Current Medicinal Chemistry - Anti-Infective Agents - Volume 2, Issue 4, 2003

Antibiotics constitute the dominant treatment of gastrointestinal infections. However, several serious side-effects are associated with extensive use of antibiotics, including spread of bacterial resistance and allergic reactions as well as potential overgrowth of pathogenic bacteria and viruses. On the other hand, there is a growing body of evidence suggesting that certain bacteria, referred to as probiotics, have anti-bacterial properties and may counteract the development of infections. Probiotics are defined as viable non-pathogenic microorganisms, which, upon ingestion exert a positive impact in the host. This review will focus on the antiinfective mechanisms and effects of lactobacilli and suggests that administration of lactobacilli may be an effective approach to prevent and treat a vast spectrum of infections of enteric origin.

The chemistry of pyrimidines and its derivatives have been studied since past century due to their close pharmacological association with diverse pharmacological properties. Pyrimidine was first isolated by Gabriel and Colman in 1899. Though pyrimidine itself does not exist in nature but substituted pyrimidines containing pyrimidine moiety are found as a part of more complex system and are widely distributed. Pyrimidines are considered to be important not only because they are an integral part of the genetic material viz. DNA and RNA as nucleotides and nucleosides but they also impart numerous biological activities such as bactericides, fungicides, viricides, insecticides and meticides. They have also found application in agricultural and industrial chemicals. Many reviews on naturally occurring pyrimidines are available on general introduction including broad principles, detailed general procedure, synthetic procedures along with physical properties. But no collective information is available on role of pyrimidines as bioactive compound. This biodynamic property of the pyrimidine ring system prompted us to account for their pharmacological properties especially as anti-infective agents. Here we are reporting a specialized review, which focuses on different aspects of pyrimidine as anti-infective agent.

Control of microbial growth, through inhibition of proteases including serine, cysteine and metalloproteases, has been a focus of both man and nature. Although β-lactams have proven to be most successful in control of pathogens, their utility has become significantly limited as a result of development of antibiotic resistance, especially the production of extended spectrum β- lactamases. Preparations of biologically active γ- or δ-lactam mimics of penicillin, have led to the discovery of several types of bioisosters of b-lactams. These mimics can not only exhibit antimicrobial activity, but similar to their b-lactam parentage, they can also act as inhibitors of β- lactamases. Both synthetic and naturally occurring γ-lactams and β-lactones also inhibit mammalian and viral enzymes. In addition to the β-lactam analogs, several other classes of inhibitors, whose inhibitory mechanism is based on acylation of proteases have been developed. These include the heterocyclic inhibitors, such as isocoumarins, benzoxazinones, epoxides, sulfonamides, and pyrazolidinones. While acylation is the mechanism of choice for both these and β-lactam inhibitors, alternative mechanisms for enzyme inhibition are described including alkylation and chelation, as in the case of metalloproteases. Novel approaches, including mimicking nature though the use of homoserine lactones is a new direction, which may aid in reduction of bacterial loads and inhibition of colonization. The focus of this review is to compare the various structurefunction relationships of these non-β-lactam mimics.

This review addresses the general problem of the physico-chemical characterization of drugs and drug products. The characterization may be performed with a range of methods that appears to be mostly limited by imagination, and aims to fulfill one or more of the following goals: gather data relevant in predicting / optimizing performances of a drug, selecting its delivery system, planning a scaled-up production and associated quality controls, complying with regulations. In keeping with the general focus of the Journal, most examples presented will deal with antinfective agents, although the physico-chemical characterization is largely independent of the therapeutic goal. We begin by reviewing the substantial and recent advances in new classes of materials for drug delivery and in techniques for experimental and theoretical studies of physico-chemical properties of pharmaceutical compounds. We then introduce through examples the complex phenomenology of these properties, which may be investigated also with standard and inexpensive experimental techniques. The last part of the review addresses the problem of defining a fast and reliable protocol for investigating drug-excipient compatibility problems.

Phenothia zines and related compounds are tricyclic drugs used in psychiatric treatments as antidepressant, anxiolytic and antipsychotic. They accumulate in brain, provoking dopamine receptors blockade. They also have antiemetic and antihistaminic effects and many biological activities. WHO promotes the development of a single treatment for African Trypanosomiasis, Chagas'disease and Leishmaniasis. The features of the organisms that produce these diseases, the knowledge of their biology and the sequenced of the three parasites genomes, provide the basis for identifying common metabolic pathways that can provide new drug targets. Such target must be characteristic of these parasites, but absent or altered in the mammalian host. The trypanothione reductase, enzyme of the redox defense system, present in these tripanosomatides has been widely identified as a drug target. It is irreversibly inhibited by peroxidase / H2O2 / phenothiazine systems depending on the phenothiazine structure and concentration. We have studied the effect of some phenothiazines and related compounds upon the Trypanosoma cruzi, causative agent of Chagas'disease. The drugs currently used for treatment have high toxicity and frequently parasites appear resistant to them. Phenothia zines pr oduce d trypanothione reductase inhibition and other trypanocidal effects upon T. cruzi such as anticalmodulin action, disruption of mitochondria and cell membrane disorganization. This tricyclic drugs were also effective in treatment of different T. cruzi strains infected mice, since they modified the natural evolution of the infection; cardiac function and survival of infected and treated animals were not different from non-infected. Phenothiazines and related compounds are promising trypanocidal agents for treatment of Chagas'disease.

The aim of this review on the anti-infective properties of flavonoid compounds found in plants was to obtain a fresh perspective on the potential of these compounds to be developed into natural products with application potential in the pharmaceutical and agricultural industries. Flavonoids are the largest group of naturally occurring phenolic phytochemicals and more than 5000 have been described. Approximately 650 flavones and 1030 flavonols are known although most of these are glycosides of 200 flavonoid aglycones, in the case of flavones, and 300 in the case of flavonols. Small amounts of aglycones frequently are present and occasionally represent a sizable proportion of the total flavonoid compounds in or on the plant. It is estimated that about 2% of all carbon photosynthesized by plants, amounting to about 1 x 10 9 tons per annum, is converted into flavonoids or closely related compounds. In terms of the potential to develop flavonoids as natural products and to utilize it as anti-infective agents in either the agricultural, veterinarian or pharmaceutical industries, it can be said that the source of flavonoids, namely wild plants, is largely untapped. The potential of flavonoid compounds to be applied as anti-infective agents is reviewed instead of generalizing the vast other activities identified for this group of compounds. Antibacterial, antifungal and antiviral properties have been associated with individual or collective groups of flavonoids in the past. Some of the major advances, including the association of known flavonoids with the growth inhibition of specific microbes or viruses and the identification of novel flavonoids as well as the bioavailability and metabolism of flavonoids consumed by animals and man are discussed.