In Silico and In vitro Analysis of Phenolic Acids for Identification of Potential DHFR Inhibitors as Antimicrobial and Anticancer Agents.

BACKGROUND: DHFR is an indispensable enzyme required for the survival of almost all prokaryotic and eukaryotic cells, making it an attractive molecular target for drug design. OBJECTIVE: In this study, a combined in silico and in vitro approach was utilized to screen out potential anticancer and antimicrobial agents by using DHFR PDB ID 2W9S (for antimicrobial) and 1U72 (for anticancer). METHODS: Computational work was performed using Maestro Schrodinger Glide software. The DHFR inhibitory activity of the selected compounds was assessed using the DHFR test kit (CS0340-Sigma- Aldrich). RESULTS: Exhaustive analysis of in silico results revealed that some natural phenolic acids have a good docking score when compared to standards, i.e., trimethoprim and methotrexate, and have astonishing interactions with crucial amino acid residues available in the binding pocket of DHFR, such as Phe 92, Asp 27, Ser 49, Asn 18, and Tyr 98. In particular, digallic acid and chlorogenic acid have amazing interactions with docking scores of -9.9 kcal/mol and -9.6 kcal/mol, respectively, for the targeted protein 2W9S. Docking scores of -10.3 kcal/mol and -10.2 kcal/mol, respectively, for targeted protein 1U72. The best hits were then tested in vitro to evaluate the DHFR inhibitory activity of the compounds. DHFR inhibition activity results are in correlation with molecular docking results. CONCLUSION: In silico and in vitro results confirmed the good binding and inhibitory activity of some phenolic acids to the modeled target proteins. Among all the studied natural phenolic acids, chlorogenic acid, digallic acid, and rosmarinic acid appeared to be the most potential leads for future chemical alteration. This study can provide significant speculative guidance for the design and development of potent DHFR inhibitors in the future by using these compounds as leads.

In silico design of novel bioactive molecules to treat breast cancer with chlorogenic acid derivatives: a computational and SAR approach.

Introduction: Cancer is a vast group of diseases comprising abnormal cells that multiply and grow uncontrollably, and it is one of the top causes of death globally. Several types of cancers are diagnosed, but the incidence of breast cancer, especially in postmenopausal women, is increasing daily. Chemotherapeutic agents used to treat cancer are generally associated with severe side effects on host cells, which has led to a search for safe and potential alternatives. Therefore, the present research has been conducted to find novel bioactive molecules to treat breast cancer with chlorogenic acid and its derivatives. Chlorogenic acid was selected because of its known activity in the field. Methods: Several chlorogenic acid derivatives were subjected to computational studies such as molecular docking, determination of absorption, distribution, metabolism, and excretion (ADME), druglikeness, toxicity, and prediction of activity spectra for substances (PASS) to develop a potential inhibitor of breast cancer. The Protein Data Bank (PDB) IDs used for docking purposes were 7KCD, 3ERT, 6CHZ, 3HB5, and 1U72. Result: Exhaustive analysis of results has been conducted by considering various parameters, like docking score, binding energy, types of interaction with important amino acid residues in the binding pocket, ADME, and toxicity data of compounds. Among all the selected derivatives, CgE18, CgE11, CgAm13, CgE16, and CgE9 have astonishing interactions, excellent binding energy, and better stability in the active site of targeted proteins. The docking scores of compound CgE18 were -11.63 kcal/mol, -14.15 kcal/mol, and -12.90 kcal/mol against breast cancer PDB IDs 7KCD, 3HB5, and 1U72, respectively. The docking scores of compound CgE11 were -10.77 kcal/mol and -9.11 kcal/mol against breast cancer PDB IDs 3ERT and 6CHZ, respectively, whereas the docking scores of epirubicin hydrochloride were -3.85 kcal/mol, -6.4 kcal/mol, -8.76 kcal/mol, and -10.5 kcal/mol against PDB IDs 7KCD, 3ERT, 6CHZ, and 3HB5. The docking scores of 5-fluorouracil were found to be -5.25 kcal/mol, -3.43 kcal/mol, -3.73 kcal/mol, and -5.29 kcal/mol against PDB IDs 7KCD, 3ERT, 6CHZ, and 3HB5, which indicates the designed compounds have a better docking score than some standard drugs. Conclusion: Taking into account the results of molecular docking, drug likeness analysis, absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation, and PASS, it can be concluded that chlorogenic acid derivatives hold promise as potent inhibitors for the treatment of breast cancer.

Polyphenols: Natural Preservatives with Promising Applications in Food, Cosmetics and Pharma Industries; Problems and Toxicity Associated with Synthetic Preservatives; Impact of Misleading Advertisements; Recent Trends in Preservation and Legislation.

The global market of food, cosmetics, and pharmaceutical products requires continuous tracking of harmful ingredients and microbial contamination for the sake of the safety of both products and consumers as these products greatly dominate the consumer's health, directly or indirectly. The existence, survival, and growth of microorganisms in the product may lead to physicochemical degradation or spoilage and may infect the consumer at another end. It has become a challenge for industries to produce a product that is safe, self-stable, and has high nutritional value, as many factors such as physical, chemical, enzymatic, or microbial activities are responsible for causing spoilage to the product within the due course of time. Thus, preservatives are added to retain the virtue of the product to ensure its safety for the consumer. Nowadays, the use of synthetic/artificial preservatives has become common and has not been widely accepted by consumers as they are aware of the fact that exposure to preservatives can lead to adverse effects on health, which is a major area of concern for researchers. Naturally occurring phenolic compounds appear to be extensively used as bio-preservatives to prolong the shelf life of the finished product. Based on the convincing shreds of evidence reported in the literature, it is suggested that phenolic compounds and their derivatives have massive potential to be investigated for the development of new moieties and are proven to be promising drug molecules. The objective of this article is to provide an overview of the significant role of phenolic compounds and their derivatives in the preservation of perishable products from microbial attack due to their exclusive antioxidant and free radical scavenging properties and the problems associated with the use of synthetic preservatives in pharmaceutical products. This article also analyzes the recent trends in preservation along with technical norms that regulate the food, cosmetic, and pharmaceutical products in the developing countries.

DihydrofolateReductase (DHFR) Inhibitors: A Comprehensive Review.

BACKGROUND: Dihydrofolate reductase (DHFR) is an indispensable enzyme required for the survival of most prokaryotic and eukaryotic cells as it is involved in the biosynthesis of essential cellular components. DHFR has attracted a lot of attention as a molecular target for various diseases like cancer, bacterial infection, malaria, tuberculosis, dental caries, trypanosomiasis, leishmaniasis, fungal infection, influenza, Buruli ulcer, and respiratory illness. Various teams of researchers have reported different DHFR inhibitors to explore their therapeutic efficacy. Despite all the progress made, there is a strong need to find more novel leading structures, which may be used as better and safe DHFR inhibitors, especially against the microorganisms which are resistant to the developed drug candidates. OBJECTIVE: This review aims to pay attention to recent development, particularly made in the past two decades and published in this field, and pay particular attention to promising DHFR inhibitors. Hence, an attempt has been made in this article to highlight the structure of dihydrofolate reductase, the mechanism of action of DHFR inhibitors, most recently reported DHFR inhibitors, diverse pharmacological applications of DHFR inhibitors, reported in-silico study data and recent patents based on DHFR inhibitors to comprehensively portray the current scenery for researchers interested in designing novel DHFR inhibitors. CONCLUSION: A critical review of recent studies revealed that most novel DHFR inhibitor compounds either synthetically or naturally derived are characterized by the presence of heterocyclic moieties in their structure. Non-classical antifolates like trimethoprim, pyrimethamine, and proguanil are considered excellent templates to design novel DHFR inhibitors, and most of them have substituted 2,4-diamino pyrimidine motifs. Targeting DHFR has massive potential to be investigated for newer therapeutic possibilities to treat various diseases of clinical importance.

A Concise Review of Common Plant-derived Compounds as a Potential Therapy for Alzheimer's Disease and Parkinson's Disease: Insight into Structure-Activity-Relationship.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurological illnesses that affect people in their later years. Memory loss is the hallmark of Alzheimer's disease, while dyskinesia, or loss of mobility, is associated with muscle rigidity and tremors in PD. Both diseases are unrelated, however, they do have a few similarities associated with extrapyramidal abnormalities, particularly stiffness, which has been linked to concomitant PD in many AD patients. Increased levels of IL-1, IL-6, and TNF in the AD and PD patients can be regarded as evidence of systemic inflammation associated with each of these neurodegenerative disorders. One of the primary variables in the progression of neurodegenerative disorders is oxidative stress. Many medicinal plants and their secondary metabolites have been claimed to be able to help people with neurodegenerative disorders like AD and PD. Anti-inflammatory, antioxidant, antiapoptotic, monoamine oxidase inhibition, acetylcholinesterase, and neurotrophic pursuits are among the major mechanisms identified by which phytochemicals exert their neuroprotective effects and potential maintenance of neurological health in old age. In regard to neurodegenerative disorders, numerable plant-based drugs like alkaloids, iridoids, terpenes, and flavones are employed for the treatment. Structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) are used to investigate the link between bioactivity and the chemical configuration of substances. The SAR and QSAR of natural plant components employed in AD and PD are discussed in the current review.

Phenolic Acids - Versatile Natural Moiety with Numerous Biological Applications.

BACKGROUND: Medicinal uses of natural phenolic acids and their synthetic derivatives have been augmented in recent years. Phenolic acids are chemically defined secondary plant metabolites and being moieties or leads are much versatile in nature with a wide scope of biological activities which seek the attention of researchers across the world to synthesize different derivatives of phenolic acids and screen them for their various biological properties. These compounds are of meticulous interest due to the properties they possess and their occurrence. Based on the convincing evidence reported in the literature, it is suggested that phenolic acids and their derivatives are promising molecules as a drug. OBJECTIVES: The present review article aims to bring together the information on the biosynthesis, metabolism, and sources of phenolic acids and emphasize the therapeutic potential of phenolic acid and its synthetic derivatives to comprehensively portray the current scenery for researchers interested in designing drugs for furthering this study. CONCLUSION: Phenolic acids being moieties or lead, are much versatile in nature as they possess a wide range of biological activities like antimicrobial, antioxidant, antiviral, antiulcer, antiinflammatory, antidiabetic, anticancer and many more offers researchers to explore more about these or many untapped benefits in the medicinal field. The information mentioned in this article will be helpful to the forthcoming researchers working in this area. Phenolic acids have massive potential to be investigated for novel medicinal possibilities and for the development of new chemical moieties to treat different diseases of clinical importance.

Docking Related Survey on Heterocyclic Compounds Based on Glucosamine-6- Phosphate Synthase Inhibitors and their Antimicrobial Potential.

The synthetic heterocyclic compounds have their importance due to their wide applications in various fields of science. The heterocyclic compounds have been reported for their anticancer, antitubercular, insecticides, analeptics, analgesic, anti-bacterial, anti-viral, anti-fungal, and weedicidal activity. Researchers have tried various newer targets in search of better antimicrobials acting via novel mechanisms. Glucosamine-6-Phosphate synthase is an enzyme present in microbial cells. The inactivation of G-6-P synthase may serve as a novel approach to find better antimicrobials. The increasing demands development of newer and effective antimicrobial drugs has reported in search of newer techniques for the generation of new drugs. Hence, the molecular docking technique shall be explored to find or investigate the newer target finding the novel compounds which can be an active antimicrobial compound. The present review has focused on the reported heterocyclic compounds which have been evaluated for their antimicrobial potential using G-6-P synthase as a target. The results of in silico methods and in vitro methods have been compared and critically discussed.

Comparative Evaluation of Conventional and Novel Extracts of Stem Bark of Terminalia arjuna for Antihypertensive Activity in BSO Induced Oxidative Stress based Rat Model.

BACKGROUND: Terminalia arjuna (TA) has been reported and explored traditionally for its cardiotonic properties while the mechanism of antihypertensive effect of TA has not been clearly reported. METHOD: The oxidative stress is a major cause for hypertension, hence different extracts of TA having variable marker yield were evaluated for their antihypertensive effect in buthionine sulfoxamine (BSO) induced oxidative stress based model. Soxhlet extraction (SE), room temperature extraction (RTE), microwave assisted extraction (MAE), and ultrasound assisted extraction (USAE) were quantitatively estimated for marker compounds arjunolic acid and arjunic acid through HPTLC. RESULTS: The hypertension was induced using buthionine sulfoxamine (2 mmol/kg b.w. i.p.) and results suggested that the MAE and USAE showed better recovery of systolic blood pressure (110.33±0.10 and 118.33±0.10) and GSH level (3.62±0.07 nmoles/mL and 3.22±0.13 nmoles/mL), respectively as compared to the positive control group treated with ascorbic acid (Systolic BP: 119.67±0.10, GSH level: 3.11±0.10 nmoles/mL). The RTE and SE also showed a decrease in hypertension but were having moderate effect as compared with the standard positive control. CONCLUSION: The total percentage yield, the yield of the marker compounds arjunolic and arjunic acid, the IC50 values for antioxidant activity as well as the antihypertensive effect were in order: MAE>USAE>SE>RTE that suggested the role of biomarkers arjunolic acid and arjunic acid in reversing the effect of buthionine sulfoxamine.

Therapeutic Potential of Citronella Essential Oil: A Review.

Mosquito-borne diseases such as malaria, filariasis, chikunguniya, yellow fever, dengue and Japanese encephalitis are the major cause of remarkable morbidity and mortality in livestock and humans worldwide. Since ancient times, aromatic plants are used for their medicinal value. Essential oils derived from these plants may be used as effective alternatives/adjuvants in pharmaceuticals, biomedical, cosmetic, food, veterinary and agriculture applications. These oils have also gained popularity and interest for prevention and treatment of various disorders. However, several reports on adverse effects including skin eruption, contact artricaria or toxic encephalopathy in children are available for synthetic repellent in the literature. Thus, natural insect repellents like essential oils have been explored recently as an alternative. One such essential oil studied widely, is citronella oil, extracted mainly from Cymbopogon nardus. This essential oil has exhibited good efficacy against mosquitoes. It is a mixture of components including citronellal, citronellol, geraniol as major constituents contributing to various activities (antimicrobial, anthelmintic, antioxidant, anticonvulsant antitrypanosomal and wound healing), besides mosquito repellent action. Citronella essential oil is registered in US EPA (Environmental protection agency) as insect repellent due to its high efficacy, low toxicity and customer satisfaction. However, poor stability in the presence of air and high temperature limits its practical applications. Since specific knowledge on properties and chemical composition of oil is fundamental for its effective application, the present review compiles and discusses biological properties of citronella oil. It also sheds light on various formulations and applications of this essential oil.