Letters in Drug Design & Discovery - Volume 5, Issue 1, 2008

The effect of combining RDC-11 (a new ruthenium organometallic complex) and fast neutrons (high-LET radiations) has been evaluated in RDM4 and U-87 tumor cell lines. After co-treatment, a substantial reduction of cell growth was recorded, which appears not to be correlated with the induction of apoptosis.

1,4-dihydropyridines are the emerging class of antitubercular agents. In this protocol we present, the syntheses, characterization details for the conformation of structures, antitubercular and anticancer activity results for some novel 1,4-dihydropyridines. The comparative molecular field analysis (CoMFA) model for 1,4-dihydropyridines was derived. The 3D QSAR model demonstrated good ability to predict activity of studied compounds (r2 = 0.97, q2 = 0.81). Based on the CoMFA steric and electrostatic contour maps, structure activity relationships were established for antitubercular activity.

Fifteen new hydrazones were synthesized as derivatives of 1H-1-pyrrolylcarbohydrazides. Six products exhibited 73-98% inhibition against Mycobacterium tuberculosis H37Rv at 6.25 μg/mL using Microplate Alamar Blue Assay, the most active evaluated at HTS Level 2 with IC50=0.966 and IC90=3.236. The activities correlate with molecular volumes in simplified second order QSAR model.

Multi-drug resistant tuberculosis is a worldwide problem where despite treatment; mortality can range up to 18%. An N-aryl 2-aminothiazole-4-carboxamide derivative was identified as a lead compound in a Tuberculosis Coordinating Antimicrobial Acquisition Facility (TCAAF) screen. Synthesis and biological evaluation of additional analogs led to structure-activity relationships for activity against TB.

Many studies on macrolide immunomodulatory properties in the treatment of chronic pulmonary disorders reveal dependable positive outcomes, and these effects, accompanied by their inhibitory action on biofilms, have the prospective to make them a useful alternative. The stimulation of gastrointestinal motility, a frequent macrolide side-effect, may be beneficial in patients with deprived gut motility. There are also initial data suggesting that the currently available macrolide antibiotics possess anti-tumour activity. The purpose of this review is to abridge existing evidence on the effects of macrolides beyond their antimicrobial activity. We believe this issue is of great interest to many physicians, mainly those engaged with the care of patients suffering from chronic inflammatory pulmonary diseases. Therefore, we have carried out a systematic search in the medical literature focusing on the mechanisms by which this class of antibiotics exerts these valuable immunomodulating effects and their influence on the management of certain human medical conditions.

Niric Oxide (NO) is a free radical which plays an important role in cellular signalling in mammals. NO is involved in the regulation of vascular tone, modulation of platelet adhesion, whereas in the central nervous system NO isgenerated following the activation of the ionotropic and the metabotropic receptors of the excitatory aminoacid. Larginine has been shown to be obligatory for the formation of the NO. Substances capable of antagonising the effect of NO could be suitable in the therapy of some forms in which there is an excessive vasodilator response or over-activation of the central excitatory circuits. A series of new arginine derivatives named MCS1, MCS2, MCS3, MCS4, MCS5, MCS6, MCS7 have been synthetized and their action on the NO synthase (NOS) has been tested. The NOS activity has been tested in homogenates of both human umbilical endothelial cells (HUVEC) and rat brain, by evaluating the conversion of 14C-L-arginine in 14C-L-citrulline in the presence and absence of scalar concentration of MCS compounds (10 μM- 100 μM). In both HUVEC and rat brain, the 14C-L-citrulline formation was completely inhibited by MCS3, MCS4, MCS5, MCS6 and MCS7 at the 100 μM concentration; MCS1 and MCS2 inhibited the NOS activity in the rat brain, but failed to inhibit NOS activity in HUVEC, MCS3, MCS4, MCS5, MCS6 were equiactive on the neuronal NOS and endotelial NOS whereas MCS7 was more active in inhibiting both. The results of the present study suggest that some arginine derivative compounds are able to block the NOS. Some of these compounds are able to inhibit the NOS production at both endothelial and neuronal level, whereas others are active only on one substrate. In particular, MCS1, MCS2 and MCS7 are relatively selective for neuronal NOS whereas MCS7 is also active on endothelial NOS.

In this paper we reported the design, synthesis of a series 2-azetidinones with ester or amide group in C-3 sidechain. Their cholesterol absorption inhibition activity was assessed in orally dosed, cholesterol-fed hamsters. It was demonstrated that compound 20c∼d with amid group in C-3 sidechain exhibited high cholesterol absorption inhibition activity.

A set of 4-[N'-(2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzamides focused on specific interactions at the ATP binding cleft of CDK2 was synthesized. The synthetic strategy towards potential inhibitors included the preparation of p-nitrophenyl activated esters and use of polymer scavengers to facilitate amide bond formation and purification. Using this methodology, a focused library of 244 compounds was prepared.

We report the results of the biochemical evaluation of a series of imidazole-based compounds against the hydroxysteroid dehydrogenase (HSD) family of enzymes, in particular, types 1 and 3 of 17β-HSD and 3β-HSD. The results show that the synthesised compounds were good inhibitors of this family of enzymes.

A variety of oxazolones (3-18) with structural variation at C-2 and C-4 were synthesized and evaluated as chymotrypsin inhibitors. The synthesized compounds showed varying degree of chymotrypsin inhibitory activity ranging IC50 values from 12.62 ± 1.32 - 126.57 ± 1.06 μM, if compared to standard chymostatin (IC50 = 7.01 ± 0.1 μM). Compounds 3,9,10,13,14, and 15 have IC50 values 17.03 ± 0.78, 69.05 ± 1.48, 12.62 ± 1.32, 17.29 ± 0.93, 126.57 ± 1.06, and 31.55 ± 1.31 μM, respectively. This study reveals that the substitution of functional group (s) at C-2 and C-4 positions plays a vital role in the activity of this series of compounds. The size and electron donating or withdrawing effects of substituents influenced the activity.

Cyclic imides have been widely employed in drug design research due to their multiple pharmacological and biological properties. In the present study, two-dimensional quantitative structure-activity relationship (2D QSAR) studies were conducted on a series of potent analgesic cyclic imides using both classical and hologram QSAR (HQSAR) methods, yielding significant statistical models (classical QSAR, q2 = 0.80; HQSAR, q2 = 0.84). The models were then used to evaluate an external data test, and the predicted values were in good agreement with the experimental results, indicating their consistency for untested compounds.

Carnosine (β-alanyl-L-histidine) is rich in the skeletal muscle and brain, but the function of dipeptides like carnosine in the brain has not been clarified. We previously showed that β-alanyl dipeptides with carboxyl terminal branched chain amino acids induced hyperactivity in chicks when intracerebroventricularly (i.c.v.) administrated. In the present study we investigated the effect of amino terminal histidine related dipeptides under isolation induced stress. I.c.v. injection of L-seryl-L-histidine and L-isoleucyl-L-histidine induced sedation with a weak hypnotic effect, and L-valyl-Lhistidine lowered spontaneous activity in chicks. However, L-alanyl-L-histidine, glycyl-L-histidine and L-methionyl-Lhistidine had no significant effects in all parameteres determined. These results indicate that L-seryl-L-histidine and Lisoleucyl- L-histidine dipeptides may be effective in improving anxiety and have novel functional effects in the brain.

Several flavylium salts showed potent (albeit nonselective) activity against L. donovani axenic amastigotes and T. b. brucei bloodstream forms in vitro (IC50 values ranging from 0.75 to 35 μM). The trans-chalcone, which forms from the corresponding flavylium salt at neutral pH in aqueous solution, is proposed to be the active species.

A large number of human diseases are caused by fungus and the plant kingdom has proven to be a source of antifungal compounds. This work describes the in vitro activity of the natural product (R)-goniothalamin and its synthetic enantiomer, (S)-goniothalamin, against eleven strains of human pathogenic fungi. The minimum inhibitory concentration (MIC) values for both enantiomers were lower than 100 μg/mL for nine of the fungus strains studied. MIC values for both enantiomers against isolates of the dimorphic fungus Paracoccidioides braziliensis were in the range of 7-22 μg/mL. (R)- and (S)- goniothalamin were selective for the fungi strains presenting minimal toxic effects on mammalian kidney (Vero) and lung (V79) cell lines.