Synthesis and in vitro and in vivo evaluation of antimalarial polyamines

Abstract

We recently reported that 1,14-diphenylacetamide derivatives of spermine exhibit potent nM in vitro growth inhibition properties of Plasmodium falciparum. In an effort to expand the structure-activity relationship of this compound class towards malaria, we have prepared and biologically tested a library that includes benzamide and 3-phenylpropanamide 'capping acid' groups, and polyamines that include spermine (PA3-4-3) and chain extended analogues PA3-8-3 and PA3-12-3. 2-Hydroxy and 2,5-dimethoxy analogues were typically found to exhibit the most potent activity towards the dual drug resistant strain K1 of P. falciparum with IC50's in the range of 1.3-9.5 nM, and selectivity indices (SI) of 42,300 to 4880. In vivo evaluation of three analogues against Plasmodium berghei was undertaken, with one demonstrating a modest 27.9% reduction in parasitaemia.

Keywords: APXWBHJJRUZQDA-UHFFFAOYSA-N; BHSCATGKXUSTKB-UHFFFAOYSA-P; BRFJLPIHQRRVHX-UHFFFAOYSA-N; CZFCZIYRRIWDDJ-UHFFFAOYSA-P; DRRVVLFDHFTOOU-UHFFFAOYSA-P; FIQILUXACGTQSZ-UHFFFAOYSA-N; HEEYMMGFYFUZCC-UHFFFAOYSA-P; HUQOMVFXIMRFNL-UHFFFAOYSA-P; IACYYBYZFJCKOC-UHFFFAOYSA-N; ICRQUOTYMOKABC-UHFFFAOYSA-N; IGTFIYYATOISLG-UHFFFAOYSA-P; JAHOTGNKQLAZRL-UHFFFAOYSA-P; JUBYMDHTMMQDKL-UHFFFAOYSA-P; KCELOMAULGIILO-UHFFFAOYSA-P; LNJVONNGUVLIBU-UHFFFAOYSA-P; LZAMYBLYNWHXAL-UHFFFAOYSA-P; MRKQBADTCCVFMQ-UHFFFAOYSA-N; Malaria; NRSGODYVIJSISU-UHFFFAOYSA-N; Natural product; New orthidine F analogues; OLGIVYGGZBMPOY-UHFFFAOYSA-N; OUJGGEWZJSZKHI-UHFFFAOYSA-P; OZERGKJKBWAFBP-UHFFFAOYSA-P; Polyamine; QPKSCLJXBAIYOD-UHFFFAOYSA-N; QUPSRDCVVDDTPI-UHFFFAOYSA-P; RCHFVEZUNHGKQX-UHFFFAOYSA-P; RTGWJIPPNNUSIO-UHFFFAOYSA-P; SAQHQBAFWQPENK-UHFFFAOYSA-N; SSWZRMJTXGYLMQ-UHFFFAOYSA-N; SUPDFRQHPWZCIF-UHFFFAOYSA-P; TXHPDPYBSCVGAE-UHFFFAOYSA-N; UMXXHVMEVAXDSN-UHFFFAOYSA-P; WIYQXLGSYAITSV-UHFFFAOYSA-P; WKBYDIDHSSQYPY-UHFFFAOYSA-N; ZEZUQFYOVLUSMG-UHFFFAOYSA-N; ZHBFJMDGGWIGHC-UHFFFAOYSA-N; ZJPGKHGUMDPKOZ-UHFFFAOYSA-P; ZRSLKYGEDBLSSG-UHFFFAOYSA-P; ZSTPDMFXEGINLF-UHFFFAOYSA-P.