Antiplasmodial activity of sulfonylhydrazones: in vitro and in silico approaches.

Malaria is still a life-threatening public health issue, and the upsurge of resistant strains requires continuous generation of active molecules. In this work, 35 sulfonylhydrazone derivatives were synthesized and evaluated against Plasmodium falciparum chloroquine-sensitive (3D7) and resistant (W2) strains. The most promising compound, 5b, had an IC50 of 0.22 µM against W2 and was less cytotoxic and 26-fold more selective than chloroquine. The structure-activity relationship model, statistical analysis and molecular modeling studies suggested that antiplasmodial activity was related to hydrogen bond acceptor count, molecular weight and partition coefficient of octanol/water and displacement of frontier orbitals to the heteroaromatic ring beside the imine bond. This study demonstrates that the synthesized molecules with a simple scaffold allow the hit-to-lead process for new antimalarials to commence.

Fragment-based drug discovery as alternative strategy to the drug development for neglected diseases.

Neglected diseases (NDs) affect large populations and almost whole continents, representing 12% of the global health burden. In contrast, the treatment available today is limited and sometimes ineffective. Under this scenery, the Fragment-Based Drug Discovery emerged as one of the most promising alternatives to the traditional methods of drug development. This method allows achieving new lead compounds with smaller size of fragment libraries. Even with the wide Fragment-Based Drug Discovery success resulting in new effective therapeutic agents against different diseases, until this moment few studies have been applied this approach for NDs area. In this article, we discuss the basic Fragment-Based Drug Discovery process, brief successful ideas of general applications and show a landscape of its use in NDs, encouraging the implementation of this strategy as an interesting way to optimize the development of new drugs to NDs.

An integrated approach towards the discovery of novel non-nucleoside Leishmania major pteridine reductase 1 inhibitors.

Despite the fact that Leishmania ssp are pteridine auxotrophs, Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) inhibitors are ineffective against Leishmania major. On the other hand Pteridine Reductase 1 (PTR1) inhibitors proved to be lethal to the parasite. Aiming at identifying hits that lie outside the chemical space of known PTR1 inhibitors, pharmacophore models that differentiate true-binders from decoys and explain the structure-activity relationships of known inhibitors were employed to virtually screen the lead-like subset of ZINC database. This approach leads to the identification of Z80393 (IC50 = 32.31 ± 1.18 µM), whose inhibition mechanism was investigated by Thermal Shift Assays. This experimental result supports a competitive mechanism and was crucial to establish the docking search space as well as select the best pose, which was then investigated by molecular dynamics studies that corroborate the hit putative binding profile towards LmPTR1. The information gathered from such studies shall be useful to design more potent non-nucleoside LmPTR1 inhibitors.