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This review describes the usefulness of in silico design approaches in the design of new radiopharmaceuticals, especially peptide-based radiotracers (including peptidomimetics). Although not part of the standard arsenal utilized during radiopharmaceutical design, the use of in silico strategies is steadily increasing in the field of radiochemistry as it contributes to a more rational and scientific approach. The development of new peptide-based radiopharmaceuticals as well as a short introduction to suitable computational approaches are provided in this review. The first section comprises a concise overview of the three most useful computeraided drug design strategies used, namely i) a Ligand-based Approach (LBDD) using pharmacophore modelling, ii) a Structure-based Design Approach (SBDD) using molecular docking strategies and iii) Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) predictions. The second section summarizes the challenges connected to these computer-aided techniques and discusses successful applications of in silico radiopharmaceutical design in peptide-based radiopharmaceutical development, thereby improving the clinical procedure in Nuclear Medicine. Finally, the advances and future potential of in silico modelling as a design strategy is highlighted.

A series of artemisininetriazine hybrids and hybrid-dimers were synthesized and their in vitro antimalarial activity against the chloroquine sensitive (CQS), the gametocytocidal (NF54) and the choroquine resistant (CQR) Dd2 strains of Plasmodium falciparum determined, while their toxicity against CHO cells were also established. These compounds were prepared by linking artemisinin and triazine pharmacophores through nucleophilic substitution, using conventional and microwave assisted methods. These hybrids and hybrid-dimers were all found to be active against all three Plasmodium strains, with the panisidino- substituted triazine hybrid-dimer 22 being the most active of all. It showed good antigametocytocidal activity against the NF54 strain, with a 50% inhibitory concentration value in the nanomolar range, while having a potency comparable to that of artesunate against the Dd2 strain. This hybrid-dimer further demonstrated selective toxicity towards the parasitic cells. This dimer hence showed the necessary potential as candidate for further investigation in the search for malaria transmission blocking drugs so desperately needed http://dx.doi.org/10.1016/j.ejmech.2014.01.040 http://www.journals.elsevier.com/european-journal-of-medicinal-chemistry/ Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ejmech.2014.01.040 National Research Foundation (NRF) of South Africa; North-West University, Potchefstroom Campus; German Academic Exchange Service

A series of n-alkyl/aryl esters were synthesized and their in vitro antiplasmodial activity was measured alongside that of previously synthesized aminoethylethers of artemisinin ozonides against various strains of Plasmodium falciparum. The cytotoxicity against human cell lines was also assessed. The esters were synthesized in a one-step reaction by derivatization on carbon C-10 of dihydroartemisinin. Both classes were active against both the 3D7 and K1 strains of P. falciparum, with all compounds being significantly more potent than artemether against both strains. The majority of compounds possessed potency either comparable or more than artesunate with a high degree of selectivity towards the parasitic cells. The 10a-n-propyl 11 and 10a-benzyl 18 esters were the most potent of all synthesized ozonides, possessing a moderate ( 3-fold) and significant (22- and 12-fold, respectively) potency increases against the 3D7 and K1 strains, respectively, in comparison with artesunate. http://www.journals.elsevier.com/bioorganic-chemistry/

Series of bisquinolines 4e15 and bispyrrolo[1,2a]quinoxalines 16e20 containing various polyamine linkers were synthesized. The aqueous solubility and distribution coefficient were experimentally determined. The compounds were screened for antimalarial activity alongside chloroquine against D10 and Dd2 strains of Plasmodium falciparum. The growth inhibitory effects of biscompounds 4e9 were assessed against various cancer cell lines. The aqueous solubility was found to increase with an increase in potential proton.ation sites. Bisquinolines 8 and 9 featuring triethylenetetramine and N,N0-bis(3- aminopropyl)ethylene-diamine linkers, respectively, were the most active of all synthesized compounds. They were found as potent as chloroquine against D10 but significantly more potent against the Dd2 strain, with good selectivity towards parasitic cells. Compound 4 containing a diethylenetriamine bridge displayed the most important anticancer activity of the series, and was a more effective antiproliferative inhibitor than etoposide against all three TK10, UACC62 and MCF7 cancer cell lines National Research Foundation (NRF) and the North-West University (NWU)

In this study, a series of 11 10-aminoethylether derivatives of artemisinin were synthesised and their antimalarial activity against both the chloroquine sensitive (D10) and resistant (Dd2) strains of Plasmodium falciparum was determined. The compounds were prepared by introducing aliphatic, alicyclic and aromatic amine groups with linkers of various chain lengths through an ethyl ether bridge at C-10 of artemisinin using conventional and microwave assisted syntheses, and their structures were confirmed by NMR and HRMS. All derivatives proved to be active against both strains of the parasite. The highest overall activity was displayed by the short chain aromatic derivative 8 (IC50 = 1.44 nM), containing only one nitrogen atom, while long chain polyamine derivatives were found to have the lowest activity against both strains. An interesting correlation between the IC50, pKa values and resistance index (RI) was found National Research Foundation (NRF), the North- West University (NWU)

The aim of this study was to synthesize a series of mono-, di- and trisubstituted derivatives of the human African trypanosomiasis drug eflornithine (alpha-difluoromethylornithine, DMFO, CAS 70052-12-9) to determine their partition coefficients, and to assess whether they deliver the parent drug in the plasma. If increased plasma concentrations of eflornithine could be achieved in this way, an oral dosage form would be possible. The derivatives, nine in total, were successfully synthesized by multi-step derivatisation of eflornithine on either its alpha-carboxylic or/and alpha-amino or/and delta-amino groups by either esterification or/and amidation or/and carbamylation, and their structures confirmed by NMR and MS spectroscopy. The majority of derivatives were more lipophilic than eflornithine with log D values in phosphate buffer solution (pH 7.4) ranging from -1.34 to 1.59 (vs. -0.98 for eflornithine). The in vivo absorption after oral administration to Sprague-Dawley rats showed that no derivative delivered eflornithine in the plasma, indicating that the derivatives were either not absorbed from the gastrointestinal tract or not metabolized to the parent drug. Two of the monosubstituted activities were toxic for T. brucei blood stream forms.