Roberta Tesch

Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors

Novel 2-chloro-4-anilino-quinazolines designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for inhibitory effects. EGFR and VEGFR-2 are validated targets in cancer therapy and combined inhibition might be synergistic for both antitumor activity and resistance prevention. The biological data obtained proved the potential of 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, highlighting compound 8o, which was approximately 7-fold more potent on VEGFR-2 and approximately 11-fold more potent on EGFR compared to the prototype 7. SAR and docking studies allowed the identification of pharmacophoric groups for both kinases and demonstrated the importance of a hydrogen bond donor at the para position of the aniline moiety for interaction with conserved Glu and Asp amino acids in EGFR and VEGFR-2 binding sites.

Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats.

Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N‐acylhydrazone derivative, 3,4‐dimethoxyphenyl‐N‐methyl‐benzoylhydrazide (LASSBio‐1359), on monocrotaline (MCT)‐induced pulmonary hypertension in rats.

Acylhydrazone derivatives: a patent review

Introduction: The N-acylhydrazone (NAH) moiety has been characterized as a privileged structure, capable of providing ligands points for more than one type of bioreceptor. Modifications of the subunits bonded to its acyl and imine functions resulted in several derivatives, which modulate a great diversity of molecular targets. In this context, this patent review reflects the use of the NAH moiety in different compounds. Areas covered: In this review, the authors perform an analysis of the therapeutic profile of NAH compounds together with their perspective of its usability. The Espacenet and Delphion databases were used as main sources of search, and ‘N-acylhydrazone,’, ‘Acylhydrazone’ and ‘hydrazone’ were used as keywords. From a total of 117 patents retrieved, 22 presented pharmacological activities described in the document, thus being chosen for this review. Expert opinion: In the last century, only six patents disclosing NAH derivatives for therapeutic purposes were published, and only in 2010, this subunit started receiving some real attention regarding its therapeutic potential. In this review, the Brazilian and Chinese Universities were identified as the major patent applicants, especially for drug candidates for the treatment of chronic pain, inflammatory disorders and cancer. The NAH subunit is very versatile both from synthetic and medicinal chemistry point of view. This feature is a direct result from the conformational diversity that this framework presents, achievable by subtle and simple chemical changes. Therefore, our opinion is that this moiety suits a lot more drug discovery projects than it seems to at first glance. In conclusion, we strongly support and encourage a raise in the use of this unique subunit.

Phenylpiperazine derivatives: a patent review (2006 – present)

Introduction: The N-phenylpiperazine subunit represents one of the most versatile scaffolds used in the medicinal chemistry field. Recently, some N-phenylpiperazine derivatives have reached late stage clinical trials for the treatment of CNS disorders, thus, this is clearly a molecular template that already has proven its “druglikeness,” However, this scaffold is still strictly seen as a “CNS structure” by great part of the scientific community. The aim of this review is to draw a contemporary profile of the patents regarding N-phenylpiperazine derivatives and, them, suggest new research fields to be explored. Areas covered: The site of the World Intellectual Property Organization (WIPO) was used as the main source in order to perform the research of the patents containing N-phenylpiperazine compounds with therapeutic uses. This review highlights some examples to show that this heterocyclic moiety can successfully yield new classes of hits and prototypes for many other therapeutic fields through appropriate substitution of the molecular skeleton. Expert opinion: The patent research concerning N-phenylpiperazine derivatives indicated for therapeutic uses from 2006 to present date resulted in thirty three documents. It is a low number if one considers the several compounds bearing the N-phenylpiperazine nucleus that reached the market and/or clinical trials. Therefore, this subunit seems to be much underrated at the moment. The adequate use of the N-phenylpiperazine moiety, through modulation of its basicity and substitution pattern of the aromatic ring, can yield pharmacokinetic and pharmacodynamic improvements that are certainly useful in several therapeutic areas, thus, being able to diversify the application and utility of this scaffold. We expect and strongly suggest the growth of this diversification.

Identification and further development of potent TBK1 inhibitors.

The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related signaling and its relevance in tumor progression. Herein, we undertake the activity-based screening for unique inhibitors of TBK1 and their subsequent optimization. Initial screening approaches identified a selection of TBK1 inhibitors that were optimized using methods of medicinal chemistry. Variations of the structural characteristics of a representative 2,4,6-substituted pyrimidine scaffold resulted in improved potency. Prospective use as tool compounds or basic contributions to drug design approaches are anticipated for our improved small molecules.

Prevention and Reversal of Morphine-Induced Tolerance by Novel Muscarinic Receptor Agonist in Rats with Neuropathic Pain

Objective: To investigated the effectiveness of a novel M2 muscarinic receptor agonist, the pyrazolo[3,4b]pyrrolo[3,4-d]pyridine derivative LASSBio-981, on the prevention and reversal of morphine-induced antinociceptive tolerance in a rat model of neuropathic pain. Methods: Thermal hyperalgesia and mechanical allodynia were induced in rats by spinal nerve ligation in L5. After rats displayed signs of sustained pain, continuous infusions of morphine were delivered in the peritoneum through osmotic mini-pumps. LASSBio-981 was daily administered by oral gavage starting at the same day of morphine infusion (prevention protocol) or after development of morphine-induced tolerance (reversion protocol). To access the mechanism of LASSBio-981 action on the M2 muscarinic receptor, a single dose of the specific antagonist, methoctramine, was injected through intrathecal route. In addition, the crystallographic structure of human M2 muscarinic receptor and the computer program GOLD 5.2 (genetic algorithm software: CCDC) simulated the docking of LASSBio-981 into the orthosteric binding site of the receptor. Results: Morphine inhibited the thermal and mechanical hyperalgesia induced by spinal nerve ligation and this effect decreased time-dependently and totally disappeared (tolerance) 16 days of infusion. LASSBio-981 prevented and reversed morphine-induced antinociceptive tolerance. Treatment with methoctramine inhibited LASSBio-981 effect in reversing the morphine-induced tolerance suggesting the involvement of M2 muscarinic receptor activation. This hypothesis was strengthened because the molecular docking analyses determined that LASSBio-981 interacts with the orthosteric binding site of the M2 muscarinic receptor. Conclusion: This study provides evidence that a novel M2 muscarinic receptor agonist (LASSBio-981) may prevent and reverse morphine-induced tolerance in rat model of neuropathic pain.

Novel Potent Imidazo[1,2-a]pyridine-N-Glycinyl-Hydrazone Inhibitors of TNF-α Production: In Vitro and In Vivo Studies

In this work, we describe the design, synthesis and pharmacological evaluation of novel imidazo[1,2-a]pyridine-N-glycinyl-hydrazone derivatives (1a–k) intended for use as inhibitors of tumor necrosis factor alpha (TNF-α) production. The compounds were designed based on the orally active anti-inflammatory prototype LASSBio-1504 (2), which decreases the levels of the pro-inflammatory cytokine TNF-α in vitro and in vivo. The in vitro pharmacological evaluation of the imidazo[1,2-a]pyridine compounds (1) showed that substitution of the N-phenylpyrazole core present in prototype 2 by a bioisosteric imidazo[1,2-a]pyridine scaffold generated anti-TNF-α compounds that were more potent than the previously described N-phenylpyrazole derivative 2 and as potent as SB-203580, a p38 MAPK inhibitor. The most active derivative (E)-2-(2-tert-butylimidazo[1,2-a]pyridin-3-ylamino)-N’-(4-chlorobenzylidene) acetohydrazide, or LASSBio-1749 (1i) was orally active as an anti-inflammatory agent in a subcutaneous air pouch model, reducing expressively the levels in vivo of TNF-α and other pro-inflammatory cytokines at all of the tested doses.

An Unusual Intramolecular Halogen Bond Guides Conformational Selection.

PIK-75 is a phosphoinositide-3-kinase (PI3K) α-isoform-selective inhibitor with high potency. Although published structure-activity relationship data show the importance of the NO2 and the Br substituents in PIK-75, none of the published studies could correctly determine the underlying reason for their importance. In this publication, we report the first X-ray crystal structure of PIK-75 in complex with the kinase GSK-3β. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3β that is likely stabilized by an atypical intramolecular Br⋅⋅⋅NO2 halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding-competent preorganization of the PIK-75 molecule, thus explaining its high potency. We therefore suggest that the site-specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies.

LASSBio-897 Reduces Lung Injury Induced by Silica Particles in Mice: Potential Interaction with the A2A Receptor

Silicosis is a lethal fibro-granulomatous pulmonary disease highly prevalent in developing countries, for which no proper therapy is available. Among a small series of N-acylhydrazones, the safrole-derived compound LASSBio-897 (3-thienylidene-3, 4-methylenedioxybenzoylhydrazide) raised interest due to its ability to bind to the adenosine A2A receptor. Here, we evaluated the anti-inflammatory and anti-fibrotic potential of LASSBio-897, exploring translation to a mouse model of silicosis and the A2A receptor as a site of action. Pulmonary mechanics, inflammatory, and fibrotic changes were assessed 28 days after intranasal instillation of silica particles in Swiss–Webster mice. Glosensor cAMP HEK293G cells, CHO cells stably expressing human adenosine receptors and ligand binding assay were used to evaluate the pharmacological properties of LASSBio-897 in vitro. Molecular docking studies of LASSBio-897 were performed using the genetic algorithm software GOLD 5.2. We found that the interventional treatment with the A2A receptor agonist CGS 21680 reversed silica particle-induced airway hyper-reactivity as revealed by increased responses of airway resistance and lung elastance following aerosolized methacholine. LASSBio-897 (2 and 5 mg/kg, oral) similarly reversed pivotal lung pathological features of silicosis in this model, reducing levels of airway resistance and lung elastance, granuloma formation and collagen deposition. In competition assays, LASSBio-897 decreased the binding of the selective A2A receptor agonist [3H]-CGS21680 (IC50 = 9.3 μM). LASSBio-897 (50 μM) induced modest cAMP production in HEK293G cells, but it clearly synergized the cAMP production by adenosine in a mechanism sensitive to the A2A antagonist SCH 58261. This synergism was also seen in CHO cells expressing the A2A, but not those expressing A2B, A1 or A3 receptors. Based on the evidence that LASSBio-897 binds to A2A receptor, molecular docking studies were performed using the A2A receptor crystal structure and revealed possible binding modes of LASSBio-897 at the orthosteric and allosteric sites. These findings highlight LASSBio-897 as a lead compound in drug development for silicosis, emphasizing the role of the A2A receptor as its putative site of action.

Revisiting the Message-Address Concept in Medicinal Chemistry

O conceito mensagem-endereço foi postulado na década de 70 e desde então vem sendo aplicado no entendimento da seletividade de compostos em subtipos de receptores, sendo o principal exemplo os receptores opioides. A interpretação deste conceito também pode ser aplicada em outros sistemas. O presente trabalho tem como objetivo revisitar este conceito e demonstrar sua aplicação no sistema adenosinérgico.