Structure-activity and structure-property relationship studies of spirocyclic chromanes with antimalarial activity.

Malaria is a prevalent and lethal disease. The fast emergence and spread of resistance to current therapies is a major concern and the development of a novel line of therapy that could overcome, the problem of drug resistance, is imperative. Screening of a set of compounds with drug/natural product-based sub-structural motifs led to the identification of spirocyclic chroman-4-one 1 with promising antimalarial activity against the chloroquine-resistant Dd2 and chloroquine-sensitive 3D7 strains of the parasite.

Marine Microbiome as a Source of Antimalarials.

It is important to discover novel antimalarial pharmacophores because of the widespread emergence of isolates resistant to the available drugs. Secondary metabolites derived from microbes associated with marine invertebrates are a valuable resource for the discovery of novel drug leads. However, the potential of marine microbes as a source of antimalarials has not been explored.

Identification of Bis-Cyclic Guanidines as Antiplasmodial Compounds from Positional Scanning Mixture-Based Libraries.

The screening of more than 30 million compounds derived from 81 small molecule libraries built on 81 distinct scaffolds identified pyrrolidine bis-cyclic guanidine library (TPI-1955) to be one of the most active and selective antiplasmodial libraries. The screening of the positional scanning library TPI-1955 arranged on four sets of sublibraries (26 + 26 + 26 + 40), totaling 120 samples for testing provided information about the most important groups of each variable position in the TPI-1955 library containing 738,192 unique compounds. The parallel synthesis of the individual compounds derived from the deconvolution of the positional scanning library led to the identification of active selective antiplasmodial pyrrolidine bis-cyclic guanidines.

Characterization of Plasmodium falciparum Atypical Kinase PfPK7 Dependent Phosphoproteome.

PfPK7 is an "orphan" kinase displaying regions of homology to multiple protein kinase families. PfPK7 functions in regulating parasite proliferation/development as evident from the phenotype analysis of knockout parasites. Despite this regulatory role, the functions of PfPK7 in signaling pathways are not known.

4-Nitro styrylquinoline is an antimalarial inhibiting multiple stages of Plasmodium falciparum asexual life cycle.

Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant.

Dragmacidin G, a Bioactive Bis-Indole Alkaloid from a Deep-Water Sponge of the Genus Spongosorites.

A deep-water sponge of the genus has yielded a bis-indole alkaloid which we have named dragmacidin G. Dragmacidin G was first reported by us in the patent literature and has recently been reported by Hitora et al. from a sponge of the genus .

Spirocyclic chromanes exhibit antiplasmodial activities and inhibit all intraerythrocytic life cycle stages.

We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile.

The bis(indolyl)imidazole alkaloid nortopsentin a exhibits antiplasmodial activity.

A library of enriched marine natural product fractions was screened for their antiplasmodial activity using a SYBR green I fluorescence-based assay. Fractions derived from a sponge of the genus Spongosorites exhibited potent inhibition of Plasmodium falciparum growth. This genus of sponge has been reported to contain the nortopsentin and topsentin class of bis-indole imidazole alkaloids.