Susan Little

The design, synthesis, in silico ADME profiling, antiplasmodial and antimycobacterial evaluation of new arylamino quinoline derivatives.

A series of new arylamino quinoline derivatives was designed based on the quinine and mefloquine scaffolds and evaluated in vitro for antiplasmodial and antimycobacterial activities. A number of these compounds exhibited significant activity against the drug-sensitive 3D7 and drug-resistant K1 strains of Plasmodium falciparum. Furthermore, two compounds, 4.12b and 4.12d, also showed 94 and 98% growth inhibitory activity against non-replicating and replicating Mycobacterium tuberculosis strains, respectively.

Synthesis and Evaluation of 1-Amino-6-halo-β-carbolines as Antimalarial and Antiprion Agents

Malaria is one of the world’s most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6‐halo‐β‐carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl‐based antimalarial agents, the 1‐amino‐β‐carboline libraries were also found to possess significant bioactivity against a prion‐infected cell line.

Synthesis of Aminoquinoline-based Aminoalcohols and Oxazolidinones and Their Antiplasmodial Activity.

Novel aminoquinoline β‐aminoalcohol and oxazolidinone derivatives were designed, synthesized, and evaluated for in vitro antiplasmodial activity against a chloroquine‐sensitive (3D7) and chloroquine‐resistant (K1) strains of Plasmodium falciparum. A few β‐aminoalcohol derivatives were more potent than chloroquine against chloroquine‐sensetive Plasmodiums. The potency of these derivatives decreased against chloroquine‐resistant species in all cases (higher resistance indices), suggesting a possible cross‐resistance between this group of compounds and chloroquine which could be due to their structural similarity. Although changing β‐aminoalcohols to their oxazolidinone counterparts decreased the potency in all the cases, the compounds were still active and the resistance indices for these compounds improved significantly in comparison with those of β‐aminoalcohols. This may indicate the absence of cross‐resistance between these new derivatives and chloroquine.

Synthesis and antiprotozoal evaluation of new N4-(benzyl)spermidyl-linked bis(1,3,5-thiadiazinane-2-thiones).

The synthesis and in‐vitro antiprotozoal evaluation of novel N4‐(benzyl)spermidyl‐linked bis(1,3,5‐thiadiazinane‐2‐thione) (bis‐THTT) derivatives from N4‐(benzyl)spermidine is disclosed. Several of the new bis‐THTT have in‐vitro activities against L. donovani and T. cruzi that are comparable or superior to those of currently employed protozoocidal agents.

2,4-diarylthiazole antiprion compounds as a novel structural class of antimalarial leads.

A significant intersection between antimalarial and antiprion activity is well established for certain compound classes, specifically for polycyclic antimalarial agents bearing basic nitrogen-containing sidechains (e.g., chloroquine, quinacrine, mefloquine). Screening a recently reported set of antiprion compounds with such sidechains showed these 2,4-diarylthiazole based structures also possess significant antimalarial activity. Of particular note, all but one of the compounds displayed activity against a chloroquine-resistant Plasmodium falciparum strain, identifying them as interesting leads for further development in this context. In addition, three new members of the series showed superior antiprion activity compared to the earlier-reported compounds.