Abstract
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.
Highlights
Malaria globally still causes 216 million clinical cases and ~445,000 deaths each year, but the drugs that are available for treatment are rapidly losing their efficacy because of widespread prevalence of drug resistant parasites [1,2]
The parallel synthesis of all individual compounds named TPI‐2359 derived from the deconvolution of TPI‐1955 representing all the combination (3 × 2 × 3 × 4 = 72) of active mixtures with defined R1, R2, R3, and R4 (Figure 3) was performed using the strategy outlined in Scheme 1
Synthesis of the desired pyrrolidine bis-cyclic guanidines: Our approach involved the use of proline as a spacer, which, following the exhaustive reduction of the amide groups, yielded resin-bound pentaamine containing two pairs of secondary amines separated by a pyrrolidine ring
Summary
Malaria globally still causes 216 million clinical cases and ~445,000 deaths each year, but the drugs that are available for treatment are rapidly losing their efficacy because of widespread prevalence of drug resistant parasites [1,2]. The appearance of parasites resistant to artemisinin derivatives in wide areas of Southeast Asia underscores the fragility of the available malaria treatment measures. Given the global toll of malaria, it is urgent to identify novel leads directed against new cellular targets for the generation of malaria therapeutics [3,4]. To find a solution to the problem of resistance, even to future malaria medicines, there is an urgent need to continue with the development of novel leads to create a pipeline of malaria therapeutics, directed against new cellular targets [9]. Artemisinin and its semisynthetic derivatives are prime examples in the malaria arena. Such chemotypes remain severely underrepresented in modern screening campaigns due to Molecules 2019, 24, 1100; doi:10.3390/molecules24061100 www.mdpi.com/journal/molecules. The TPIMS collection of libraries contains a large number of small molecule compounds residing largely in the underexplored areas of chemical space [12,13,14,15,16]
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