Letters in Drug Design & Discovery - Volume 4, Issue 7, 2007

The cytotoxic activity of (PdCl2)2(spermine) against a human cancer cell line (HSC-3) was evaluated. The results show an activity higher than that of the analogous Pt(II) chelate and, for 24 h incubations, identical to that of cisplatin. They also suggest a faster intracellular uptake and DNA binding relative to cisplatin.

The microwave-promoted cyclization method has been used for the synthesis of a series of novel substituted 2,4-diarylthiazoles from α-halo ketones and thioamides using ethanol as solvent. This rapid method produces compounds in good yield within one minute in comparison with conventional heating method. The synthesized molecules have been evaluated for their antiproliferative effects against five different cancer cell lines.

A new series of 1- and 6-Substituted 1H-indazoles 2-6 were synthesized in moderate yield, through a simple synthetic strategy using 6-nitroindazole as key intermediate. The cytotoxicity of synthetic compounds was evaluated against kidney carcinoma cell line (BSR) and the human larynx carcinoma (Hep). Some of the newly prepared compounds indicated significant inhibitory activity against these cells in vitro.

We previously reported a bi-functional betulinic acid derivative, A12-2 (4), containing an optimized C-28 side chain that exhibits potent anti-HIV activity by inhibiting both HIV-1 entry and maturation. Compound 4 contains C-3 and C-28 side chains that are pharmacophores for anti-HIV maturation and entry activity, respectively. The betulinic acid core, which serves as a molecular scaffold for compound 4, is also important for anti-HIV activity. The main purposes of the present study were to investigate the structure-activity relationships (SAR) of both the C-3 side chain and scaffold of 4. Further modification of the C-3 side chain of 4 suggested that both bulkier and smaller C-3 substituents negatively impacted the anti-HIV-1 activity. SAR study of the scaffold indicated that the betulinic acid moiety of 4 could be replaced with other scaffolds while still remaining active against HIV-1 replication. Among the synthesized compounds, the most effective molecular scaffold for anti-HIV activity remained to be betulinic acid (0.0026 μM), followed by moronic acid, ursolic acid, and oleanolic acid. On the other hand, substitution of the betulinic acid moiety of 4 with glycyrrhetinic acid or lithocholic acid completely abolished anti-HIV activity. Mechanism of action studies indicated that all active terpenoid analogs of 4 retained both anti-HIV-1 entry and anti-HIV-1 maturation activities.

We report the preliminary results into the synthesis and evaluation of triazole-based compounds against the components of 17α-hydroxylase/17,20-lyase (P45017α), namely 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results show that the compounds are weaker than ketoconazole but are good lead compounds in the search for inhibitors of P45017α, in particular, lyase.

Human Leucocyte Elastase (HLE) is a serine protease, which is released from neutrophils in response to inflammatory stimuli. Under normal conditions, the body protects itself from the potential damaging effects from extracellular HLE with the endogenous α1-proteinase inhibitor. Sometime, the action of these endogenous inhibitors seems to be insufficient because there is an unbalance between HLE and antiprotease levels which causes a greater proteolitic activity of this enzyme. This unbalance comes out from an inhibitor decrease, often due to a genetic deficit. The excess HLE, produced by this unbalance, hydrolyzes elastin, the structural protein which gives to the lungs their elasticity, thus initiating and/or contributing to the development of diseases such as pulmonary emphysema, chronic bronchitis, adult respiratory distress syndrome, rheumatoid arthritis, atherosclerosis, cystic fibrosis, chronic bowel disease, and other inflammatory disorders. For these reasons, we are carrying out in a vitro screening programme of new molecular entities’s evaluation such as Human Leucocyte Elastase (HLE) inhibitors. In this work we have processed beta-lactams derivatives by examining azetidinone structures, replaced in position 3, in order to find molecules possessing both a satisfactory inhibition of the HLE and a good chemical stability. The results of our experiments indicate that compounds 3d-3e-3f and 3h (450 -ÊM) were able to induce a significative inhibition of HLE (% of inhibition was 30, 45, 57 and 69, respectively, P<0.01) indicating that these ..-lattamics could be potential inhibitors of HLE.

IL-10 is an anti-inflammatory cytokine widely regarded as an inhibitor of immunity. Thus IL-10 and IL-10 antagonist have been proposed as promising therapeutic factors for the treatment of inflammatory diseases and pathogen infections. Here the potential risk of favoring secondary pathogen infections with these therapies is underscored.

A quantitative structure-activity relationship (QSAR) study has been made on a series of aryl sulfonyl amido and ureido derivatives acting as matrix metalloproteinase (MMP) inhibitors. It is found that the inhibition potencies of the compounds against all the MMPs (MMP-1, MMP-2, MMP-8, and MMP-9) and a bacterial collagenase called Clostridium histolyticum collagenase (ChC) studied are significantly correlated with the electrotopological state indices of the sulfur and nitrogen atoms that are present, bonded to each other, in amido or ureido moiety. This study suggested the involvement of some electronic interactions between the compounds and some subsites of the enzymes.

Human plasma protein binding (PPB) is an important pharmacokinetic property in drug design. Hologram quantitative structure-activity relationships (HQSAR) were conducted on a series of structurally diverse molecules with known PPB. The best statistical model (q2 = 0.72, r2 = 0.91) was used to predict the PPB of 62 test set compounds, and the predicted values were in good agreement with the experimental results.

As it is generally known, different anions of pharmaceutical preparations are generally developed to achieve better pharmacological effect through their adsorption phase. In this article, reactivation potency of twelve salts (sulfate, chloride, acetate, bromide, phosphate, mesylate, tartarate, iodide, malonate, salicylate, maleinate, tosylate) of bisquaternary acetylcholinesterase reactivator HI-6 was tested to elucidate that chemically different anions have no effect on the reactivation of nerve agent-inhibited acetylcholinesterase. For this purpose, cyclosarin was taken as the appropriate member of the nerve agent family. It was found that the use of different salts has no effect on the reactivation potency.

3-Substituted pyrrole-2,5-diones were synthesised from mucohalogen acids and the antibacterial activity was subsequently determined in biological assays. The minimum inhibitory concentration and the minimum bactericidal concentration of 2a were determined for a wide range of microorganisms in the low micromolar range. Protein identification using SDS-PAGE and LC/MS/MS demonstrated a partly degradation of OprF-related proteins giving an insight into the underlying mechanism of these novel antibacterial agents.

The scope of 6,8-dioxa-3-aza-bicyclo(3.2.1)octane derivatives as morpholine replacing groups in bioactive compounds was investigated. Four derivatives were synthesized and subjected to the routinary screening strategy, as part of a project directed to obtain new tachykinin NK2 antagonists. The obtained results encourage further study on the heterobicycle 6,8-dioxa-3-aza-bicyclo(3.2.1)octane as morpholine surrogate.

Artemisinin induces the growth inhibition of Plasmodium falciparum by sphingomyelinase-generated ceramide. To understand whether artemisinin could have another effect, sphingolipid biosynthesis was studied. Our result shows that a delay in the formation of final products (globoside, cerebrosides) production might be involved in the increase of ceramide.

The approximate representation of the active site of the type 3 isozyme of the enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD3) has been derived from the consideration of the proposed mechanism for the reduction reaction. Using the transition-state (TS), the mode of action of a number of inhibitors has been rationalised.