Advances in mycobacterial isocitrate lyase targeting and inhibitors.

Isocitrate lyase plays a key role for survival of Mycobacterium tuberculosis in the latent form during a chronic stage of infection. This enzyme is important for M. tuberculosis during steady stage growth when it converts isocitrate to succinate and glyoxylate. Then, the glyoxylate is condensed with acetyl-CoA to form malate by malate synthase. The carbon conserving glyoxylate pathway has not been observed in mammals; therefore, it has been determined as a potential drug target for discovery of a new antituberculosis agent. Novel active molecules should shorten the duration of therapy, prevent resistance development and eliminate latent disease. The review summarizes recent progresses in isocitrate lyase inhibitors, overviews structural analogues of several metabolic intermediates (3-nitropropionate, 3-bromopyruvate, itaconate, itaconic anhydride), peptide inhibitors, and recently developed inhibitors with various chemical structures. The largest inhibitory activity against isocitrate lyase (IC(50) of 0.10 ± 0.01 µM) and concomitantly a significant antimycobacterial activity has been presented by fluoroquinolone derivative 1-cyclopropyl-7-[3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which has incorporated 3-nitropropionyl group as one of the structural analogue of succinate, a metabolic intermediate.

Antiviral activity of substituted salicylanilides--a review.

Chemotherapy of viral infections is still challenging. Salicylanilides demonstrated a wide range of biological activities including antiviral potency and the review summarizes this field. Niclosamide was described to be able to affect coronaviruses. Some salicylanilides and salicylamides could inhibit HIV virus by targeting of HIV-1 integrase or reverse transcriptase. Hepatitis C virus is another virus, which could be potentially afflicted by salicylanilides on the level of two enzymes--NS3 protease and NS5B RNA polymerase. Nitazoxanide is a nitrothiazole derivative of salicylamide useful for the treatment of protozoal and bacterial infections with an extended range of antiviral activity and innovative mechanism of action, especially against hepatitis and influenza viruses or rotaviruses. Nitazoxanide, its metabolite tizoxanide and their derivatives are a very promising stream in the development of new antiviral compounds. In this review, we summarize the antiviral activity of structures containing salicylanilide and partly salicylamide moiety.

Prodrug design of phenolic drugs.

Phenolic group in therapeutic drugs can be used for a prodrug modification to overcome various undesirable drug properties that may become pharmacological, pharmaceutical or pharmacokinetic barriers for application. Several strategies have been used in order to overcome the limited bioavailability of phenolic drugs. Classical design represents a nonspecific chemical approach to mask undesirable drug properties, limited bioavailability or chemical instability. Targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrug to specific enzyme or specific membrane transporter has potential as selective drug delivery system mainly in cancer therapy. The article brings examples of ester, sulphate, carbamate, carbonate, phosphate and ether prodrugs as well as the limitations of these prodrug strategies. Some specific enzyme targets are also presented.

Recent advances in drugs and prodrugs design of chitosan.

The aim of this review is to outline the recent advances in chitosan molecular modeling, especially its usage as a prodrug or drug in a field of antibacterial, anticarcinogenic and antioxidant activity. Polymeric materials like peptides, polysaccharides and other natural products have recently attracted attention as biodegradabile drug carriers. They can optimize clinical drug application, minimize the undesirable drug properties and improve drug efficiency. They are used for the slow release of effective components as depot forms, to improve membrane permeability, solubility and site-specific targeting. Chitosan is such a prospective cationic polysaccharide which has shown number of functions in many fields, including bio medicinal, pharmaceutical, preservative, microbial and others. This article discusses the structure characteristics of chitosan, a number of factors such as degree of polymerization, level of deacetylation, types of quarternisation, installation of various hydrophilic substituents, metal complexation, and combination with other active agents. Biodegradable, non-toxic and non-allergenic nature of chitosan encourages its potential use as a carrier for drug delivery systems in all above mentioned targets. The use of chitosan prodrug conjugates is aimed at the site-specific transport to the target cells use, for example, a spacer tetrapeptide Gly-Phe-Leu-Gly, promotion of drug incorporation into cells via endocytosis, hybridization or synergism of two types of drugs or a drug with a bioactive carrier. The design of chitosan macromolecule prodrugs is also discussed.

[Salicylanilides: still a potential antibacterially active group]. / Salicylanilidy--stále aktuální skupina s potenciální antibakteriální aktivitou.

The review presents a survey of potential biologically active salicylanilides, focusing particularly on their antibacterial activity. Emergence of bacterial resistance to a large number of antibacterial agents represents a major world-wide problem. On that account, perpetual attention is paid to the preparation of new bioactive antibacterial compounds. Salicylanilides belong to the group of compounds that have shown activity against gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, the strains representing the most significant problem in clinical practice. In 1998, a new mechanism of their action was proposed. Salicylanilides are inhibitors of two-component regulatory systems in bacteria. Electron-accepting substituents on the salicylic and hydrophobic groups on the anilide ring are most essential for the activity, but other electronic and structural parameters may also play an important role. Our aim, based on SAR analysis, is to develop new active drugs esterified by amino acid and later peptides. Furthermore, analogues carrying the hydroxybenzamide moiety may uncouple oxidative phosphorylation.

[Biologically active benzoxazoles]. / Biologicky aktivní benzoxazoly.

This review presents a survey of preparations and biological activities of substituted benzoxazoles. The structural similarity of benzoxazole derivatives with nucleic bases, such as adenine and guanine, probably allows their easy interaction with biopolymers in the living systems. Consequently, these compounds posses a wide range of biological activities. Their preparation includes cyclocondensation reactions and contractions of ortho-fused heterocycles or their photochemical rearrangement. They are being studied predominantly for their antibacterial, antifungal, antiviral, and antitumor activities, and also as insecticides, herbicides, anthelmintics, histamine antagonists, and fluorescent dyes.

Effect of alaptide, its analogues and oxiracetam on memory for an elevated plus-maze in mice.

In the present study, the elevated plus-maze was used to evaluate memory in female mice. In Experiment 1, the mice retested on day 1, 4 or 7 after the initial session escaped from the open arm into the enclosed arm in a significantly shorter time than those retested on day 10 or 14. Thus, a 10-day inter-session interval was chosen for testing drugs which were expected to enhance memory. In Experiment 2, in the retest performed on day 10, both alaptide (cyclo(L-alanyl-1-amino-1- cyclopentanecarbonyl)) and oxiracetam, given immediately after the 1st session, reduced the transfer latency from the open arm into the enclosed arm as compared with that of the controls. In Experiment 3, a similar effect, i.e., the retention of spatial information, was facilitated by post-session injections of 5 out of 21 alaptide analogues. The new compounds represent the 2,5-piperazinedione derivatives which contain 1-amino-1-cyclo-alkanecarboxylic acid (C3 to C7 ring). The cyclopentane- and cyclohexane-ring was substituted by an alkyl group. In the series with the cycloalkane ring, the importance of the structure of alaptide was confirmed again, which underlines the importance of the cyclopentane ring; the active structures had L-alanine instead of glycine as the second amino acid. Isomers of the cyclohexane series which contained methyl or tert-butyl were most active when the substitution was at position 3. Our results demonstrate that the model of long-term memory can be used to discriminate between closely related chemical structures.

Craniofacial morphology as a marker of predisposition to isolated cleft palate.

The etiology and pathogenesis of isolated cleft palate (CP) is largely unknown. Undoubtedly, bot genetic and environmental factors play a role in initiating this malformation. Although the predictions of the multifactorial threshold model have never been satisfied when subjected to statistical analysis, there is no a priori reason to dismiss the possibility that multiple genes may be segregating in CP families that give rise to specific and predictive phenotypes in the parents of CP offspring. We examined a sample composed of 52 parent pairs whose children were born with CP, as well as 75 normal controls with no family history of CP. Using anthropometric and roentgencephalometric methods, along with discriminant function analysis, we searched for craniofacial variables predictive of parents who were ¿at risk¿ for CP offspring. For fathers of CP children, 32 of the studied variables differed significantly from controls; for mothers of CP children 25 variables differed significantly from controls. These results support the hypothesis that there are characteristic morphometric signs in the craniofacies of the parents of children with CP. To confirm these findings, it will be necessary to prospectively ascertain the incidence of CP in the offspring of ¿at risk¿ parents and ¿not at risk¿ parents from families with and without a history of CP in other family members.

[The effect of 1-p-bromphenyl-5-mercapto-1,2,3,4-tetrazole (Br FMT) on thyroid gland function in rats]. / Vliv 1-p-bromfenyl-5-merkapto-1,2,3,4-tetrazolu (Br FMT) na funkci stítné zlázy potkana.

The effects of the novel potential thyrostatic agent 1-p-bromphenyl-5- mercapto-1,2,3,4-tetrazole (Br-FMT) on the serum levels of thyroxine, thyrotropic hormone (TSH), the content of cyclic adenosine monophosphate (cAMP) in the thyroid gland, the body weight and the weight of the thyroid gland in liver transaminases and the white blood picture in Wistar strain rats were investigated. The effect of Br-FMT was compared with the effect of the well-known thyrostatic agent and goitrogen ethylester of 3-methyl-2-thio-4-imidazoline-1- carboxylic acid, carbimazole (Spofa) and with the control group, which received placebo only. The drugs tested were administered to animals in the dose do 7.5 mumol/animal via a gastric tube for the period of one month. Br-FMT and carbimazole decreased the level of serum thyroxine in a statistically significant manner. The serum level of TSH was evidently decreased after Br-FMT; it was not changed after administration of carbimazole in the given dose. The content of cAMP in the thyroid gland was significantly increased only after carbimazole. The weight of the thyroid gland was not significantly changed in any group under study, though after carbimazole the mean value was higher by a quarter as compared with the control group. The body weight and white blood picture were not significantly changed in all groups under study. ALT and AST values were evidently lower after carbimazole and Br-FMT, most probably due to the hypothyroid state of the animals.(ABSTRACT TRUNCATED AT 250 WORDS)

[5-Substituted 3-mercapto-4H-1,2,4-triazoles as a potential thyrostaticagent]. / 5-Substituované 3-merkapto-4H-1,2,4-triazoly jako potenciální thyreostatika.

Within the framework of the study of the relationships between the structure and thyreostatic activity of cyclic analogues of thiourea, a series of 5-substituted 3-mercapto-4H-1,2,4-triazoles was prepared in order to answer the question of how the presence of another nitrogen atom in position 1 and the presence of the substituent in position 5 would influence thyreostatic activity. The synthesis was based on 1-acylsubstituted thiosemicarbazides which were cyclized to the pertinent 3-mercapto-4H-1,2,4-triazoles. Furthermore, esters of dicarboxylic acids were used, which with thiosemicarbazide in alcoholate yielded the pertinent mercaptotriazoles. Selected 5-substituted 3-mercapto-4H-1,2,4-triazoles were tested on adult male rats of Wistar strain. The effects of the agents under study on the level of serum thyroxine (T4), total body weight, heart weight, thyroid gland weight, and the number of leucocytes were investigated. The results of the tests show that whereas the presence of nitrogen in position 1 influenced the thyreostatic activity of the agents prepared in an insubstantial manner only, the presence of a substituent in position 5 acts, except a methyl or ethyl group, dystherapeutically, and with the increasing volume of the substituent therapeutic activity disappears regardless of the fact whether an aliphatic or aromatic substituent is concerned.