Letters in Drug Design & Discovery - Volume 6, Issue 4, 2009

Triazoloacridinones (TA) are a class of antitumor agents including a new compound C-1305 now in preclinical trials. In this study, the ability of triazoloacridinones to DNA minor groove binding and relevance to biological activity was investigated, using fluorochrome displacement method. From selected seven triazoloacridinone derivatives, differing in chemical structures, as well as in cytotoxic and antitumour activities only four of them showed C50 parameters (stronger DNA-binders in the minor groove). Weak or lack of correlation between minor groove binding and cytotoxic activities, suggested that these modes of interaction do not play a major role in the mechanism of biological action of TA.

The ability of the docking program AutoDock in studying the binding of small molecules to DNA is examined. Herein, we report molecular dynamic studies with the relaxed complex method applied to DNA, and viscosimetric titration results, performed to investigate a possible DNA-binding mode of a model compound of the previously reported “two armed” class of binders.

Compounds (5a-5f) containing acridine and imidazole moieties in one molecular union were synthesized, characterized and screened against Japanese Encephalitis virus (JEV) (P 20778) and Herpes Simplex virus type-1 (HSV-1) (753166) in-vitro and in-vivo, both. Compound (5e) exhibited the highest activity against both the test microbe (50% inhibition) while (5a) was moderately active (30% inhibition).Compound (5f) displayed 40% inhibition of HSV-1. Investigation revealed that 2-hydroxyphenyl substituent at position-4 is a key factor for bioactivity.

Increasing resistance of malaria parasites, P. falciparum in particular, towards existing antimalarial drugs demands a serious search for novel targets for the development of new antimalarial drugs. In this direction, the cysteine protease falcipain-2, provides an important target to design chemotherapeutic agents for the treatment of malaria due to its key role in hemoglobin degradation. Two series of conformationally constrained compounds, one with pyrrolidinone and the second with imidazolidinone ring, containing electrophilic nitrile warheads were designed and synthesized. The synthesized compounds were evaluated against falcipain-2 enzyme by performing enzyme binding studies. Most of the synthesized compounds showed weak inhibition in micromolar range for the enzyme falcipain-2, presumably due to unfavorable orientation of the molecules caused by the conformationally constrained five-membered rings. To determine the selectivity and specificity, these compounds were also evaluated against cathepsins B and L (analogous cysteine proteases for falcipain) displaying no detectable inhibition of these enzymes. The data indicates that the conformational constraint interferes with the normal binding mode of falcipain-2 to these derivatives.

A novel series of substituted tetrahydropyrimidinediones has been synthesized and evaluated for their schistosomicidal activity both in vitro and in vivo using praziquantel as a therapeutic control. All the tested compounds except compounds (4), (6) and (7a) showed in vitro schistosomicidal activity, however only compound (9) showed in vivo activity in Swiss strain albino mice as evidenced by significant reduction in worm load , tissue egg count , liver granuloma number and size, and histopathological study of the liver. Moreover, electron microscopy scanning of adult S. mansoni recovered from treated animals with compound 9 revealed tegumental changes. These data point to 2-(2,6-dioxo-1,2,3,6- tetahydropyrimidin-4-yl)isoindoline-1,3-dione (9) as a promising new antischistosomal agent.

A lipidic matrix pellet based on Gelucire® was developed for delivering drug to both distal small intestine and proximal colon. Sodium Dodecyl Sulfate (SDS) was used to extend the time of the mixture in solidification. Alpha- Cyclodextrin a cyclic oligosaccharide was added to the mixture to prevent drug degradation and provide appropriate release profile. Gelucire 50/02 matrix pellets were coated with an outer layer of pH-dependent polymer: Eudragit FS30D. Three formulations were retained as good to have sustained release profiles 40/45/15, 35/50/15 and 30/55/15 (Gelucire/4- ASA/α-CD). These mixtures are convenient to obtain a solid pellet with good friability rate close to 1%. Dissolution test was conducted for uncoated pellets and release rates were between 76.82±0.12% and 83.35±0.7% for formulations with SDS 0.25%, between 76.1±0.83% and 83.7±0.7% for formulations with SDS 0.5% and between 67.86±0.48% and 92.44±0.3% for formulations with SDS 0.75%. Furthermore release profile of 4-aminosalicylic acid (4-ASA) coated pellets was studied in a phosphate buffer after a simulated gastric for 2 hours in pH 1.5 media. For 2 hours no significant drug release was detected at this pH (<3%). There was a delayed release of 4-aminosalicylic acid (4-ASA) for 2 hours and no lag time at pH 7.5. Extended release was observed in this later condition for 5hours to reach release rate close to 90%. Scanning electron micrograph (SEM) pictures of the coated and uncoated pellets showed a relative uniformity of the coating layer around the pellets. Delayed release system would be useful to deliver the drug to diseased sites and to achieve gradually the adequate drug release profile through the Gastrointestinal tract (GIT).

This paper describes the comparative QSAR studies on the novel series of thiazolones and tetrazole derivatives as HCV NS5B polymerase allosteric inhibitors, using PRECLAV and DRAGON descriptors. The statistical analyses using the PRECLAV software showed that the model based on both DRAGON and PRECLAV descriptors (r2=0.8929, Se=0.1141, F=35.0183, r2cv=0.8199) is better than the one using either PRECLAV descriptors (r2=0.75, Se=0.1743, F=16.5022, r2cv=0.5691) or DRAGON descriptors (r2=0.7387, Se=0.1782, F=11.8759, r2cv= 0.596). The results are critically discussed using Ridge statistics.

Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. The indole nucleus, frequently encountered as a molecular fragment in natural products and pharmaceutically active compounds, was employed as the initial building block for the synthesis of a series of pyrazino[1,2- a]indoles 1a-k, variably substituted at the 6, 7, 8 and 9-positions. Compound 1e, bearing the methoxy group at the 8- position of the pyrazino[1,2-a]indole nucleus was identified as a novel potent antiproliferative agent against the human chronic myelogenous leukemia K562 cell line, but it was much less active against several other cancer cell lines. Comparison of positional isomers indicated that moving the methoxy group from the 8- to the 7- or 6-position, to furnish compounds 1f and 1g, respectively, yielded inactive compounds. The analysis of structure-activity relationships observed in the series of investigated compounds may represent the basis for the design of more active molecules.

Rectal anti-inflammatory poloxamer gel systems composed of Poloxamer and bioadhesive polymers were developed and evaluated. Hydroxypropylmethyl cellulose (HPMC), poly(vinyl) pyrrolidone (PVP), methyl cellulose (MC), hydroxyethylcellulose (HEC) and carbopol (CP) were examined as mucoadhesive polymers. The characteristics of the suppositories differed according to the properties of mucoadhesive polymers. The physicochemical properties such as gelation temperature, gel strength and bioadhesive force of various formulations were investigated. The gelation temperature was between 20.4 and 38.8 °C, the gel strength was between 20.4 and 88.3 sec, mucoadhesive force was between 30.5 and 110.3 x 102 dyne/cm2. The analysis of release mechanism showed that the release of etodolac was proportional to the square root of time, indicating that etodolac might be released from the suppositories by Fickian diffusion (n ranged from 0.220 - 0.498). The release rate constant was between 5.431 and 17.349 %/minn. The anti-inflammatory effect of etodolac poloxamer gel was also studied in rats. Moreover, liquid suppository of etodolac did not cause any morphological damage to the rectal tissues. These results suggested that in situ gelling liquid suppository with etodolac and mucoadhesive polymer was a physically safe, convenient, and effective rectal dosage form for etodolac.

Boceprevir is a novel hepatitis C virus (HCV) protease inhibitor undergoing clinical investigation for use in the treatment of human HCV infection. Preclinical in vivo pharmacokinetic studies have been performed in rat, dog, and/or monkey after single administration by oral and intravenous routes for about one thousand compounds prior to the selection of boceprevir as the development candidate. In vitro pharmacokinetic assessments of metabolic stability, cell permeability, and plasma protein binding have been performed. The compound has physicochemical properties (molecular weight of 519.7 and moderate lipophilicity and H-bonding functionalities) that are borderline for good pharmacokinetic behavior. Absorption in animals ranges from 12 to 37%, indicating incomplete absorption. Based on in vitro permeability studies in Caco-2 cells, boceprevir appears to be an efflux substrate displaying a saturable efflux profile at high dosing concentrations and a reversible efflux profile in the presence of P-glycoprotein (P-gp) inhibitors. Boceprevir displayed a rather high liver/plasma average ratio of 30 in rats, indicating good uptake by the target tissue. The rat liver/plasma ratio of boceprevir appeared to be higher than those for compounds that are under clinical evaluation. Based on the preclinical pharmacokinetic data, boceprevir appears to have limited absorption, but reasonable liver distribution which is a primary factor for selecting boceprevir as a development candidate. Recent clinical proof-of-concept study confirmed that boceprevir is efficacious in reducing the viral load in patients.