventional hypocholesterolemic claims associated with ginger-, garlic-, and lemon-based herbal formulations; however, deeper insight into their dose-dependent response in hypercholesterolemia is necessitated to rule out the toxicological impact on the consumer.

Diagnostic Performance and Appropriate Cut-Offs of Different Anthropometric Indicators for Detecting Children with Overweight and Obesity.

In the clinical settings, different anthropometric indicators like neck circumference (NC), waist circumference (WC), midupper arm circumference (MUAC), waist-to-height ratio (WHtR), and arm-to-height ratio (AHtR) have been suggested for evaluating overweight and obesity in children. The comparative ability of these indicators in Pakistan is yet unknown. This study is aimed at examining the validity of different anthropometric indicators of overweight and obesity simultaneously and at determining their superlative cut-off values that would correctly detect overweight and obesity in children. For this purpose, the dataset of anthropometric measurements height, weight, WC, MUAC, and NC of 5,964 Pakistani children, aged 5-12 years collected in a cross-sectional multiethnic anthropometric survey (MEAS), was used. Receiver operating characteristic (ROC) curve analysis was performed to assess the validity of different anthropometric indicators. The most sensitive and specific cut-off points, positive and negative predictive values of each indicator were also calculated. The results of the ROC curve indicated that all the studied indicators had a good performance but the indicators AHtR and WHtR had the highest value of the area under the curve (AUC) for the screening of children with overweight and obesity (AUC > 0.80). In the overall sample, AHtR, WHtR, MUAC, WC, and NC cut-off points indicative of overweight, in both boys and girls, were 0.14, 0.46, 18.41 cm, 62.86 cm, and 26.36 cm and 0.14, 0.47, 18.16 cm, 64.39 cm, and 26.54 cm, respectively; the corresponding values for obesity were 0.14, 0.47, 18.67 cm, 62.10 cm, and 26.36 cm and 0.14, 0.48, 20.19 cm, 64.39 cm, and 25.27 cm. We concluded that the sex-specific cut-off points for AHtR, WHtR, MUAC, WC, and NC can be used to diagnose overweight and obesity in Pakistani children.

Formulation, Optimization, In Vitro and In Vivo Evaluation of Saxagliptin-Loaded Lipospheres for an Improved Pharmacokinetic Behavior.

The development and optimization of controlled release lipospheres (LS) from safe biocompatible behenic acid (BA) was performed for not only enhancing patient's compliance against highly prevailed chronic diabetes but also to vanquish the insufficiencies of traditional methods of drug delivery. The Box-Bhenken design (BBD) was utilized to statistically investigate the impact of formulation variables on percentage yield (Y 1), entrapment efficiency (Y 2), and SG-release (Y 3) from saxagliptin- (SG-) loaded LS, and the chosen optimized LS were subjected to a comparative in vivo pharmacokinetic analysis against commercially available SG brand. The compatibility analysis performed by DSC and FTIR established a complete lack of interaction of formulation components with SG, while p-XRD suggested a mild transformation of crystalline drug to its amorphous form during encapsulation process. The spherical, free flowing smooth surface LS having zeta potential of -32 mV and size range of 11-20 µm were conveniently formulated. The obtained data for Y 1 (30-80%), Y 2 (30-70%), and Y 3 (40-90%) showed a best fit with quadratic model. The pharmacokinetics analysis of LS showed a significantly decreased C max of SG (75.63 ± 3.85) with a sufficiently elevated T max (10.53 h) as compared to commercial brand of SG (99.66 ± 2.97 ng/mL and 3.55 ± 2.18 h). The achievement of greater bioavailability of SG was most probably attributed to higher level of half-life, mean residence time (MRT), and AUC0-24 for SG released from LS. Conclusively, the novel approach of SG-loaded LS had successfully sustained the plasma SG level for a prolonged time without increasing C max which would ultimately bring an effective management of chronic diabetes.

Isolation, Characterization and Preliminary Cytotoxic and Antifungal Evaluations of Novel Lancifoliate Isolated from Methanol Extract of Conocarpus lancifolius.

BACKGROUND: Combretaceae is a large family comprising of 500 species and 20 genera distributed in subtropical and tropical regions of the world. Conocarpus genus is an ornamental tree native to coastal and riverine areas of East Africa and is also planted as an ornamental plant in different areas of Pakistan. This genus has proved medicinal value as a cytotoxic, antibacterial, antiprotozoal, anti-leishmanial, antifungal and antidiabetic agent. OBJECTIVE: The current study was designed to screen the selected pharmacological attributes of sulphur containing novel compound isolated from Conocarpus lancifolius using a series of in vitro and molecular docking models. MATERIALS AND METHODS: After collection and authentication of plant material, methanolic extract was prepared from which various secondary metabolites were qualitatively examined. The compound was isolated using open column chromatography and the structure was established with spectroscopic techniques such as UV-visible, infrared spectroscopy, proton nuclear magnetic resonance (1H-NMR), 13C NMR (BB, DEPT-135, 90), twodimensional correlation techniques (HMBC, HSQC) and mass spectrometry (HRMS) respectively. C. lancifolius extract and isolated compound were studied for cytotoxic and antifungal potentials using in vitro Sulforhodamine B (SRB) and disc diffusion methods, respectively. Molecular docking studies were conducted to check the interaction of the isolated compound with major oncogenic proteins. RESULTS: Qualitative phytochemical screening revealed the presence of saponins, steroids, flavonoids, anthraquinones, and cardiac glycosides while alkaloids were absent in C. lancifolius extract. Isolated compound was characterized as lancifoliate, which showed cytotoxic activity towards a variety of cancer cell lines including murine lymphocytic leukemia (P-388, IC50 = 2.65µg/ml), human colon cancer (Col-2, IC50 = 0.84µg/ml), human breast cancer (MCF-7, IC50 = 0.72µg/ml) while no cytotoxic activity was observed towards human lung cancer (Lu-1), rat normal glioma cells (ASK, IC50 = 11.6µg/ml) and human embryonic kidney cells (Kek293, IC50 = 6.74µg/ml) respectively. Minimum Inhibitory Concentration (MIC) of Lancifoliate towards Aspergillus fumigatus, Aspergillus nigar (skin sample), Aspergillus flavus (pleural fluid) and Candida albicans (urine and blood samples) was found to be 54.5, 44.8, 43.5, 22.4 and 20.2µg/ml respectively. Moreover, docking results are in strong agreement with our experimental finding, which has identified lancifoliate to be a more potent antiproliferative agent than previously known compound ellipticine. CONCLUSION: C. lancifolius extract and lancifoliate possess potent cytotoxic and antifungal properties and thus has potential to be further studied. To the best of our knowledge, this is the first study that highlights isolation, identification and pharmacological activities of lancifoliate from Conocarpus lancifolius.

Antiplatelet Aggregation, Cardiotonic, Anti-Inflammatory, Antioxidant, and Calcium Channel Antagonistic Potentials of Nepeta ruderalis Buch.

The objective of this study was to authenticate the ethnobotanical claims of the Nepeta ruderalis Buch.-Ham. (N. ruderalis) extract in the traditional system of medicine. Crude extract was prepared via a simple maceration process. DPPH free radical scavenging and carrageenan-induced rat paw edema models were used to monitor antioxidant and anti-inflammatory responses of the N. ruderalis extract. Furthermore, it was tested for antiplatelet aggregation, cardioprotective, and calcium channel antagonistic activities via standard documented protocols. The N. ruderalis extract exhibited 80.82% antioxidant activity (IC50 = 207.51 ± 4.36 µg) while the anti-inflammatory response was significant (p < 0.05 to p < 0.01) at 50 mg/kg (45.58%) and 100 mg/kg (60.90%) doses. Moreover, it was found to inhibit platelet aggregation (IC50 = 1.06 and 0.91 mg/mL) and, in addition, to increase the force of contraction at the concentration of 3.0-10 mg/mL with a decrease in the heart rate on isolated paired atria (EC50 = 11.78 mg/mL). Relaxant activity was observed on the isolated rabbit jejunum (EC50 = 0.96 mg/mL) and trachea (EC50 = 0.89 mg/mL). However, in a cumulative way, an 80-millimolar potassium-induced contraction was evaluated (EC50 = 1.31 mg/mL). The N. ruderalis extract exhibited antioxidant, anti-inflammatory, platelet aggregating, cardiotonic, and calcium channel antagonistic activities, therefore proving scientifically its effectiveness in the traditional system of medicine.

Sulfonamide-Based Azaheterocyclic Schiff Base Derivatives as Potential Carbonic Anhydrase Inhibitors: Synthesis, Cytotoxicity, and Enzyme Inhibitory Kinetics.

A series of sulfonamide-bearing azaheterocyclic Schiff base derivatives 3(a-j) were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides 1(a-d) were reacted with N2H4 to get aromatic sulfonyl hydrazides 2(a-d). The intermediate hydrazides 2(a-d) were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases 3(a-j). The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of 3(a-j) on carbonic anhydrase activity were determined, and it was found that derivative 3c exhibited the most potent activity with IC500.84 ± 0.12 µM among all other derivatives and is also more active than standard acetazolamide (IC500.91 ± 0.12). The enzyme inhibitory kinetics results determined by Lineweaver-Burk plots revealed that compound 3c inhibits the enzyme by noncompetitive mode of inhibition with K i value 8.6 µM. The molecular docking investigations of the synthesized analogues 3(a-j) were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF-7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose-dependent manner. Based on our investigations, it was suggested that analogue 3c may serve as core structure to project carbonic anhydrase inhibitors with greater potency.

Dexibuprofen amide derivatives as potential anticancer agents: synthesis, in silico docking, bioevaluation, and molecular dynamic simulation.

BACKGROUND: The amide derivatives of nonsteroidal anti-inflammatory drugs have been reported to possess antitumor activity. The present work describes the synthesis of dexibuprofen amide analogues (4a-j) as potential anticancer agents. METHODS: The title amides (4a-j) were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data. RESULTS: The brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide (4e) and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide (4g) exhibited excellent antitumor activity compared to all other derivatives. The compound 4e bearing 2,5-dichloro substituted phenyl ring and 4g possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative 4e exhibited excellent growth inhibition of cancer cells with IC50 value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds 4e and 4g showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds 4e and 4g. The MD simulation analysis assured that the 4e formed a more stable complex with the target protein than the 4g. The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found. CONCLUSION: Based upon our wet lab and dry lab findings we propose that dexibuprofen analogue 4e may serve as a lead structure for the design of more potent anticancer drugs.

Glycemic and Insulinemic Responses of Vegetables and Beans Powders Supplemented Chapattis in Healthy Humans: A Randomized, Crossover Trial.

Vegetables and beans are nutrient-dense foods with innate potential to mediate diabetes in a variety of cultures. The present study aims at evaluating vegetables and beans for assessing their glycemic index and response in raising glucose levels in human model. Powdered formulations of vegetables and beans were designed to modulate glycemic response of carbohydrate-rich staples. A randomized, crossover trial was conducted in healthy young adults (n = 24) who were challenged with vegetable powder-supplemented chapatti (VPSC), bean powder-supplemented chapatti (BPSC) and all-purpose wheat flour chapatti (APFC) to evaluate their postprandial glucose (PPG) and postprandial insulin (PPI) responses. In comparison with APFC, feeding VPSC and BPSC to healthy volunteers anticipated significant reduction in PPG (44% reduction in incremental area under the curve (AUC) for VPSC and 46% reduction in incremental AUC for BPSC, p = 0.005). Likewise, significant reduction in PPI levels was observed for VPSC (59%, p = 0.012) and BPSC (47%, p = 0.002) compared to APFC-treated group. The study concludes wheat flour enrichment with vegetables and beans powder as a viable approach to develop cost effective and culturally acceptable low glycemic foods bearing acceptable sensory attributes.