Isolation, chemical characterization, antimicrobial activity, and molecular docking studies of 2,6-dimethoxy benzoquinone isolated from medicinal plant Flacourtia jangomas.

In the present investigation one compound, 2,6-dimethoxy benzoquinone (FJL-1), was isolated from the dichloromethane (DCM) fraction of the organic leaf extract of Flacourtia Jangomas for the first time. The compound structure was elucidated using extensive spectral analysis, including 1H, and 13C NMR. Furthermore, the DPPH and ABTS methods were used to evaluate the antioxidant activity of the organic extract, its fractions, and the isolated compound FJL-1. Antioxidant activity of the petroleum, ether, DCM, and methanol fractions of the organic extract and the isolated compound of F. Jangomas revealed moderate to strong radical scavenging ability. Additionally, the antimicrobial activity of FJL-1 against Staphylococcus aureus (MTCC 737 and MTCC 96 strains) was observed in an inhibition zone size of 21.6 ± 0.6 to 21.7 ± 0.58 mm showing potential inhibitory activity. The isolated compound FJL-1 shows excellent binding with the 2W9S proteins in terms of docking score compared with the drug Trimethoprim, which also exhibited similar types of interaction and potency against S. aureus. The leaves of F. jangomas can be considered a great source for the identification of numerous important phytoconstituents with potential uses in nutrition, aromatherapy, and the pharmaceutical sector. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04002-w.

Stilbenes: a journey from folklore to pharmaceutical innovation.

In modern times, medicine is predominantly based on evidence-based practices, whereas in ancient times, indigenous people relied on plant-based medicines with factual evidence documented in ancient books or folklore that demonstrated their effectiveness against specific infections. Plants and microbes account for 70% of drugs approved by the USFDA (U.S. Food and Drug Administration). Stilbenes, polyphenolic compounds synthesized by plants under stress conditions, have garnered significant attention for their therapeutic potential, bridging ancient wisdom with modern healthcare. Resveratrol, the most studied stilbene, initially discovered in grapes, red wine, peanuts, and blueberries, exhibits diverse pharmacological properties, including cardiovascular protection, antioxidant effects, anticancer activity, and neuroprotection. Traditional remedies, documented in ancient texts like the Ayurvedic Charak Samhita, foreshadowed the medicinal properties of stilbenes long before their modern scientific validation. Today, stilbenes are integral to the booming wellness and health supplement market, with resveratrol alone projected to reach a market value of 90 million US$ by 2025. However, challenges in stilbene production persist due to limited natural sources and costly extraction methods. Bioprospecting efforts reveal promising candidates for stilbene production, particularly endophytic fungi, which demonstrate high-yield capabilities and genetic modifiability. However, the identification of optimal strains and fermentation processes remains a critical consideration. The current review emphasizes the knowledge of the medicinal properties of Stilbenes (i.e., cardiovascular, antioxidant, anticancer, anti-inflammatory, etc.) isolated from plant and microbial sources, while also discussing strategies for their commercial production and future research directions. This also includes examples of novel stilbenes compounds reported from plant and endophytic fungi.

Therapeutic Implications of Dietary Polyphenols-Loaded Nanoemulsions in Cancer Therapy.

Cancer is one of the major causes of death worldwide, even the second foremost cause related to non-communicable diseases. Cancer cells typically possess several cellular and biological processes including, persistence, propagation, differentiation, cellular death, and expression of cellular-type specific functions. The molecular picture of carcinogenesis and progression is unwinding, and it appears to be a tangled combination of processes occurring within and between cancer cells and their surrounding tissue matrix. Polyphenols are plant secondary metabolites abundant in fruits, vegetables, cereals, and other natural plant sources. Natural polyphenols have implicated potential anticancer activity by various mechanisms involved in their antitumor action, including modulation of signaling pathways majorly related to cellular proliferation, differentiation, relocation, angiogenesis, metastatic processes, and cell death. The applications of polyphenols have been limited due to the hydrophobic nature and lower oral bioavailability that could be possibly overcome through encapsulating them into nanocarrier-mediated delivery systems, leading to improved anticancer activity. Nanoemulsions (NEs) possess diverse feasible properties, including greater surface area, modifiable surficial charge, higher half-life, site-specific targeting, and formulation imaging capability necessary to create a practical therapeutic impact, and have drawn increased attention in cancer therapy research. This review has summarized and discussed the basic concepts, classification, delivery approaches, and anticancer mechanism of various polyphenols and polyphenols-encapsulated nanoemulsions with improved cancer therapy.

C-30 analogues of betulinic acid as potent cytotoxic agents: design, synthesis, biological evaluation and in-silico studies.

In an endeavour to improve the anti-cancer activity of betulinic acid (BA), a series of C-30 derivatives were envisaged and synthesized with a novel synthetic approach. All the derivatives were evaluated for cytotoxic activity by MTT assay against six different human cancer cell lines: prostate (PC3), lung (A549), human hepatocellular carcinoma (HepG2), human leukemia (Molt-4), pancreatic (Panc-1) and breast (MCF-7). The data revealed that compound 16 was observed most promising cytotoxic agent with IC50 values of 7.43 µM, 9.1 µM, and 9.64 µM against A549, MCF-7, and PC3 cancer cell lines respectively. A further mechanistic study confirmed compound 16 showed significant cell death by arresting the cell cycle in the G1 phase and inducing apoptosis in A549 cells.Communicated by Ramaswamy H. Sarma.

Benchmarking institutional geriatric hip fracture management: a prelude to a care quality improvement initiative.

BACKGROUND: Fractures around the hip in older adults have increased in the last two decades, and the numbers are projected to rise over the next 30 years with estimates that half of them will occur in Asia. Proximal hip fractures should be operated within 48 h of injury to prevent poor outcomes. This study aims to benchmark current hip fracture care using quality improvement tools of care structure, care processes, and outcomes in a tertiary care hospital in Eastern India and determine the evidence-practice gaps and barriers to implementing the six best practices that reduce mortality and morbidity in fragility hip fractures. METHODS: A total of 101 consecutive patients above 50 years of age with proximal femoral fractures after a trivial fall were included. Patients were divided into two groups: those operated within [Group A] and beyond [Group B] 72 h of admission. Care structure assessment included delays in admission, delay in surgery, and anesthesia risk grading. Care processes included the type of surgery performed and postoperative complications. The primary outcomes were the 30-day and 1-year mortality and the secondary outcomes included the length of stay, mobility at 6 months, return to pre-fracture independence, activity limitations, pressure sores, and readmission to the hospital. RESULTS: Group A comprised 26 individuals, and the remaining 75 were in Group B. There were two deaths in Group A as compared to one death in Group B at 30 days; however, there were no new deaths at 1 year in Group A and 14 deaths in Group B (p = 0.187). Group B had lengthier hospital stays, poorer mobility, and higher physical and mental difficulties. No patients had re-operation on the initial fracture. CONCLUSION: This study emphasizes the importance of early admission and fast provision of surgical fixation to reduce mortality and morbidity. Benchmarking institutional practices allows for defining the evidence-practice gaps and barriers to best practice implementation. This is an essential step to begin care quality improvement for geriatric patients with proximal femur fragility fractures.

Harnessing the action mechanisms of microbial endophytes for enhancing plant performance and stress tolerance: current understanding and future perspectives.

Microbial endophytes are microorganisms that reside within plant tissues without causing any harm to their hosts. These microorganisms have been found to confer a range of benefits to plants, including increased growth and stress tolerance. In this review, we summarize the recent advances in our understanding of the mechanisms by which microbial endophytes confer abiotic and biotic stress tolerance to their host plants. Specifically, we focus on the roles of endophytes in enhancing nutrient uptake, modulating plant hormones, producing secondary metabolites, and activating plant defence responses. We also discuss the challenges associated with developing microbial endophyte-based products for commercial use, including product refinement, toxicology analysis, and prototype formulation. Despite these challenges, there is growing interest in the potential applications of microbial endophytes in agriculture and environmental remediation. With further research and development, microbial endophyte-based products have the potential to play a significant role in sustainable agriculture and environmental management.

Functional implications and therapeutic targeting of androgen response elements in prostate cancer.

The androgen receptor (AR) plays an essential role in the growth and progression of prostate cancer (CaP). Ligand-activated AR inside the nucleus binds to the androgen response element (ARE) of the target genes in dimeric form and recruits transcriptional machinery to facilitate gene transcription. Pharmacological compounds that inhibit the AR action either bind to the ligand binding domain (LBD) or interfere with the interactions of AR with other co-regulatory proteins, slowing the progression of the disease. However, the emergence of resistance to conventional treatment makes clinical management of CaP difficult. Resistance has been associated with activation of androgen/AR axis that restores AR transcriptional activity. Activated AR signaling in resistance cases can be mediated by several mechanisms including AR amplification, gain-of-function AR mutations, androgen receptor variant (ARVs), intracrine androgen production, and overexpression of AR coactivators. Importantly, in castration resistant prostate cancer, ARVs lacking the LBD become constitutively active and promote hormone-independent development, underlining the need to concentrate on the other domain or the AR-DNA interface for the identification of novel actionable targets. In this review, we highlight the plasticity of AR-DNA binding and explain how fine-tuning AR's cooperative interactions with DNA translate into developing an alternative strategy to antagonize AR activity.

Purification of ursolic acid and ß-sitosterol from endophytic Alternaria alternata for their alpha-amylase inhibitory activity.

Fungal endophytes are a known warehouse of bioactive compounds with multifarious applications. In the present investigation two compounds, ß-Sitosterol (1) and ursolic acid (2), were isolated from Alternaria alternata, an endophytic fungus associated with Morus alba Linn for the first time. The structure of the compounds was elucidated on the basis of comprehensive spectral analysis (UV, IR, 1 H-, 13 C- and 2D-NMR, as well as HRESI-MS). In the in vitro alpha amylase inhibitory assay both compounds (1) and (2) show potent antidiabetic activity. In support, Docking studies indicate significant binding affinity of the isolated compounds. Hence from the present study, it can be concluded that endophytic fungi in Morus alba Linn can find use in antidiabetic drug development in the medicinal industry.Communicated by Ramaswamy H. Sarma.

Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival.

It is well known that solid hypoxic tumour cells oxidise glucose through glycolysis, and the end product of this pathway is fermented into lactate which accumulates in the tumour microenvironment (TME). Initially, it was proclaimed that cancer cells cannot use lactate; therefore, they dump it into the TME and subsequently augment the acidity of the tumour milieu. Furthermore, the TME acts as a lactate sink with stope variable amount of lactate in different pathophysiological condition. Regardless of the amount of lactate pumped out within TME, it disappears immediately which still remains an unresolved puzzle. Recent findings have paved pathway in exploring the main role of lactate acidosis in TME. Cancer cells utilise lactate in the de novo fatty acid synthesis pathway to initiate angiogenesis and invasiveness, and lactate also plays a crucial role in the suppression of immunity. Furthermore, lactate re-programme the lipid biosynthetic pathway to develop a metabolic symbiosis in normoxic, moderately hypoxic and severely hypoxic cancer cells. For instance: severely hypoxic cancer cells enable to synthesizing poly unsaturated fatty acids (PUFA) in oxygen scarcity secretes excess of lactate in TME. Lactate from TME is taken up by the normoxic cancer cells whereas it is converted back to PUFAs after a sequence of reactions and then liberated in the TME to be utilized in the severely hypoxic cancer cells. Although much is known about the role of lactate in these biological processes, the exact molecular pathways that are involved remain unclear. This review attempts to understand the molecular pathways exploited by lactate to initiate angiogenesis, invasiveness, suppression of immunity and cause re-programming of lipid synthesis. This review will help the researchers to develop proper understanding of lactate associated bimodal regulations of TME.

Zoledronic Acid Does Not Retard Bone Union: A Randomized Controlled Trial in Fragility Intertrochanteric Femur Fractures.

BACKGROUND: Fragility hip fracture is a leading cause of death in the elderly and is common in postmenopausal women and elderly people. In the treatment of osteoporosis, bisphosphonates (BPs) are often considered first-line medications. Zoledronic acid is the most potent and long-acting BP in clinical use and is administered as an intravenous infusion. In the context of acute fractures, the use of BPs has been controversial due to conflicting reports of their positive and negative effects on fracture healing. The purpose of this study was to determine the effect of zoledronic acid on fracture healing in intertrochanteric (IT) fragility fractures. METHODS: The study was conducted in a tertiary healthcare center after receiving scientific and ethical approval. The study included 136 patients of either gender over the age of 50 who presented with an IT femur fracture after minor trauma between November 2020 and November 2022. The total number of patients had been classified into two groups, and grouping involved random sampling: Group T (test group, n = 68; zoledronic acid injections were given on postoperative day 3) and Group C (control group, n = 68; interventions were given after fracture healing). Patients were evaluated using the Radiographic Union Score for Hip (RUSH) and Singh Index for radiological outcomes and the Harris Hip Score (HHS) for functional outcomes. The patients were followed for six months. RESULTS: The overall mean age was 73.25 years; in Group T, it was 72.5 ± 11.9 years, and in Group C, it was 73.7 ± 11.8 years. Of 136 patients, 69 (51%) were males and 67 (49%) were females. The average fracture healing time in Group T was 12.2 ± 3.6 weeks, while it was 13.0 ± 2.8 weeks in Group C. Functional outcomes, including HHS, were found to be better in Group T than in Group C (p < 0.005). No significant difference was observed between the two groups with respect to the radiological union, the RUSH score, or Singh Index, implying no negative effect of zoledronic acid. CONCLUSIONS: This study demonstrates that postoperative intravenous zoledronic acid therapy does not retard fracture healing. Osteoporosis management is frequently neglected because of a surgeon's fear of ZOL retarding fracture healing and a lack of awareness among patients, resulting in low compliance. Thus, opportunistic administration of zoledronic acid postoperatively can be beneficial and will increase compliance for osteoporosis management and fracture prevention to 100%.

Key insights into secondary metabolites from various Chaetomium species.

Endophytic fungi have proved to be a major source of secondary metabolites, wherein the genus Chaetomium has emerged as a source of multifarious bioactive natural compounds belonging to diverse classes such as chaetoglobosins, epipolythiodioxopiperazines, azaphilones, xanthones, anthraquinone, chromones, depsidones, terpenoids, and steroids. The objective of this review is to encapsulate recent findings on various Chaetomium strains, such as C. globosum, C. cupreum, C. elatum, C. subspirale, C. olivaceum, C. indicum, and C. nigricolor known for production of beneficial secondary metabolites, with an insight into their origin and function. A thorough literature survey was conducted for obtaining Chaetomium-derived secondary metabolites, with a scope of future application into drug development efforts. More than 100 secondary metabolites, with various beneficial properties such as antitumor, cytotoxic, antimalarial, and enzyme inhibitory activities, were enlisted. We believe this review will enhance the understanding of beneficial effects conferred by various Chaetomium-derived secondary metabolites and emphasize their potential in serving novel drug development efforts. KEY POINTS: • Identified Chaetomium-derived metabolites with potential for drug development. • More than 100 beneficial metabolites are enlisted. • Benefits include anti-cancerous, antimalarial, and anti-enzymatic properties.

Capsicum annuum L. and its bioactive constituents: A critical review of a traditional culinary spice in terms of its modern pharmacological potentials with toxicological issues.

Capsicum annuum L., commonly known as chili pepper, is used as an important spice globally and as a crude drug in many traditional medicine systems. The fruits of C. annuum have been used as a tonic, antiseptic, and stimulating agent, to treat dyspepsia, appetites, and flatulence, and to improve digestion and circulation. The article aims to critically review the phytochemical and pharmacological properties of C. annuum and its major compounds. Capsaicin, dihydrocapsaicin, and some carotenoids are reported as the major active compounds with several pharmacological potentials especially as anticancer and cardioprotectant. The anticancer effect of capsaicinoids is mainly mediated through mechanisms involving the interaction of Ca2+ -dependent activation of the MAPK pathway, suppression of NOX-dependent reactive oxygen species generation, and p53-mediated activation of mitochondrial apoptosis in cancer cells. Similarly, the cardioprotective effects of capsaicinoids are mediated through their interaction with cellular transient receptor potential vanilloid 1 channel, and restoration of calcitonin gene-related peptide via Ca2+ -dependent release of neuropeptides and suppression of bradykinin. In conclusion, this comprehensive review presents detailed information about the traditional uses, phytochemistry, and pharmacology of major bioactive principles of C. annuum with special emphasis on anticancer, cardioprotective effects, and plausible toxic adversities along with food safety.

Isolation of Alpha Amylase-Producing Bacteria from Local Region of Ambala and Production of Amylase Under Optimized Factors Using Solid-State Fermentation.

Enzymes are one of the most significant products produced primarily from microbial sources for human requirements. The purpose of this work was to isolate, screen, and optimize enzyme production under solid-state fermentation. In the present study, amylase-producing bacteria were isolated from the local region of Ambala. A total of six samples were taken, out of which 14 isolates were isolated, among which seven isolates were found to be amylase producing. Highest amylase yield was obtained from isolate A11, further studied for the production of amylase under solid substrate fermentation (SSF), and also optimized the conditions for increased production of amylase. The molecular and biochemical characterization confirmed it as a strain of Alkalihalobacillus clausii. It was observed that growth parameters showed a profound effect on the production. The bacterium produces ample amount (7.3 × 103 IU/g) of alpha amylase using wheat bran using OVAT (one variable at a time) approach. Further using RSM (Response Surface Methodology) resulted in 3.78-fold increase in alpha amylase production, i.e., 27.57 × 103 IU/g.

Mortality from fall: A descriptive analysis of a multicenter Indian trauma registry.

INTRODUCTION: Fall is the second most common mechanism of trauma worldwide after road traffic injuries. Data on fall predominantly comes from the high-income countries (HICs) and mostly includes injuries in children and elderly. There are very few studies from low- and middle-income countries(LMICs) that describe fall related injuries other than fragility fractures in elderly. This study describes the profile of poly-trauma patients admitted with a history of 'fall' and assesses the variables associated with mortality. METHOD: We analyzed data from the 'Towards Improved Trauma Care Outcome' (TITCO) database which prospectively collected data of poly-trauma patients admitted to four major tertiary care hospitals of India between 2013 to 2015. Patients across all age groups admitted to hospital with the history of 'fall'; were included in our study. Single bone fractures were excluded.  The Kaplan Meier survival analysis was used to estimate the survival probability in different age groups. RESULTS: A total of 3686 patients were included in our study. The median age of the patients was 28 years (IQR: 9, 47) with the majority being males (73.6%). Almost one-third of the patients were within the age group of 0-14 (30.4%). Most of the patients (79.9%) had a diagnosis of traumatic brain injury (TBI). The overall in-hospital mortality was 18% (664), but higher at 39.0% among patients over 65 years of age. Probability of survival decreased with increase of age. CONCLUSION: Falling from height is a common injury mechanism in India, occurring more in young males and usually associated with TBI. Isolated TBI and TBI associated with other injuries are the main contributors of mortality in fall injuries. Mortality from these injuries increased with age and ISS.

Microbial endophytes: application towards sustainable agriculture and food security.

Microbial endophytes are ubiquitous and exist in each recognised plant species reported till date. Within the host plant, the entire community of microbes lives non-invasively within the active internal tissues without causing any harm to the plant. Endophytes interact with their host plant via metabolic communication enables them to generate signal molecules. In addition, the host plant's genetic recombination with endophytes helps them to imitate the host's physicochemical functions and develop identical active molecules. Therefore, when cultured separately, they begin producing the host plant phytochemicals. The fungal species Penicillium chrysogenum has portrayed the glory days of antibiotics with the invention of the antibiotic penicillin. Therefore, fungi have substantially supported social health by developing many bioactive molecules utilised as antioxidant, antibacterial, antiviral, immunomodulatory and anticancerous agents. But plant-related microbes have emanated as fountainheads of biologically functional compounds with higher levels of medicinal perspective in recent years. Researchers have been motivated by the endless need for potent drugs to investigate alternate ways to find new endophytes and bioactive molecules, which tend to be a probable aim for drug discovery. The current research trends with these promising endophytic organisms are reviewed in this review paper. KEY POINTS: • Identified 54 important bioactive compounds as agricultural relevance • Role of genome mining of endophytes and "Multi-Omics" tools in sustainable agriculture • A thorough description and graphical presentation of agricultural significance of plant endophytes.

Inhibitory activities of grape bioactive compounds against enzymes linked with human diseases.

A quest for identification of novel, safe and efficient natural compounds, as additives in the modern food and cosmetic industries, has been prompted by concerns about toxicity and side effects of synthetic products. Plant phenolic compounds are one of the most documented natural products due to their multifarious biological applications. Grape (Vitis vinifera) is an important source of phenolic compounds such as phenolic acids, tannins, quinones, coumarins and, most importantly, flavonoids/flavones. This review crisply encapsulates enzyme inhibitory activities of various grape polyphenols towards different key human-ailment-associated enzymes: xanthine oxidase (gout), tyrosinase (hyperpigmentation), α-amylase and α-glucosidase (diabetes mellitus), pancreatic lipase (obesity), cholinesterase (Alzheimer's disease), angiotensin i-converting enzymes (hypertension), α-synuclein (Parkinson's disease) and histone deacetylase (various diseases). The review also depicts the enzyme inhibitory mechanism of various grape polyphenols and briefly discusses their stature as potential therapeutic and drug development candidates. KEY POINTS: • Nineteen major bioactive polyphenols from the grape/grape products and their disease targets are presented • Sixty-two important polyphenols as enzyme inhibitors from grape/grape products are presented • A thorough description and graphical presentation of biological significance of polyphenols against various diseases.

Response surface statistical optimization of fermentation parameters for resveratrol production by the endophytic fungus Arcopilus aureus and its tyrosinase inhibitory activity.

OBJECTIVE: The present investigation primarily focusses on enhancement of resveratrol production by endophytic production from the endophytic fungus, Arcopilus aureus via one variable at a time approach (OVAT) followed by statistical approach using response surface methodology (RSM). The paper also highlights the characterization of fungal resveratrol using spectroscopic techniques. Further the tyrosinase inhibitory property was also explored in this communication for its possible use as a cosmeceutical ingredient. RESULTS: Optimization of physicochemical and nutritional parameters using OVAT approach exhibited 1.23-fold enhancement in production of resveratrol when compared to initial yield, 89.1 ± 0.08 µg/mL. Further RSM resulted in 1.49-fold enhancement in resveratrol production i.e. 133.53 µg/ml. Further, 25 mg of fungal resveratrol in pure form was obtained from the spent broth of Arcopilus aureus by column chromatography using a mobile phase comprising of MeOH: DCM in a ratio of 1.75:98.25. Further its purity on TLC was checked using 5% MeOH: DCM as mobile phase. Symmetrical peak with Rt of 3.36 min using a C18 reverse phase column confirmed the homogeneity of the purified fungal resveratrol with standard resveratrol and further corroborated by 1H-NMR, 13C-NMR and HR-MS analysis. Fungal resveratrol exhibited a good tyrosinase inhibition with an IC50 of 2.654 ± 0.432 µg/mL as compared to Kojic acid (1.329 ± 0.333). CONCLUSIONS: The present study has provided sufficient lead that process optimization techniques can complement each other for optimized production of bioactive compounds by microorganisms apart from strain improvement techniques which are generally adopted in the industry. The enhancement of resveratrol production by Arcopilus aureus by process optimization further opens up avenues for strain improvement for commercial resveratrol production through fermentation for nutraceutical and cosmeceutical applications.

Effect of IS01957, a para-coumaric acid derivative on pharmacokinetic modulation of diclofenac through oral route for augmented efficacy.

Diclofenac is one of the world's largest selling nonsteroidal anti-inflammatory drugs. The major concerns related to oral diclofenac therapy are gastrointestinal and cardiovascular side effects for which explicitly emphasis has been given to use it at lowest effective dose for the shortest duration. On the other hand, IS01957 has been designed under the purview of anti-inflammatory drug and bioavailability enhancer. IS01957 have dual action on inflammation and nociception with acceptable safety profile. In the quest for a suitable combination with improved therapeutic efficacy and better tolerability, pharmacodynamic and pharmacokinetic interaction studies were performed for diclofenac with or without IS01957 in mice model. Results showed that IS01957 enhanced both anti-inflammatory effect and plasma concentration of diclofenac upon concomitant oral administration. These interesting results steered to enumerate the possible role of IS01957 towards diclofenac pharmacokinetics through a panel of mechanistic investigations: (a) BCRP dependent ATPase activity was markedly interfered by IS01957; (b) IS01957 increased the intestinal permeability of diclofenac in the single pass in-situ perfusion model; (c) IS01957 inhibited the CYP2C9 catalyzed diclofenac 4-hydroxylation in human liver microsomes. Immunoblotting results suggest that diclofenac action was improved significantly in the presence of IS01957 involving MAPK pathways. Finally acute gastric damage study showed that IS01957 in combination with diclofenac was better to improve the desired PGE2 level as compare to alone. In nutshell, IS01957 have potential to augment the efficacy of diclofenac through pharmacokinetic modulation. Further investigations are required for dose reduction of diclofenac to combat its liabilities before going into clinical setting.

Synthesis of amides from (E)-3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid and substituted amino acid esters as NorA efflux pump inhibitors of Staphylococcus aureus.

Inhibitors for NorA efflux pump of Staphylococcus aureus have attracted the attention of many researchers towards the discovery and development of novel efflux pump inhibitors (EPIs). In an attempt to find specific potent inhibitors of NorA efflux pump of S. aureus, a total of 15 amino acid conjugates of 3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid (4-18) were synthesized using a simple convenient synthetic approach and bioevaluated against NorA efflux pump. Two compounds 7 and 8 (each having MEC of 1.56 µg/mL) were found to restore the activity of ciprofloxacin through reduction of the MIC elucidated by comparing the ethidium bromide efflux in dose dependent manner in addition to ethidium bromide efflux inhibition and accumulation study using NorA overexpressing strain SA-1199B. Most potent compounds among these were able to restore the antibacterial activity of ciprofloxacin completely against SA-1199B. Structure activity relationship (SAR) studies and docking study of potent compounds 7 and 8 could elucidate the structural requirements necessary for interaction with the NorA efflux pumps. On the whole, compounds 7 and 8 have ability to reverse the NorA efflux mediated resistance and could be further optimized for development of potent efflux pump inhibitors.

Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception.

In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para-coumaric acid (p-CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p-CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in-silico, in-vitro and in-vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles.