Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids

With its strong effect on vector-borne diseases, and insecticidal effect on mosquito vectors of malaria, inhibition of sporogonic and blood-stage development of Plasmodium falciparum, as well as in vitro and in vivo impairment of the P. berghei development inside hepatocytes, ivermectin (IVM) continues to represent an antimalarial therapeutic worthy of investigation. The in vitro activity of the first-generation IVM hybrids synthesized by appending the IVM macrolide with heterocyclic and organometallic antimalarial pharmacophores, against the blood-stage and liver-stage infections by Plasmodium parasites prompted us to design second-generation molecular hybrids of IVM. Here, a structural modification of IVM to produce novel molecular hybrids by using sub-structures of 4- and 8-aminoquinolines, the time-tested antiplasmodial agents used for treating the blood and hepatic stage of Plasmodium infections, respectively, is presented. Successful isolation of regioisomers and epimers has been demonstrated, and the evaluation of their in vitro antiplasmodial activity against both the blood stages of P. falciparum and the hepatic stages of P. berghei have been undertaken. These compounds displayed structure-dependent antiplasmodial activity, in the nM range, which was more potent than that of IVM, its aglycon or primaquine, highlighting the superiority of this hybridization strategy in designing new antiplasmodial agents.

Multi-Target Directed Ligands (MTDLs): Promising Coumarin Hybrids for Alzheimer's Disease

: Alzheimer's disease (AD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cog- nitive domains, including executive function. The progression of AD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AD include a decreased concentration of acetylcholine (ACh), deposi- tion of amyloid-β (Aβ)peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the simultaneous progression of diverse pathogenetic pathways, no ideal therapeutic agent has been developed to date. The drugs which are available against AD provide only symptomatic benefits and do not have disease-modifying activity. Therefore, in search of ideal therapeutic candidates, the concept of molecular hybrids has been under keen investigation for the past few years. Hybrid mole- cules are able to inhibit or activate or modify the physiology of more than one target simultaneously. Coumarin scaffolds have shown the excellent potential of ACh esterase inhibition, MAO-B inhibition, and anti-Aβ aggregation. In the present review, we have focused on different reported coumarin hy- brids as multi-target-directed agents against AD. These include hybrids of coumarin with carbazole, benzofuran, dithiocarbamate, quinoline, pargyline, tacrine, N-benzyl pyridinium, donepezil, purine, piperidine, morpholine, aminophenol, benzylamino, halophenylalkylamidic, thiazole, thiourea, hy- droxypyridinone, triazole, piperazine, chalcone, etc. Along with the therapeutic potentials of these hy- brids, important clinical investigations and the structure-activity relationship has also been discussed in this compilation.

Recent Neglected Drug Design Studies

Background: Neglected diseases require special attention when looking for new therapeutic alternatives, as these are diseases of extreme complexity and severity that affect populations belonging to lower social classes who are lacking access to basic rights such as basic sanitation. Introduction: Among the alternatives available for obtaining new drugs is Medicinal Chemistry, which is responsible for the discovery, identification, invention and preparation of prototypes. In this perspective, the present work aims to make a bibliographic review on the recent studies of Medicinal Chemistry applied to neglected diseases. Method: A literature review was carried out by searching the “Web of Sciences” database, including recent articles published in the Neglected Drug Design. Results: In general, it was noticed that the most studied neglected diseases corresponded to Chagas disease and leishmaniasis, with studies on organic synthesis, optimization of structures and molecular hybrids being the most used strategies. It is also worth mentioning the growing number of computationally developed studies, providing speed and optimization of costs in the procurement process. Conclusion: The CADD approach and organic synthesis studies, when applied in the area of Medicinal Chemistry proved to be important in the research and discovery of drugs for Neglected Diseases, since the planning of the experimental methodology used to obtain it, as well as in the selection of compounds with greater activity potential.

Synthetic Integrin-Targeting Dextran-Fc Hybrids Efficiently Inhibit Tumor Proliferation In Vitro

Herein, we present the design, synthesis, and biological evaluation of novel integrin-targeting molecular hybrids combining RGD peptides and a potent cytotoxin presented on dextran polysaccharides. Based on an aglycosylated Fc as a centerpiece, endosomal-cleavable cytotoxic agent monomethyl auristatin E (MMAE) and dextran as multimerization site were covalently connected by two bioorthogonal enzyme-mediated reactions site-specifically. Decoration of dextran with cyclic RGD peptides, introduced by copper “click” reaction, resulted in the final constructs with the potential to kill integrin-overexpressing tumor cells. We found that these modifications had little impact on the stability of the Fc scaffold and the RGD-bearing construct showed good binding properties of αvβ3-expressing U87MG cells. Furthermore, the construct showed a remarkable antiproliferative activity. These results demonstrate the general capability of our design to provoke receptor-mediated endocytosis upon binding to the cellular surface, followed by endosomal cleavage of the linkage between Fc-dextran and MMAE and its subsequent release. Our approach opens new avenues to transcribe small molecule binders into tailor-made multimeric molecular hybrids with antitumor potential.

Synthesis and Evaluation of Chalcone-Quinoline Based Molecular Hybrids as Potential Anti-Malarial Agents

Molecular hybridization is a drug discovery strategy that involves the rational design of new chemical entities by the fusion (usually via a covalent linker) of two or more drugs, both active compounds and/or pharmacophoric units recognized and derived from known bioactive molecules. The expected outcome of this chemical modification is to produce a new hybrid compound with improved affinity and efficacy compared to the parent drugs. Additionally, this strategy can result in compounds presenting modified selectivity profiles, different and/or dual modes of action, reduced undesired side effects and ultimately lead to new therapies. In this study, molecular hybridization was used to generate new molecular hybrids which were tested against the chloroquine sensitive (NF54) strain of P. falciparum. To prepare the new molecular hybrids, the quinoline nucleus, one of the privileged scaffolds, was coupled with various chalcone derivatives via an appropriate linker to produce a total of twenty-two molecular hybrids in 11%–96% yield. The synthesized compounds displayed good antiplasmodial activity with IC50 values ranging at 0.10–4.45 μM.

Computer-aided design, synthesis, and characterization of molecular hybrids of dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones as potential inhibitors of the penicillin-binding protein 3 (PBP-3) of Escherichia coli

A computer-assisted approach was used to model and study privileged heterocyclic scaffolds containing dihydropyrazole, pyrimidin-2-amine, and thiazolidin-4-one moieties (hybrid pharmacophores) to obtain novel and promising antimicrobial prototype molecules. Main bioavailability descriptors were determined in order to assess the drug-likeness of the designed compounds and to pre-filter eleven compounds exhibiting the best profiles, thus passing to molecular docking study against a key penicillin-binding protein type-3 from enterotoxygenic E. coli. Seven structures were chosen by theirenergies of affinity and docking interactions with key residues in the active site of the receptor. Seven compounds with the highest docking scores belonging to the series of chalcones, dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones were prepared via condensation or cyclocondensation reactions. The structural elucidation of the final products was carried out by infrared spectra analysis and NMR experiments. Such molecular hybrids considered as potential hits in the search for new antibacterial compounds will be tested in vitro in further studies.