Newly synthesized acridone derivatives targeting lung cancer: A toxicity and xenograft model study.

AKT is one of the overexpressed targets in nonsmall cell lung cancer (NSCLC) and plays an important role in its progression and offers an attractive target for the therapy. The PI3K/AKT/mTOR pathway is upregulated in NSCLC. Acridone is an important heterocycle compound which treats cancer through various mechanisms including AKT as a target. In the present work, the study was designed to evaluate the safety profile of three acridone derivatives (AC-2, AC-7, and AC-26) by acute and repeated dose oral toxicity. In addition to this, we also checked the pAKT overexpression and its control by these derivatives in tumor xenograft model. The results from acute and repeated dose toxicity showed these compounds to be highly safe and free from any toxicity, mortality, or significant alteration in body weight, food, and water intake in the rats. In the repeated dose toxicity, compounds showed negligible variations in a few hematological parameters at 400 mg/kg. The histopathology, biochemical, and urine parameters remained unchanged. The xenograft model study demonstrated AC-2 to be inhibiting HOP-62 induced tumor via reduction in p-AKT1 (Ser473) expression significantly. In immunofluorescence staining AC-2 treated tissue section showed 2.5 fold reduction in the expression of p-AKT1 (Ser473). Histopathology studies showed the destruction of tumor cells with increased necrosis after treatment. The study concluded that AC-2 causes cell necrosis in tumor cells via blocking the p-AKT1 expression. The findings may provide a strong basis for further clinical applications of acridone derivatives in NSCLC.

Using nanotechnology to progress the utilization of marine natural products in combating multidrug resistance in cancer: A prospective strategy.

Achieving targeted, customized, and combination therapies with clarity of the involved molecular pathways is crucial in the treatment as well as overcoming multidrug resistance (MDR) in cancer. Nanotechnology has emerged as an innovative and promising approach to address the problem of drug resistance. Developing nano-formulation-based therapies using therapeutic agents poses a synergistic effect to overcome MDR in cancer. In this review, we aimed to highlight the important pathways involved in the progression of MDR in cancer mediated through nanotechnology-based approaches that have been employed to circumvent them in recent years. Here, we also discussed the potential use of marine metabolites to treat MDR in cancer, utilizing active drug-targeting nanomedicine-based techniques to enhance selective drug accumulation in cancer cells. The discussion also provides future insights for developing complex targeted, multistage responsive nanomedical drug delivery systems for effective cancer treatments. We propose more combinational studies and their validation for the possible marine-based nanoformulations for future development.

Gut microbial metabolites of dietary polyphenols and their potential role in human health and diseases

Polyphenols contribute as one of the largest groups of compounds among all the phytochemicals. Common sources of dietary polyphenols are vegetables, fruits, berries, cereals, whole grains, etc. Owing to their original form, they are difficult to get absorbed. Dietary polyphenols after undergoing gut microbial metabolism form bioaccessible and effective metabolites. Polyphenols and derived metabolites are all together a diversified group of compounds exhibiting pharmacological activities against cardiovascular, cancer, oxidative stress, inflammatory, and bacterial diseases. The formed metabolites are sometimes even more bioavailable and efficacious than the parent polyphenols. Studies on gut microbial metabolism of dietary polyphenols have introduced new approach for the use of polyphenol-rich food in the form of supplementary diet. This review provides insights on various aspects including classification of polyphenols, gut microbiota-mediated metabolism of polyphenols, chemistry of polyphenol metabolism, and pharmacological actions of gut microbial metabolites of polyphenols. It also suggests the use of polyphenols from marine source for the microbial metabolism studies. Till date, gut microbial metabolism of polyphenols from terrestrial sources is extensively studied as compared to marine polyphenols. Marine ecosystem is a profound but partially explored source of phytoconstituents. Among them, edible seaweeds contain high concentration of polyphenols, especially phlorotannins. Hence, microbial metabolism studies of seaweeds can unravel the pharmacological potential of marine polyphenol-derived metabolites. (AU)

Gut microbial metabolites of dietary polyphenols and their potential role in human health and diseases.

Polyphenols contribute as one of the largest groups of compounds among all the phytochemicals. Common sources of dietary polyphenols are vegetables, fruits, berries, cereals, whole grains, etc. Owing to their original form, they are difficult to get absorbed. Dietary polyphenols after undergoing gut microbial metabolism form bioaccessible and effective metabolites. Polyphenols and derived metabolites are all together a diversified group of compounds exhibiting pharmacological activities against cardiovascular, cancer, oxidative stress, inflammatory, and bacterial diseases. The formed metabolites are sometimes even more bioavailable and efficacious than the parent polyphenols. Studies on gut microbial metabolism of dietary polyphenols have introduced new approach for the use of polyphenol-rich food in the form of supplementary diet. This review provides insights on various aspects including classification of polyphenols, gut microbiota-mediated metabolism of polyphenols, chemistry of polyphenol metabolism, and pharmacological actions of gut microbial metabolites of polyphenols. It also suggests the use of polyphenols from marine source for the microbial metabolism studies. Till date, gut microbial metabolism of polyphenols from terrestrial sources is extensively studied as compared to marine polyphenols. Marine ecosystem is a profound but partially explored source of phytoconstituents. Among them, edible seaweeds contain high concentration of polyphenols, especially phlorotannins. Hence, microbial metabolism studies of seaweeds can unravel the pharmacological potential of marine polyphenol-derived metabolites.

Design, synthesis and evaluation of acridone-2-carbohydrazide derivatives as p-AKT Ser473 kinase inhibitors.

Aim: A series of benzylidene- and phenylethylidene-substituted acridone-2-carbohydrazide derivatives were designed, synthesized and evaluated for their cytotoxicity and response to p-AKT Ser473. Methods: The structures of the synthesized compounds were confirmed by spectroscopic techniques and evaluated for AKT enzyme inhibition activities. Molecular docking and in silico absorption, distribution, metabolism, elimination and toxicity studies were also performed. Results: Compounds 8k, 8v and 9h demonstrated good cytotoxicity against breast cancer cell lines. Especially, compounds 8v and 9h exhibited remarkable inhibition, with IC50 values of 1.75 and 2.40 µM, respectively. These compounds inhibited p-AKT Ser473 more specifically than total AKT in a dose-dependent manner. Moreover, they caused G0/G1-phase cell cycle arrest and cell apoptosis. Conclusion: This study identified compound 8v as a potent p-AKT Ser473 inhibitor.

Evaluation of N 10 -substituted acridone-based derivatives as AKT inhibitors against breast cancer cells: in vitro and molecular docking studies.

A series of N 10 -substituted acridone-2-carboxamide derivatives were synthesized and evaluated for their potent anti-cancer agents targeting AKT kinase. In vitro cytotoxicity activity of the target compounds was tested against breast cancer cell lines (MCF-7 and MDA-MB-231). Among the tested compounds, four compounds (7f, 8d, 8e, and 8f) exhibited promising anti-cancer activity against both cancer cell lines. Notably, compound 8f demonstrated the highest activity against MCF-7 and MDA-MB-231 at IC50 values of 4.72 and 5.53 µM, respectively. In vitro AKT kinase activity revealed that compounds 7f and 8f were the most potent AKT inhibitors with IC50 values of 5.38 and 6.90 µM, respectively. In addition, the quantitative ELISA method of testing confirmed that compound 8f effectively inhibited cell proliferation by suppressing the activation of p-AKT Ser473. Furthermore, molecular docking studies revealed that compound 8f can bind well to the active site of the AKT enzyme. The in silico ADME studies suggested that all synthesized molecules showed good oral bioavailability with a low-toxicity profile and can be used for further optimization as AKT kinase inhibitors in the treatment of breast cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03524-z.

The implications of quorum sensing inhibition in bacterial antibiotic resistance- with a special focus on aquaculture.

The aquaculture industry is an expanding and demanding industry and due to an increase in urbanization, with rise in income of developing countries population, it offers to provide a sustainable food supply. However, the industry is facing a number of challenges, out of which few needs to be tackled immediately to maximise the productivity. An upcoming problem is the emergence of antibiotic resistant pathogens due to the unchecked use of antibiotics in aquaculture and human clinical practices. A wide variety of aquatic pathogens such as Edwardsiella, Vibrio, and Aeromonas spp. use quorum sensing (QS) systems, a regulatory process involving cell communication via signalling molecules for the collective function of pathogens which regulates the genes expression including virulent genes. Quorum sensing results in bacterial biofilms formation, which leads to their reduced susceptibility towards antimicrobial agents. The usage of quorum sensing inhibitors (QSIs) has been proposed as an attractive strategy to tackle this problem. Due to the modulation of virulence genes expression, QSIs can be used as novel and viable approach to overcome antibiotic resistance in aquaculture. In this review, we direct our attention to the quorum sensing phenomenon and its viability as a target pathway for tackling the ever-growing problem of antimicrobial resistance in aquaculture. This review also provides a concise compilation of the currently available QSIs and investigates possible natural sources for quorum quenching.

Antifungal and antibacterial activity of marine sponges from Ratnagiri coast of India.

Marine sponges have proved to be a rich source of bioactive metabolites with multiple pharmacological properties. In this study, we have investigated the antifungal and antibacterial activities of methanol extracts of Cliona, Haliclona cratera, Hyrtios cavernosus, Spongia obscura, Sarcotragus foetidus, and Xestospongia carbonaria and fractions from X. carbonaria S. obscura and H. cratera. The antibacterial activity was determined by agar disc diffusion method against clinical gram-positive- Staphylococcus aureus, Bacillus subtilis and gram negative- Escherichia coli, Pseudomonas aeruginosa bacteria. The antifungal activity of the extracts and fractions was determined against Candida albicans and Aspergillus niger. S. obscura, X. carbonaria, H. cavernosus, and H. cratera exhibited good antibacterial activity against the tested gram-positive bacteria with larger zones of inhibition at 19±6 mm, 19.5±5.5mm, 20±0 mm and 23±0 mm. S. foetidus gave good inhibition of gram-negative bacteria at 19±0 mm. They showed moderate antifungal activities against C. albicans and A. niger. Cliona, H. cratera and H. cavernosus gave inhibition with 20±5 mm, 15.5±0.5 mm and 25.5±14.5 mm for A. niger. The MIC for Xc_PE_2, Sob_n but_1 and Hc_n but_3 was determined. H. cavernosus, S. foetidus, S. obscura and X. carbonaria showed presence of fatty acids and sterol type of compounds. The mass of molecular ions in purified fractions helped in characterization of known compounds in H. cratera, X. carbonaria and S. obscura which exhibited good antimicrobial activity.

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure-Activity Relationship.

Epidermal growth factor receptor (EGFR) belongs to the family of tyrosine kinase that is activated when a specific ligand binds to it. The EGFR plays a vital role in the cellular proliferation process, differentiation, and apoptosis. In the case of cancer, EGFR undergoes uncontrolled auto-phosphorylation that results in increased cellular proliferation and decreased apoptosis, causing cancer promotion. From the literature, it shows that pyrimidine is one of the most commonly studied heterocycles for its antiproliferative activity against EGFR inhibition. The authors have collated some interesting results in the heterocycle-fused pyrimidines that have been studied using different cell lines (sensitive and mutational) and in animal models to determine their activity and potency. It is quite clear that the fused systems are highly effective in inhibiting EGFR activity in cancer cells. Therefore, the structure-activity relationship (SAR) comes into play in determining the nature of the heterocycle and the substituents that are responsible for the increased activity and toxicity. Understanding the SAR of heterocycle-fused pyrimidines will help in getting a better overview of the molecules concerning their activity and potency profile as future EGFR inhibitors.

Microbial Diversity in the Indian Ocean Sediments: An Insight into the Distribution and Associated Factors.

Indian Ocean is the third largest oceanic division of the world and shelter to a huge microbial diversity. These microbes play an important role in the metabolism of carbon, sulfur, nitrogen, and phosphorus in the ocean water. They are also major contributors of carbon fixing and sequestration, as much as terrestrial plants to achieve CO2 emissions reduction. The prokaryotic community in the East Indian Ocean primarily comprises of heterotrophic bacteria like Alphaproteobacteria and Gammaproteobacteria, followed by Firmicutes and Actinobacteria. The Arabian Sea and the Bay of Bengal are typically characterized by presence of vast areas of oxygen minimum zones (OMZs) and have been witnessing a shift in the microbial diversity due to the changing conditions in the ocean water. Several canonical correspondence analyses reveal temperature, salinity, and phosphate levels as crucial environmental factors in propelling the distribution of diazotrophs. The viral consortia are dominated by the Caudovirales, an order of tailed bacteriophages. Due to the rapid change in the environmental factors such as topography, temperature, and sunlight contributing toward climate change, their role in sustaining the chemical composition of the ocean can be drastically affected especially with the evidence of several bacterial and fungal communities responding to latitudinal and temperature change. Therefore, we aim to critically review the status of microbial diversity in Indian Ocean to predict their response toward climate change as they are the sentinels of change in marine life and to understand the dynamics of microbial communities in the various locations of Indian Ocean.

Studies on ligand-based pharmacophore modeling approach in identifying potent future EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is a validated drug target for cancer chemotherapy. Mutations in EGFR are directly linked with the development of drug resistance and this has led for the development of newer drugs in quest for more efficacious inhibitors. The current research is focused on identifying potential and safe molecules as EGFR inhibitors by using both structure and ligand based computational approaches. In quest for finding newer moieties, we have developed a pharmacophore model utilizing drugs like lazertinib, osimertinib, nazartinib, avitinib, afatininb, and talazoparib that are known to inhibit EGFR along with their downstream signaling. Ligand-based pharmacophore model have been developed to screen the ZINC database through ZINCPharmer webserver. The server has identified 9482 best possible ligands with high pharmacophoric similarity i.e., RMSD value less than 0.2 Å. The top 10 ligands with the criteria of dock score(s) and interactions were further subjected to in silico ADMET studies giving two plausible ligands that were further subjected to Molecular Dynamics and MM/PBSA free energy calculations to ensure stability to the target site. Results deduced by in silico work in the current study may be corroborated biologically in the future. The current work, therefore, provides ample opportunity for computational and medicinal chemists to work in allied areas to facilitate the design and development of novel and more efficacious EGFR inhibitors for future experimental studies.

Design, synthesis, modelling studies and biological evaluation of 1,3,4-oxadiazole derivatives as potent anticancer agents targeting thymidine phosphorylase enzyme.

A series of novel 1,3,4-oxadiazole derivatives with substituted phenyl ring were designed and synthesized with an objective of discovering newer anti-cancer agents targeting thymidine phosphorylase enzyme (TP). The 1,3,4-oxadiazole derivatives were synthesized by simple and convenient methods in the lab. Chemical structure of the all the synthesized compounds were characterized by IR, 1H NMR and mass spectral methods and evaluated for cytotoxicity by MTT method against two breast cancer cell lines (MCF-7 and MDA-MB-231). Further, results of TP assay identified that 1,3,4-oxadiazole molecules displayed anti-cancer activity partially by inhibition of phosphorylation of thymidine. The TP assay identified SB8 and SB9 as potential inhibitors with anti-cancer activity against both the cell lines. The molecular docking studies recognized the orientation and binding interaction of molecule at the active site amino acid residues of TP (PDB: 1UOU). Acute toxicity studies of compound SB8 at the dose of 5000 mg/kg has identified no signs of clinical toxicity was observed. The SARs study of synthesized derivatives revealed that the substitution of phenyl ring with electron withdrawing group at ortho position showed significant TP inhibitory activity compared to para substitution. The experimental data suggests that 1,3,4-oxadiazole with substituted phenyl can be taken as a lead for the design of efficient TP inhibitors and active compounds which can be taken up for further studies.

Toxicological effects of marine seaweeds: a cautious insight for human consumption.

Marine environment is a rich and diverse source for many biologically active substances including functional foods and nutraceuticals. It is well exploited for useful compounds, natural products and aquaculture industry; and seaweeds is one of the major contributors in terms of both food security and healthy nutrition. They are well-known due to their enormous benefits and is consumed globally in many countries. However, there is lack of attention toward their toxicity reports which might be due toxic chemical compounds from seaweed, epiphytic bacteria or harmful algal bloom and absorbed heavy metals from seawater. The excess of these components might lead to harmful interactions with drugs and hormone levels in the human body. Due to their global consumption and to meet increasing demands, it is necessary to address their hazardous and toxic aspects. In this review, we have done extensive literature for healthy seaweeds, their nutritional composition while summarizing the toxic effects of selected seaweeds from red, brown and green group which includes- Gracilaria, Acanthophora, Caulerpa, Cladosiphon, and Laminaria sp. Spirulina, a microalgae (cyanobacteria) biomass is also included in toxicity discussion as it an important food supplement and many times shows adverse reactions and drug interactions. The identified compounds from seaweeds were concluded to be toxic to humans, though they exhibited certain beneficial effects too. They have an easy access in food chain and thus invade the higher trophic level organisms. This review will create an awareness among scientific and nonscientific community, as well as government organization to regulate edible seaweed consumption and keep them under surveillance for their beneficial and safe consumption.

Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer's Disease.

BACKGROUND: The only conclusive way to diagnose Alzheimer's is to carry out brain autopsy of the patient's brain tissue and ascertain whether the subject had Alzheimer's or any other form of dementia. However, due to the non-feasibility of such methods, to diagnose and conclude the conditions, medical practitioners use tests that examine a patient's mental ability. OBJECTIVE: Accurate diagnosis at an early stage is the need of the hour for initiation of therapy. The cause for most Alzheimer's cases still remains unknown except where genetic distinctions have been observed. Thus, a standard drug regimen ensues in every Alzheimer's patient, irrespective of the cause, which may not always be beneficial in halting or reversing the disease progression. To provide a better life to such patients by suppressing existing symptoms, early diagnosis, curative therapy, site-specific delivery of drugs, and application of hyphenated methods like artificial intelligence need to be brought into the main field of Alzheimer's therapeutics. METHODS: In this review, we have compiled existing hypotheses to explain the cause of the disease, and highlighted gene therapy, immunotherapy, peptidomimetics, metal chelators, probiotics and quantum dots as advancements in the existing strategies to manage Alzheimer's. CONCLUSION: Biomarkers, brain-imaging, and theranostics, along with artificial intelligence, are understood to be the future of the management of Alzheimer's.

Targeting telomerase for its advent in cancer therapeutics.

Telomerase has emerged as an important primary target in anticancer therapy. It is a distinctive reverse transcriptase enzyme, which extends the length of telomere at the 3' chromosomal end, and uses telomerase reverse transcriptase (TERT) and telomerase RNA template-containing domains. Telomerase has a vital role and is a contributing factor in human health, mainly affecting cell aging and cell proliferation. Due to its unique feature, it ensures unrestricted cell proliferation in malignancy and plays a major role in cancer disease. The development of telomerase inhibitors with increased specificity and better pharmacokinetics is being considered to design and develop newer potent anticancer agents. Use of natural and synthetic compounds for the inhibition of telomerase activity can lead to an opening of new vistas in cancer treatment. This review details about the telomerase biochemistry, use of natural and synthetic compounds; vaccines and oncolytic virus in therapy that suppress the telomerase activity. We have discussed structure-activity relationships of various natural and synthetic telomerase inhibitors to help medicinal chemists and chemical biology researchers with a ready reference and updated status of their clinical trials. Suppression of human TERT (hTERT) activity through inhibition of hTERT promoter is an important approach for telomerase inhibition.

Marine sponges Sarcotragus foetidus, Xestospongia carbonaria and Spongia obscura constituents ameliorate IL-1 ß and IL-6 in lipopolysaccharide-induced RAW 264.7 macrophages and carrageenan-induced oedema in rats.

Marine sponges are prolific producers of an array of diverse chemical structures containing compounds with multiple biological activities. In this study, whole methanol extracts and fractionated compounds from three marine sponges namely Xestospongia carbonaria, Sarcotragus foetidus and Spongia obscura were thoroughly investigated for their antibacterial, antifungal, antioxidant and anti-inflammatory activities. Methanol extracts and fractionated compounds were characterised using high performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Extracts were checked for cytotoxicity in RAW macrophages by MTT assay, before using them for the treatment study. Enzyme linked immunosorbent assay kits were used to check the effects on inflammatory mediator's levels (PGE2, COX-2, IL-6, IL-1ß, TNF-α) in vitro. The results demonstrated good anti-inflammatory activity of all the three marine sponges; X. carbonaria, S. foetidus and S. obscura suppressed the levels of anti-inflammatory cytokines in vitro. Reverse transcriptase-polymerase chain reaction confirmed the inhibition of IL-1ß and IL-6 genes expression by the isolates of X. carbonaria and S. foetidus, while reducing cytokine levels in lipopolysaccharide-induced inflammation in vitro as well as in carrageenan-induced inflammation in rats. Two semi pure compounds isolated from X. carbonaria and S. foetidus also confirmed suppression of IL-1ß and IL-6 genes expression in RAW macrophages.

Combination Therapies of Artemisinin and its Derivatives as a Viable Approach for Future Cancer Treatment.

BACKGROUND: Many anticancer drugs have been developed for clinical usage till now, but the major problem is the development of drug-resistance over a period of time in the treatment of cancer. Anticancer drugs produce huge adverse effects, ultimately leading to death of the patient. Researchers have been focusing on the development of novel molecules with higher efficacy and lower toxicity; the anti-malarial drug artemisinin and its derivatives have exhibited cytotoxic effects. METHODS: We have done extensive literature search for artemisinin for its new role as anti-cancer agent for future treatment. Last two decades papers were referred for deep understanding to strengthen its role. RESULT: Literature shows changes at 9, 10 position in the artemisinin structure produces anticancer activity. Artemisinin shows anticancer activity in leukemia, hepatocellular carcinoma, colorectal and breast cancer cell lines. Artemisinin and its derivatives have been studied as combination therapy with several synthetic compounds, RNA interfaces, recombinant proteins and antibodies etc., for synergizing the effect of these drugs. They produce an anticancer effect by causing cell cycle arrest, regulating signaling in apoptosis, angiogenesis and cytotoxicity activity on the steroid receptors. Many novel formulations of artemisinin are being developed in the form of carbon nanotubes, polymer-coated drug particles, etc., for delivering artemisinin, since it has poor water/ oil solubility and is chemically unstable. CONCLUSION: We have summarize the combination therapies of artemisinin and its derivatives with other anticancer drugs and also focussed on recent developments of different drug delivery systems in the last 10 years. Various reports and clinical trials of artemisinin type drugs indicated selective cytotoxicity along with minimal toxicity thus projecting them as promising anti-cancer agents in future cancer therapies.

Synthesis of novel gefitinib-based derivatives and their anticancer activity.

Drug latentiation is a process of modifying a drug molecule structurally to improve its binding affinity as well as increasing the drug-receptor interactions and potentiate its therapeutic potential. In the quest for discovering more potent epidermal growth factor receptor (EGFR) inhibitors, gefitinib-based derivatives were designed by simple structural modification at the secondary amine of gefitinib by N-alkylation. Three gefitinib derivatives (gefitinib-NB, -NP, and -NIP) were synthesized by N-alkylation and phase transfer catalysis. Structural characterization, physicochemical parameters such as solubility, log P, and p K a were determined. Molecular docking studies were carried out to investigate the binding interactions at the active site. Further drug-bovine serum albumin (BSA) protein and drug-calf thymus (CT) DNA interactions were performed to understand the pharmacokinetics of the synthesized derivatives. All the compounds were screened for preliminary in vitro cytotoxic activity against A549, A431 lung, and MDA-MB-231 breast cancer cell lines by MTT assay. The gefitinib-NP and gefitinib-NB derivatives exhibited strong cytotoxic activity compared with gefitinib. They also showed higher drug-BSA and drug-DNA interactions. Molecular docking studies showed the orientation and binding interactions with the EGFR as well as with BSA and CT DNA. The results establish a strong correlation between the experimental and molecular docking studies. EGFR inhibition studies were also carried out for the derivatives and we identified the NP derivative of gefitinib as a potential lead compound. The gefitinib-based derivatives reported herein are cytotoxic agents and can be tested for further pharmacokinetic profiles and toxicity studies which might be helpful for designing more potent gefitinib-based derivatives in the future.

Peptides and Peptidomimetics as Potential Antiobesity Agents: Overview of Current Status.

There is a high occurrence of obesity worldwide without many new medications being approved for its treatment. Therefore, there is an urgent need to introduce new approaches for treating obesity. Bioactive peptides have been used to treat metabolic disorders- such as type-2 diabetes and obesity; while also possessing anti-oxidant, anti-inflammatory, anti-microbial, and anti-viral properties. However, the development of these peptides has taken backstage due to their size, reduced stability, poor delivery and bioavailability, fast rate of degradation etc. But with the emergence of newer techniques for multifunctional peptides, mimetics, peptide analogs, and aptamers, there is a sudden revival in this therapeutic field. An increased attention is required for development of the natural peptides from food and marine sources which can mimic the function of mediators involved in weight management to avoid obesity. Herein, the search for the structures of anti-obesity peptides was carried out in order to establish their potential for drug development in future. An extensive search for the current status of endogenous, food and marine peptides, with reference to novel and interesting experimental approaches based on peptidomimetics for controlling obesity, was performed. Apolipoprotein A-I (apoA-I), melanocortin-4 receptor (MC4R)-specific agonist, GLP-1 dual and triple agonists, neuropeptides and prolactin-releasing peptide mimetics were specifically examined for their anti-obesity role. Novel peptides, mimetics, and synthesis interventions are transpiring and might offer safer alternatives for otherwise scarcely available safe antiobesity drug. A deeper understanding of peptides and their chemistry through the use of peptide engineering can be useful to overcome the disadvantages and select best mimetics and analogs for treatment in future.

Ligand based design and synthesis of pyrazole based derivatives as selective COX-2 inhibitors.

The design and synthesis of novel pyrazole based derivatives has been carried out using the ligand based approach like pharmacophore and QSAR modelling of reported pyrazoles from the available literature to investigate the chemical features that are essential for the design of selective and potent COX-2 inhibitors. Both pharmacophore and QSAR models with good statistical parameters were selected for the design of the lead molecule. Also by exploiting the chemical structures of selective and marketed COX-2 inhibitors, celecoxib and SC-558 were used in designing the molecules which are used in the treatment of inflammation and related disorders. The therapeutic action of the Non-Steroidal Anti-inflammatory Agents (NSAIDs) is based primarily on the COX-2 inhibition. With this background we have synthesized some azomethine derivatives of 3-methyl-1-substituted-4-phenyl-6-[{(1E)-phenylmethylene}amino]-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile 6(a-o) and were characterized by 1HNMR, 13CNMR and Mass spectral techniques. All the synthesized pyrazole derivatives were tested for in vitro membrane stability property in both COX-1 & COX-2 inhibition studies and in vivo anti-inflammatory activity by carrageenan induced rat paw edema model. Among them, compound 6k showed very good activity by in vivo anti-inflammatory activity with 0.8575 mmol/kg as ED50. Similarly compounds 6m, 6o, 6i and 6h exhibited comparable anti-inflammatory activity to standard drugs. Also the active compounds were further screened for ulcerogenic activity and were found be safer with less ulcer index compared to the marketed drugs like aspirin, ibuprofen and celecoxib.