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Design, Synthesis & Evaluation of New diamino-pyrimidine Anti-Malarial Inhibitors
Design, Synthesis & Evaluation of New diamino-pyrimidine Anti-Malarial Inhibitors
Malaria is tropical infectious disease of humans and other animals caused by mosquito-borne parasites that include Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). The former causes the greatest percentage of deaths due to its more severe symptoms. The disease is prevalent in tropical climates in the African and Asian sub-continents, affecting countries with less developed economies
In this work a series of 2,4 diamino-pyrimidines have been identified from an analysis of open access high throughput anti-malarial screening data reported by GlaxoSmithKline at the 3D7 and resistant Dd2 strains. We have developed new inhibitors using structural knowledge of the most plausible parasite target. Seventeen new analogs have been synthesized and tested against the resistant K1 strain of Plasmodium falciparum (Pf). The cytotoxicity of the compounds was assessed in Vero and A549 cells and their selectivity towards human kinases including JAK2 and EGFR were undertaken. We identified compound 5n and 5m as sub-micromolar inhibitors, with equivalent anti-malarial activity to Chloroquine (CQ). Compounds 5d and 5k, mM inhibitors of Pf, displayed improved cytotoxicity with weak inhibition of the human kinases.
Design, Synthesis & Evaluation of New Benzoxazole Anti-Cancer Agents
Design, Synthesis & Evaluation of New Benzoxazole Anti-Cancer Agents
According to the World Health Organization, lung cancer is the most common cause of cancer death. Non-small cell lung cancer (NSCLC) is the most deadly form of this disease and has a 5 year survival rate below 15%. Platinum-containing chemotherapies, DNA intercalators such as Doxorubicin and Etoposide and protein kinase inhibitors such as Lapatinib and Imatinib can be used to treat NSCLC. This range of treatment options is necessary to reduce patient specific side-effects and to avoid disease resistance in certain sub-populations. Nevertheless, the low survivability associated with lung cancer is a clear indication of the need for more effective drugs, particularly those that act on targets or pathways of greater relevance to the disease.
A series of 2-aminoaryl-7-arylbenzoxazole derivatives have been designed, synthesized and evaluated as anti-cancer agents. Fourteen of the compounds exhibited cytotoxic effects towards Human A549 lung cancer cells. We found compound 12l was the most potent with an EC50 of 0.4 µM, equivalent to the anti-cancer drug doxorubicin, but had low selectivity following cross screening in monkey kidney Vero cells. Eight of the most potent or most selective compounds were further profiled in additional cell lines (MCF7, NCI-H187 and KB) to better understand their cytotoxic activity. Only compound 12l had a measurable EC50 in a single cell line (3.3 µM in the KB cell line). Taken together, this data suggests the series as a whole display specific cytotoxicity towards A549 cells. Cheminformatics searches pointed to JAK2 as a possible target. A subset of compounds assayed at this target showed IC50s ranging from 10 µM to 0.08 µM, however no clear correlation between JAK potency and A549 cytotoxicity was observed.
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