Letters in Drug Design & Discovery - Volume 5, Issue 3, 2008

Antioxidant potential of nineteen imidazolones derivatives has been evaluated and their structure-activity relationships established. A rapid and efficient synthesis of imidazolylbenamides was achieved from different azalactones (oxazolones) by reacting with phenyl hydrazide in basic media under microwave irradiation. Excellent yields, high purity, short reaction time and easy and simple work-up are the main features of this synthesis.

In the course of our research program to discover novel antileishmanial agents, a biological screening of natural products against Leishmania major promastigotes allowed the identification of a furoquinoline alkaloid (1) and a furanocoumarin (2) as new hits. Subsequently, an integrated ligand-based virtual screening approach was employed to search for new antileishmanial compounds using these naturally occurring molecules as templates. Fourteen out of 40 compounds selected from a database of about 800,000 compounds (extracted from ZINC, a free database for virtual screening) were experimentally confirmed to possess significant in vitro antileishmanial properties. The application of ligand-based virtual screening as a complementary approach to experimental natural product screening was a useful strategy to facilitate the identification of new promising lead candidates.

A significant percentage of the worlds population has been exposed to Mycobacterium tuberculosis. Four novel hydrazide compounds are presented in this work to discern molecular properties that effectuate bacterial inhibition. The four compounds are hydrazide derivatives of ibuprofen (A), aspirin (B), lauric acid (C), and itaconic acid (D). Of these four hydrazide compounds tested in vitro against Mycobacterium tuberculosis, drug C showed greatest inhibition of bacterial growth, followed in activity by drug A and drug B. The itaconic acid hydrazide derivative showed the least activity, but revealed striking molecular properties that affirms specific criteria for effective bacterial inhibition. Isoniazid was utilized for comparing relative efficacy in reducing proliferation. The lauric acid hydrazide showed high lipophilicity (Log P = 3.449) with low polar surface area (PSA = 55.121 A2). In contrast the itaconic acid hydrazide derivative has low lipophilicity (Log P = -3.52), high water solubility, one violation of the Rule of 5, and the highest value in PSA. Partitioning into the central nervous system via blood-brain barrier penetration, indicated by values of Log BB, is substantially lower for drug D compared to the remaining three hydrazide derivatives and isoniazid. Very high correlation (r > 0.9000) was observed among molecular properties of drugs A, B, C, D, and isoniazid. Multiple regression analysis utilizing formula weight, Log P, polar surface area, and number of atoms accounted for 99.55% of all variance. K-means nonhierarchical cluster analysis indicated isoniazid is most similar to drug D. Results of this study elucidates the influence of various molecular properties that affect inhibitory efficiency.

A series of new 3-aminosteroid derivatives was evaluated for their in vitro antimicrobial properties against human pathogens such as Gram positive bacteria. They are active against multi-resistant cocci, especially Methicillin- Resistant Staphylococcus aureus (MRSA) at average concentrations of 2.5-5.0 μg/mL and are particularly suitable for topical antibacterial use.

ATP-sensitive potassium channels (KATP-channels) provide a vital link between cellular metabolism and electrical activity and the opening of these channels leads to an efflux of K+ ions from the cell with a simultaneous transmembrane hyperpolarization that restricts the entry of ca2+ ions through voltage-gated (L-type) calcium channels and inhibits intracellular ca2+ ion release, thereby damping cellular excitability. Thus, the compound that can act as KATPchannel opener may possess a broad spectrum of potential therapeutic applications. In order to find highly potent KATPchannel openers, a quantitative structure-activity relationship (QSAR) study is made on some recently studied series of them, which provides the rationale to structure modification for the better efficacy and throws light on the mechanism of their action. The series of compounds are comprised of cromakalim analogs, 4-(N-aryl)-substituted benzopyran derivatives and 1,4-benzothiazine derivatives, respectively.

Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on essential enzymes for parasite metabolism, such as proteases, are attractive targets for drug development. In this work, the antimalarial activity of hydroxyethylamine derivatives have been evaluated in vitro against Plasmodium falciparum W2 clone chloroquine resistant. These results show that the some compounds have moderated activity against malaria parasite.

Selective Estrogen Receptor Modulators (SERMs) have been developed, but the selectivity towards the subtypes (ERα or ERβ) is not well understood. Based on three-dimensional structural properties of ligand binding domains, a model that takes into account this aspect was developed via molecular interaction fields and consensus principal component analysis (GRID/CPCA).

Simulations of the effects of DNA polymorphisms, transcriptional noise, and epigenetic differences within and among populations suggest highly divergent responses to drug dosage, resulting in considerable risk of adverse effects. These findings highlight the need for personalized calibration of drug dosage.

Intravenous thrombolysis with rt-PA within three hours of symptom onset is the only proven effective treatment for acute ischemic stroke. The European license limits the use of rt-PA to patients aged <80 years for the lack of clear evidence of safety and efficacy of this treatment in the elderly.

A series of 2-(3',4',5'-trimethoxybenzoyl)-indol-3-yl acetic acid derivatives 2a-g and 3a-j were synthesized and the effects of all the compounds on human leukemia K562 cell growth were investigated. The results showed that the presence of one or more electron-donating methoxy groups at 7- or 5- and 7- positions of N-methyl indole ring, corresponding to compounds 3d and 3f, increased antiproliferative activity against K562 cells and induced the cell apoptosis. The results demonstrated that the methylation of the nitrogen atom of indole nucleus plays an important role for the antiproliferative activities. Replacing the 3',4',5'-trimethoxybenzoyl functionality with a 3',4'-dimethoxybenzoyl, 4'- methoxybenzoy or benzoyl group (compounds 3h-j, respectively) yielded inactive compounds.

The present article describes a series of eleven N-(alkyl)-2-thiophen-2-ylacetamides, which were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory concentration (MIC) in μgmL. . The compounds 3g and 3k exhibited the respective activities of 25 and 50 μg/mL being a new class of compounds against tuberculosis.

Twenty-one 1, 2, 3-triazole-linked norcantharidin analogues have been synthesized by the efficient [3+2]1, 3- dipolar cycloaddition reaction of norcantharidin derivatives with three organic azides. All analogues have been screened for their antiproliferative activity against a panel of tumor cell lines: KB, SMMC-7721, SGC7901, ECA109, HO8910 and K562. Compound 8e showed potency for the treatment of hepatoma, with GI50 value (19.0±0.2μM) to SMMC-7721 cell line comparable to that of cantharidin (GI50 value =33.2±0.3μM).