Preparation of new series of 1-[4-(5-Phenyl-4,5 dihydro-1H-pyrazole-3-yl)-phenyl]-pyrrole-2,5-dione and 1-[4- (5-Phenyl-4,5 dihydroisooxazole-3-yl)-phenyl]-pyrrole-2,5-dione derivatives, derived from α,β-unsaturated ketones with objective of obtaining lead compounds for future development as antiviral agents. The inhibition of virus-induced cytopathicity or plaque formation in HEL [herpes simplex virus type 1 (HSV-1) (KOS), HSV-2 (G), vaccinia virus, vesicular stomatitis virus, cytomegalovirus (HCMV), and varicella-zoster virus (VZV)], Vero (parainfluenza-3, reovirus-1, Sindbis virus and Coxsackie B4), HeLa (vesicular stomatitis virus, Coxsackie virus B4, and respiratory syncytial virus) or MDCK [influenza A (H1N1; H3N2) and influenza B] cell cultures by synthesized derivatives. All the compounds were characterized by physical, spectroscopic and elemental analysis. Among the fourteen synthesized targets only compounds 3g and 4e showed activity against RSV (EC50 = 37 µM and 46 µM with affecting cell morphology at concentrations of, respectively, 254 µM and 286 µM) Compound 3g also showed weak activity against feline corona virus (EC50 value of 29 µM and a MCC of 107 µM) for CRFK cells. Feline corona virus was also weakly inhibited by compound 3f (EC50=39 µM) that altered cell morphology at a concentration of 231 µM. Except for feline corona virus, none of the other viruses was inhibited by compound 3f. Low selectivity indices (SIs), defined as ratio MCC/EC50, were observed SI=4 and SI=6 for compounds 3g and 3f against feline corona virus respectively, while SI=6 for compound 4e against RSV, and SI=7 for compound 3g against RSV. Biological evaluation was performed using acyclovir, brivudin, gancilcovir, cidofovir against herpes and poxviruses while ribavirin against RNA viruses, reference standard drugs. Keywords: Antiviral activity, 4, 5 dihydro-1H-pyrazoles, 4, 5 dihydroisoxazoles.
Chronic inflammation has been identified as a significant factor in the carcinogenesis of various tumors, including pancreatic cancer. Both hereditary and classical forms of chronic pancreatitis are associated with an increased risk of developing pancreatic cancer. Cytokines and other mediators of the inflammatory process together with an upregulation of pro-inflammatory pathways play a pivotal role in oncogenesis stimulation, tumor growth and metastasis. The presence of a strong desmoplastic reaction within and around pancreatic cancer cells renders the proteolytic degradation of extracellular matrix components an essential process for tumor invasion and metastasis. Various classes of proteases produced by the pancreatic acinar cells are involved in these proteolytic events. The multiple link between inflammation and pancreatic cancer may represent the basis for a novel antineoplastic strategy. Cytokines, proteases, reactive-oxygen-species, cyclooxygenase-2, nuclear-factor-κB and perixosome proliferator-activated receptor-γ may be a new molecular targets useful for therapeutic purpose. Keywords: Cyclooxygenase-2, cytokines, gabexate mesilate, nuclear-factor-kappaB, pancreatic neoplasms, pancreatitis, chronic, perixosome proliferator-activated receptor-gamma, proteases, reactive oxygen species, stromal cells
Naproxen is a propionic acid derivative related to the arylacetic acid group. This drug is one of the most popular non-steroidal anti-inflammatory agents. It is a non-selective cyclooxygenase inhibitor and is advocated for use in painful and inflammatory rheumatic and non-rheumatic conditions. In low risk patients, naproxen and ibuprofen may be the first choice agents because they are effective, well tolerated and inexpensive. Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95% and elimination half-life is 12 to 17 h. It has a volume of distribution of 0.16 L/Kg and at therapeutic levels, it is more than 99% albumin-bound. Although introduced long back, several efforts have been done to develop its prodrugs and analytical procedures. The current article describes chemistry, pharmacology, pharmacokinetics, adverse effects, interactions and contraindications of naproxen. A special emphasis is laid on the review of recent literature of various prodrugs synthesized and analytical methods developed for determination of naproxen in pharmaceutical preparations. Keywords: Naproxen, NSAIDs, prodrugs, analytical methods
Over recent years, non-steroidal anti-inflammatory drugs (NSAIDs) have been increasingly introduced as topical preparations as they are simple to apply and deliver high drug concentrations locally with limited side effects. Ketorolac trometamol (KT), a potent COX-2 inhibitor, produces typical side effects of NSAIDs when given orally and systemically. Hence the present investigation encompasses the development of topical formulations employing different dermatological bases and evaluated for its efficacy and safety. Standard procedures were followed to test the antiinflammatory and antihyperalgesic effects in male Wistar albino rats. Amongst the various semisolid formulations, the formulation containing hydroalcoholic carbopol gel base (KT1) was found to be significantly (p < 0.05) more effective in inhibiting hyperalgesia associated with inflammation (79.69±1.51 after 5 h of carrageenan administration) as compared to formulation containing plain carbopol gel base (68.75±2.76) and PEG base 73.44±1.23. This demonstrates the suitability of carbopol gel base as an ideal dermatological base for ketorolac trometamol topical formulation and thus providing an ample credence for better therapeutic efficacy. Keywords: COX, NSAID, hyperalgesia, topical, inflammation
Respiratory RNA viruses are constantly evolving, thus requiring development of additional prophylactic and therapeutic strategies. Harnessing the innate immune system to non-specifically respond to viral infection has the advantage of being able to circumvent viral mutations that render the virus resistant to a particular therapeutic agent. Viruses are recognized by various cellular receptors, including Toll-like receptor (TLR) 3 which recognizes double-stranded (ds)RNA produced during the viral replication cycle. TLR3 agonists include synthetic dsRNA such as poly (IC), poly (ICLC) and poly (AU). These agents have been evaluated and found to be effective against a number of viral agents. One major limitation has been the toxicity associated with administration of these drugs. Significant time and effort have been spent to develop alternatives/modifications that will minimize these adverse effects. This review will focus on the TLR3 agonist, poly (IC)/(ICLC) with respect to its use in treatment/prevention of respiratory viral infections.
An increasing fraction of bacterial isolates show reduced susceptibility to our most trusted antibiotics. In order to prevent this serious medical problem, the elaboration of new types of antibacterial agents or the expansion of bioactivity of the previous drugs is a very important task. Different targets in key areas of the bacterial cell cycle have been studied that would be a new weapon against this threat. In this review we attempt to summarize the recent progress made in the field of some represent bacterial enzyme inhibitors and the structure-based drug design of new broad-spectrum antibacterial agents. Based on the structure design and protein target, more and more novel compounds were discovered for the development of new antibacterial agents. It is expected that this review would serve as a stimulant for new thoughts in the quest for rational designs of more effective antibacterial drugs.The interaction of structure design with enzyme targets is fascinating, and this story is still unfolding for us to discover novel antibacterials. Keywords: Antibacterial, structure design, drug discovery, FabH, DNA gyrase A, DNA gyrase B, FtsZ, DdlB, VanA.
Background: We have recently reported that Lactobacillus GG (LGG) elaborates seven small peptides that exert both anti- Gram-negative and Gram-positive bactericidal activity. Among them, peptides NPSRQERR, VHTAPK and PDENK have higher activity than others. Here we further report the inhibitory function of these three peptides on antibiotic- resistant bacterial strains and preliminary structure-activity analysis. Methods: Peptides were synthesized, purified, and dissolved in related media. Lactobacillus GG conditioned medium was used as a positive control and media alone or homologous-conditioned medium were used as negative controls. A600 measurement was used to measure antibacterial activity. Results: LGG-derived peptides NPSRQERR, VHTAPK and PDENK were found to inhibit growth of kanamycin-resistant E. coli SM10 δpir and tetracycline-resistant E. coli TOPO10. Moreover, growth of methicillin-resistant Staphylococcus aureus (MRSA) was also found to be inhibited by peptides NPSEQERR, VHTAPK and PDENK. Structurefunction analyses revealed that the anti-bacterial properties of these peptides can be increased or decreased by modification of amino acid charge. Keywords: Lactobacillus GG, peptide, antibiotic-resistant bacteria, Methicillin resistant Staphylococcus aureus (MRSA)
Anthelmintic resistance in humans has been suspected but remains until now anecdotic compared to the extension of the phenomenon in helminths of livestock or Plasmodium in humans. Human mass drug treatment has been offered against several filarial diseases, schistosomiasis and soil-transmitted nematode infections, thus the appearance of resistance is expected. Up to now the used drugs remain active but a follow up of their efficacy is needed. A poor observed efficacy is not always due to resistance and cases of false resistance are recorded or suspected. In such cases, the quality of the drug may be faulty since many of the proposed drugs on shelf are counterfeit in poor countries; in other countries the unregulated internet pharmacies may also propose counterfeit drugs. The quality drug may also have a poor absorption or metabolisation due to diet or to concomitant treatments of the patients. False resistance observation may arise from poor diagnostic or misdiagnosis and then diagnostic improvement is the main solution to be proposed. The evaluations of resistance in the field are mostly derived from in vivo efficacy assessments based in majority on before and after treatment measurements. The use of control group when feasible and more refined statistical tools should be implemented. When the resistance mechanisms are partly known (several classes of drugs in malaria or benzimidazole resistance of nematodes) molecular tests on parasites would be the best instrument for a follow up of resistance. The last cause of false resistance could also be simply poor compliance of drug use, particularly when the drug exerts unpleasant side effects or when the duration of treatment is long. The assessment of resistance is not always easy in field conditions due to all these confounding effects and false resistance should be an issue to be considered in most cases. Keywords: False resistance, counterfeit drug, efficacy test, compliance, anthelmintic, malaria, nematode, schistosoma
Inadequate use of anthelmitic drugs in livestock animals has led to therapeutic failures and to the dramatic widespread development of parasite resistance. Additional scientific knowledge on how to improve the use of available and novel molecules is required to avoid/delay resistance development. The time of parasite exposure to active drug concentrations determines the efficacy and/or persistence of activity for most of the anthelmintic drugs used in ruminants. The outcome from integrated pharmaco-parasitological research approaches addressed to interpret the host-drug-parasite relationship has greatly contributed to optimise drug activity. The integrated assessment of the drug disposition in the host, the mechanisms of drug influx/efflux in different target helminths, their biotransformation/detoxification capacities and the chemically-induced modulation of those transport/metabolism processes, has signified a relevant progress on the understanding of the pharmacology of anthelmintic drugs in ruminant species. Further pharmaco-parasitological interdisciplinary work, supported by the huge progress achieved on parasite genomics, will be essential to generate the basic scientific knowledge necessary to preserve existing and particularly, novel active ingredients as useful tools for parasite control in livestock animals. The basic and clinical pharmacology issues summarised in the current article contribute in that direction. Keywords: Ruminants, anthelmintic drugs, pharmaco-parasitological assessment of drug activity
Studies in 3D molecular fields generally contain a large amount of data, some of which are redundant or not relevant. The program Volsurf, a quite fast method, is able to compress the relevant information present in 3D molecular structures into a few descriptors that represent the physicochemical properties. In this study eighteen p-substituted benzoic acid N-(5-nitrothiophen-2-yl)methylenehydrazides with antimicrobial activity were evaluated against multidrug-resistant Staphylococcus aureus, correlating the three-dimensional characteristics of the ligands with their respective bioactivities. Structures were obtained by CORINA program, and using a GRID force field, the following probes have been used to generate their corresponding 3D interaction energies (MIFs): water, DRY, carbonyl oxygen atom and amide NH group. Calculations using Volsurf resulted in a statistically consistent model with 48 structural descriptors showing that hydrophobicity is a fundamental property in the analyzed biological response. Results have shown the potential of studied compounds as alternatives to the treatment of infections caused by multidrug-resistant Staphylococcus aureus. Keywords: 3D QSAR, volsurf, nifuroxazide, MRSA, antimicrobials
The synthesis of 40 new monocyclic β-lactams bearing a morpholine moiety at their N1 positions is described. The structures of these compounds have been confirmed by IR, 1H-NMR, 13C-NMR, Mass spectra and Elemental analysis. The antimicrobial activities of the synthetic compounds have been tested against clinically important fungi including Candida, Aspergillus and Microsporum and Epidermophyton species by broth microdilution method as recommended by CLSI. Inhibition studies showed that some of the tested compounds, in particular those with phenoxy groups, exhibited strong antifungal activities against all tested fungi at concentrations of less than 8 μg/mL, while others only inhibited the growth of dermatophytes or Aspergillus species. These results suggest that the derivatives should be investigated further for possible use in antimicrobial products. Keywords: Antifungal, aspergillus, azetidine-2-one, candida, dermatophyte, fungi, monocyclic β-lactam, morpholine.
The introduction of penicillin in the 1940s, erythromycin in the 1950s and methicillin in the 1960s was quickly followed in each case by appearance of resistance to these antibiotics. By comparison, glycopeptide resistance required nearly thirty years to appear following clinical introduction of vancomycin. The reason for the delay is likely related to the clever mechanism of action of glycopeptide antibiotics. These antibiotics interfere with biosynthesis of the bacterial cell wall by binding to a critical cell wall intermediate. High level resistance required a collection of genes to reorder cell wall biosynthesis enabling bacteria to bypass the critical steps susceptible to inhibition by vancomycin and other glycopeptide antibiotics. There have been various efforts, with mixed success, to identify novel glycopeptide structures able to circumvent high level glycopeptide resistance. This review focuses on the discovery and development of oritavancin, a lipoglycopeptide antibiotic having exquisite activity against staphylococci and other gram-positive bacteria including MRSA and those resistant to high concentrations of vancomycin. The oritavancin story includes a combination of natural products screening, medicinal chemistry-directed modification, and extensive microbiological, biochemical, pharmacological, and clinical evaluation. The story behind this agent also reveals the pharmaceutical business and regulatory challenges that can have a major impact on development of new antibiotics and obtaining regulatory approval for clinical useage. Keywords: Glycopeptide, lipoglycopeptide, vancomycin, teicoplanin, chloroeremomycin, oritavancin, transglycosylation, transpeptidation, acyl-D-Ala-D-Ala, alkyl, glycopeptide resistance, dimer
During the past few decades, the potential of treating infections with nitric oxide (NO) has been firmly demonstrated in various laboratories. Both in vitro and in vivo studies have afforded promising results in terms of reducing microbial loads in chronic wounds in addition to its utility in keeping medical devices free of thrombus formation and bacterial adhesion. The latter antimicrobial effects of NO provide great help in successful integration of orthopedic and vascular implants and prolonging their in vivo life. In all such applications, NO is released from various polymeric materials in which nitrite salts, exogenous NO donors, or even simple NO(g) are incorporated. Recent developments in all such formulations of NO-releasing materials and their specific applications in combating bacteria, fungi and parasites are reviewed in this article. Keywords: Nitric oxide (NO), infection, wounds, antimicrobial, platelet adhesion, antithrombic, NO donors, polymers, NOreleasing material, metal nitrosyls.
Neuraminidase (NA), a glycoside hydrolase enzyme, plays pivotal roles in controlling biological functions not only of influenza viruses but also of humans. Zanamivir and oseltamivir designed to target influenza neuraminidase have become extensively used for influenza clinical treatment as its high anti-influenza efficacy. Unfortunately, side effects of these two drugs have been reported in clinical use. An aromatic benzene ring has been pursued as a core structure to derive stereo chemically simplified analogues with desired molecular properties. In our previous study, a series of 2-fluoro benzoic acids were synthesized and evaluated against all four human sialidase enzymes. Herein, we further evaluate the same set of 2-fluoro benzoic acids for inhibitory activity against viral sialidases expressed by influenza A virus. The most active compound 11 (4,5-diacetamido-2-fluoro benzoic acid) has an IC50 of 4.5 μM (N1) and 21 μM (N2) that is ∼60-140 fold more active than its non-fluoro counterpart 10 (3,4-diacetamido benzoic acid) that has an IC50 of 640 μM (N1) and 1400 μM (N2). Molecular docking and calculated binding free energies are in good agreement with the experimental data. Of greater significance was the observation of key interaction of 2-fluoro group with active site for improved activity and could be explored further for higher affinity and selectivity over viral sialidases with suitably substituted 2-fluoro benzoic acids. Keywords: Influenza, Sialidase, Inhibitor design, Neu5Ac2en, Benzoic Acid, Docking.
In recent years, vancomycin has received appreciable attention as an antibiotic drug of last resort. The generally accepted mechanism entails interference with bacterial cell wall synthesis. There is negligible attention to other modes, even though drug action is often multifaceted. This review provides a hypothesis for an additional mechanism of antibacterial action based on the polyphenol residue in the glycopeptide. The functionalities present are monophenol, resorcinol and hydroxybiphenyl, all of which have the potential to produce electron transfer (ET) metabolites capable of generating reactive oxygen species (ROS) and oxidative stress (OS). Considerable literature is presented in support of the thesis. Drug toxicity is rationalized based on the fundamental approach to vancomycin action. This review represents another example in support of the prior ET-ROS-OS unifying mechanism for anti-infective and toxic action. Novel insight may aid in improved drug design. Keywords: Vancomycin, mechanism, polyphenol, electron transfer, radicals, antibiotic, toxicity.
As malaria continues to be a worldwide problem due to increasing drug resistance, several drug susceptibility techniques have been reported in the literature. A particularly confounding problem is the lack of standardization between methods that result in differences in sensitivities. In this review, we report on the types of antimalarial drug susceptibility assays available to clinical and research investigators. Techniques based on enzyme-linked immunosorbent assays (ELISAs), fluorescence, molecular assays, and optical methods will be outlined. Strengths and weaknesses, as well as field applicability, will be discussed. Furthermore, assay and culture conditions, particularly for the fluorescence-based assays, will also be detailed. Keywords: Antimalarials, drug susceptibility, ELISA, fluorescence, molecular assays, real-time polymerase chain reaction, optical imaging, Plasmodium
Tuberculosis (TB) has remained an enemy of humankind before the beginning of recorded history. Although it is curable and preventable, TB claims the lives of more than 5,000 people every day. Despite of availability of effective chemotherapy and BCG vaccine in 21st century, TB remains one of the most deadly infectious diseases. The concomitant resurgence of TB with the Multi-drug resistant (MDR) or Extremely drug resistant (XDR)-TB and HIV/AIDS pandemic raises the threat posed by untreatable and fatal human TB, exposing the frailties of the current drug armatorium. No new drug is available acting through novel mechanism since last 40 years. The genome of Mycobacterium tuberculosis H37Rv was sequenced in 1998 and reannotated in 2002. This coupled with development of new genetic tools, have greatly contributed to the discovery of potential drug targets for new anti-TB agent. It is increasingly acknowledged that new drugs should not only be active against drug resistant TB, but should also kill persisters and shorten the lengthy TB treatment, which underlies the problem of drug resistance due to poor compliance to the length of therapy. This review article describes the current TB drugs, their merits and demerits as well as the new promising anti-TB agents classified on the basis of molecular framework. It is a comprehensive literature compilation on the present research paradigm of anti-TB drug discovery including advances in the new structural analogs reported in last decade. Keywords: Mycobacterium tuberculosis, MDR, &, XDR TB, novel targets, ligands
Bacterial endotoxins (lipopolysaccharide, LPS) from the outer leaflet of the outer membrane of Gram-negative bacteria are among the most effective natural compounds in triggering the human innate immune system. This may be beneficial at low but pathophysiological at high LPS concentrations, the latter leading to the severe septic shock syndrome with still high mortality rates especially in intensity care units. One approach to inactivate compounds such as LPS is the use of cationic amphiphilic peptides based on natural endotoxin- binding proteins, which are designed to neutralize bacterial LPS and thus inhibit its interaction with relevant mammalian binding proteins/ receptors such as lipopolysaccharide-binding protein (LBP), CD14, and TLR4/MD2. We have designed and synthesized peptides based on human lactoferricin, and have applied in an iterative process (first to third generation) various experimental systems to test their ability to fight against bacterial sepsis. Here, four compounds from the third generation were selected, with and without a short hydrocarbon chain, and analysed in detail starting from biophysical over cell biological and microbiological assays up to animal experiments. Thus, we were able to characterize the parameters relevant in endotoxin deactivation, as part of the bacterial cell as well as in isolated form. The most important parameters include the peptide length, number of cationic amino acids, and hydrophobicity of the peptides. Keywords: Sepsis, lipopolysaccharide, small-angle X-ray scattering, lactoferricin, antimicrobial peptides
