Letters in Drug Design & Discovery - Volume 9, Issue 1, 2012

Letters in Drug Design and Discovery is now commencing its 9th year. It has grown over the years to become a reputable international journal widely known for rapidly publishing exciting new researches in the field. I look forward to receiving continued support from the Associate and Regional Editors as well as the Editorial Board Members whose constant help and guidance has been a major factor in its growth and popularity.

Two synthetic libraries based on a core isoxazoline motif have been designed and prepared specifically to probe the S1 and S4 binding pockets of the Factor Xa enzyme active sites. A highly efficient parallel solution phase synthetic method resulted in the synthesis of 3-arylisoxazoline-5-carboxamides and 3-arylisoxazoline-5-acetamides libraries yielding 192 compounds in total. Highlights of this work include preparation of the isoxazoline cores via a [3+2] cycloaddition between oximes with acrylates or vinyl acetates and the use of activated p-nitrophenyl esters for ease of amide formation and reaction purification.

This study evaluated the antioxidant activity of five resveratrol analogs by relating the activity of the molecule with its chemical structure. The five resveratrol analogs were synthesized and the antioxidant activity was evaluated using the DPPH method. The resveratrol was used as the reference standard. A descriptive statistical analysis and ANOVA followed by the Tukey test, with the aid of software. The antioxidant activity of resveratrol analogs was considered statistically different, with the analog A which showed activity superior to the others. The five analogs presented lower antioxidant activity than the reference standard (p <0.001). According to the findings, hydroxylation was the molecular modification that gave the best evaluated antioxidant activity result. Resveratrol analogs may have an important antioxidative activity, but with the one with the higher IC50 was presented by the natural compound.

Three groups of distamycin analogues containing benzene units, potential minor groove binders, each containing six compounds, have been synthesized using Syncore Reactor. Ethidium bromide assay was used to show that these compounds bind to plasmid pBR322. The most active in fluorescence reduction appeared to be compounds with configuration meta-meta of benzene rings, formed library D.

The inhibition of Histamine N-methyltransferase (HNMT) has been recently shown to play potential roles in the treatment of neurodegenerative diseases, allergic vasoconstriction and anaphylactic manifestation. For designing and discovering new potential human HNMT inhibitors, the ligand (Hypo1) and structure-based (SB_Hypo1) pharmacophore models were developed based on the most active inhibitors and the highest resolution crystal structure of HNMT, respectively. After validating the reliability of both models with decoy dataset, they were separately used as 3D-query for virtual screening to retrieve potential hits from Maybridge and Chembridge databases. Subsequently, the hit compounds were subjected to filter by applying the ADMET, molecular docking and consensus score. Finally, 10 hits (five compounds from each model) were suggested as potential leads based on the structural diversity, good fit value, favorable binding interactions and high docking consensus score. The obtained novel hits from this study may facilitate to identify and optimize new leads for HNMT inhibition.

Fungi are some of the most neglected pathogens in terms of new drug discovery. Paracoccidioidomycosis, an endemic disease to South America, is caused by dimorphic fungi of Paracoccidioides genus. Reasonable citotoxicity, limited efficacy, and frequent use of current commercial antifungals have led to the emergence of resistance. Thus, the development of new antifungals with more selectivity and large spectrum of action is mandatory. In this work, six calix[n]arenes were synthesized and their activity explored against seven isolates of P. brasiliensis and P. lutzii. p-tert- Butylcalix[4]arene (CX1) was the most potent compound against fungal cells and exhibited the lowest toxicity on healthy mammalian cells (V79, hamster lung and MDCK, dog kidney). This is the first report on the effect of calix[n]arenes as growth inhibitors of Paracoccidioides fungi.

A series of aminoalkanol and amino acid derivatives of trans-cinnamic acid as well as aminoalkanol derivatives of α-phenylcinnamic acid was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (ScMet) induced seizures as well as neurotoxicity assessment. Six of them showed protection in MES at 100 mg/kg b.w. and one at 300 mg/kg b.w. For selected derivatives evaluation in ScMet test in rats after per os (p.o.) administration, 6-Hz test in mice and pilocarpine-induced status in rats were performed. The results are quite encouraging and further modification of the structures might lead to discovering new potential anticonvulsants.

In continuation of our program to find compounds with potent anti-human immunodeficiency virus type 1 (HIV-1) activities, seventeen 5,6-dihydro-indolo[1,2-a]quinoxaline derivatives (1-17) were preliminarily evaluated as HIV-1 inhibitors in vitro. Among all the derivatives, especially compounds 10 and 17 showed the most potent anti-HIV-1 activities with EC50 values of 2.42 and 3.39 μg/mL, and TI values of 63.76 and 53.60, respectively.

There is an obvious need to develop efficient countermeasure agents for use in emergency situations or as adjuncts to radiotherapy to protect healthy tissues from the consequences of an irradiation. To this end, we have investigated the capacity of norbadione A, a polyphenol extracted from the edible mushroom Bay boletus to reduce the toxicity of ionizing radiation towards cultured cells and whole-body exposed mice. Results indicate that this compound could slightly enhance the resistance of TK6 lymphoid cells to radiation and increase the survival rate in lethally irradiated mice. However, norbadione A was found to be cytotoxic at concentrations over 30 μM in vitro. The acute toxicity of this compound also precluded its use at higher doses for enhanced in vivo radioprotection. Norbadione A may nevertheless serve as lead for development of less toxic analogs with potentially cytoprotective/radioprotective activities.

Docking of lobeline, a partial agonist of nicotinic acetylcholine receptors (nAChRs), was investigated at once into crystallographic structures of acetylcholine binding proteins (AChBP) and into α7 and α4β2 nAChRs homology models, and compared to behavior of full agonists, nicotine and epibatidine. The homology models were built using as templates the different pocket geometries established in crystallographic AChBP structures. Systematic cross-docking of each ligand into binding pockets of the two other ligands as well as its self-docking into its own pocket were performed in order to better understand the structural features determining the binding of these three ligands chosen for their molecular diversity. In AChBPs, epibatidine and nicotine display similar docking scores in their own pocket and in other ligands pockets: in particular, they also dock favorably into the lobeline pocket. In opposite, lobeline displays different features: it only binds favorably to its own pocket in AChBPs. Furthermore, the docking poses observed starting from lobeline stereoisomers support the importance of the intramolecular hydrogen bond between the alcohol function of the β-phenyl- β-hydroxyethyl arm and the piperidinium proton for the lobeline binding to AChBP. For homology models, crossdockings are still discriminating and the specificity of lobeline for its binding pocket is conserved.

Some novel thiazolylhydrazinomethylideneferrocenes 4 and 5 bearing phenyl and coumarin analogues respectively at position-4 of 1,3-thiazole were synthesized using established procedures and were evaluated for their in vitro antibacterial activity against four pathogenic bacterial strains namely, S. aureus, B. subtilis (Gram-positive), E. coli, P. aeruginosa (Gram-negative), and in vitro antifungal activity against two pathogenic fungal strains namely, A. niger and A. flavus. Four tested compounds, 4a, 4d, 4e and 4f exhibited moderate antibacterial activity against Gram-positive bacteria and 4e exhibited moderate antifungal activity against the tested fungi. However, none of the compounds showed any activity against Gram-negative bacteria.

We report the use of sulfonate derivatives of estrone (E1) in the search for inhibitors of 17β-hydroxysteroid dehydrogenase, in particular, type 3 (17β-HSD3). Results suggest that the compounds are excellent inhibitors of 17β- HSD3 and a number were found to be extremely potent in comparison to the standard inhibitors used.

I describe a case of tachyphylaxis to pramipexole and its management in a patient with bipolar I disorder.

In order to improve the metabolic stability and bioavailability of scutellarin, some derivatives of its main metabolite (scutellarein) were designed and synthesized. The antioxidant activities of these target products were assessed by measuring its scavenging capacities toward DPPH and the protective effects on H2O2-induced cytotoxicity in PC12 cells. The results showed that the target compound 7g had a higher antioxidant activity than scutellarin. Thus 7g may be considered as a novel potent anti-Alzheimer's Disease drug candidate.

Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Constitutive oncogenic activation in cancer cells can be blocked by selective small molecule tyrosine kinase inhibitors and thus considered as a promising approach for innovative therapeutics. The remarkable success of BCR-ABL tyrosine kinase inhibitor imatinib (STI571) in the treatment of chronic myeloid leukaemia has particularly stimulated intense research in this field. At least 30 inhibitors are in various stages of clinical development in cancer, and about 120 clinical trials are ongoing worldwide. In this review, we focus on the role of tyrosine kinases in cancer and the development of specific small molecule inhibitors for therapy. We also provide a critical analysis of the current data on tyrosine kinase inhibitors and highlight areas for future research. Issues with regards to the design of clinical trials with such agents are also discussed. Herein, we also discussed the different synthetic pathway for the synthesis of small molecule inhibitors along with their pharmacokinetic, different mechanisms of resistance and side effects.