Molecular hybridization is a well-exploited medicinal chemistry strategy that aims to combine two molecules (or parts of them) in a new, single chemical entity. Recently, it has been recognized as an effective approach to design ligands able to modulate multiple targets of interest. Hybrid compounds can be obtained by linking (presence of a linker) or framework integration (merging or fusing) strategies. Although very promising to combat the multifactorial nature of complex diseases, the development of molecular hybrids faces the critical issues of selecting the right target combination and the achievement of a balanced activity towards them, while maintaining drug-like-properties. In this review, we present recent case histories from our own research group that demonstrate why and how molecular hybridization can be carried out to address the challenges of multitarget drug discovery in two therapeutic areas that are Alzheimer’s and parasitic diseases. Selected examples spanning from linker- to fragment- based hybrids will allow to discuss issues and consequences relevant to drug design.

We have recently shown that the ethanol extract of the leaves of Hedyosmum brasiliense exhibits an antidepressant-like effect in the tail suspension and forced swimming tests in mice. The present study investigates the mechanisms involved in the antidepressant-like effect of H. brasiliense extract, together with the antidepressant potential of podoandin, an isolated sesquiterpenoid. H. brasiliense (50mg/kg, i.p.) and podoandin (10mg/kg, i.p.) decreased the immobility time in the forced swimming test, without any accompanying changes in ambulation in the open-field test. The anti-immobility effect of the H. brasiliense extract was prevented by pre-treating the mice with ondansetron, NAN 190, pindolol, prazosin, yohimbine, haloperidol, SCH23390, and sulpiride. On the other hand, pre-treating the mice with: p-chlorophenylalanine (4 consecutive days), ketanserin, naloxone, naltrindole, bicuculline, phaclofen, or l-arginine did not block the antidepressant-like effect of H. brasiliense. In addition, pre-treatment of the animals with methylene blue, NG-nitro-l-arginine or 7-nitroindazole, at subeffective doses, did not cause a synergistic effect with H. brasiliense extract at an effective dose in the forced swimming test. The anti-immobility effect of podoandin was also prevented by pre-treating the mice with NAN-190, ondansetron, prazosin, yohimbine, sulpiride and haloperidol. The results indicate that the antidepressant-like effect of H. brasiliense (and podoandin) is dependent on the serotonergic, noradrenergic and dopaminergic systems, but not on the GABAergic, opioid and oxidonitrergic systems.

Alzheimer's disease (AD), a progressive neurodegenerative disorder of the aged brain with no known cause or cures, has become a major medical and social problem for industrialized countries. Cerebral deposition of amyloid-β peptide (Aβ) is a critical feature of AD. The use of medicinal plants as an alternative form of prevention, or even as a possible treatment of AD, is therefore interesting areas of research. Sesquiterpene lactones and a sesquiterpene alcohol are compounds found in H. brasiliense that have several anti-oxidative and anti-inflammatory effects. In the present study, we investigated whether these compounds have neuroprotective effects in an amyloid-β peptide-induced Alzheimer's disease mouse model. Mice were injected with Aβ1-42 peptide intracerebroventricularly and were subsequently injected (i.c.v.) with 1µg/site of IGM-A (15-acetoxy-isogermafurenolide), IGM-H (15-hydroxy-isogermafurenolide), PDA (Podoandin), EHP (1,2-epoxy-10α-hydroxy-podoandin), HDS (13-hydroxy-8,9-dehydroshizukanolide), and ARD (aromadendrane-4β,10α-diol). Seven days after treatments the animals had their memory tested in the inhibitory avoidance. After the behavioral testing of animals the brains were removed and subjected to biochemical tests for oxidative stress. The results showed that ARD, HDS and PDA significantly ameliorated the Aβ1-42 peptide-induced memory impairment in the passive avoidance task (P<0.05). In addition, GSH activity was increased while the TBARS levels were decreased by treatment with these compounds. These results suggest that these compounds inhibit the cognitive deficit of animals induced peptide amyloid and may be potential candidates for Alzheimer's disease therapy.

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Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common form of dementia, especially in the elderly. Due to the increase in life expectancy, in recent years there has been an exorbitant growth in the number of people affected by this disease, causing serious problems for health systems. In recent years, research has been intensified to find new therapeutic approaches that prevent the progression of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental brain disorders and early onset neurodegeneration, neuronal loss and dementia in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression and, therefore, is a potential treatment strategy for the prevention of age-associated neurodegeneration, including Alzheimer-type pathology. Objective: in this review, we investigate the contribution of DYRK1A inhibitors as potential anti-AD agents. Methods: A search in the literature to compile an in vitro dataset including IC50 values involving DYRK1A was performed from 2014 to the present day. In addition, we carried out structure-activity relationship studies based on in vitro and in silico data. Results: molecular modeling and enzyme kinetics studies indicate that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Conclusion: further evaluation of DYRK1A inhibitors may contribute to new therapeutic approaches for AD.

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We investigated the potential of sulfonamides derived from carvacrol as candidates for treatment of Alzheimer's disease. The results are very promising for the molecular target investigated as well as for the phenotypic assays.

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