Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure–Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents

Abstract

Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

“…This notion may sound odd, especially if one considers the first-line antituberculosis drugs: isoniazid and pyrazinamide both have negative ClogP, whereas ClogP of ethambutol is 0.35. However, it has been deeply demonstrated that compounds with antituberculosis activity are more lipophilic than the inactive ones (Ekins et al, 2011 ), and not only in general, but also within a drug class, lipophilic derivatives are in general more active against mycobacteria than their more hydrophilic counterparts (Mao et al, 2009 ; Lilienkampf et al, 2010 , 2012 ; Pieroni et al, 2010 , 2011 , 2017 ). Below, a critical analysis of the current hot biology challenges (energy depletion, PMF, and drug transporters) and their interconnection with the lipophilicity of molecules is reported.…”

Synthesis of a New Class of Spirooxindole–Benzo[b]Thiophene-Based Molecules as Acetylcholinesterase Inhibitors

“…Benzothiophene privilege structure is among the sulfur containing fused herterocycles which are interesting in drug discovery [ 18 ]. Many lead compounds having this nucleus possess divergent pharmaceutical activities, allowing them to act as anti-inflammatory, anti-cancer, anti-diabetic, anti-oxidant, anti-microbial, anti-convulsant agents, anti-tubercular, and many more [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”

Synthesis of 2‐Organylchalcogenopheno[2,3‐b]pyridines from Elemental Chalcogen and NaBH4/PEG‐400 as a Reducing System: Antioxidant and Antinociceptive Properties

“…Chalcogen-containing heterocycles are an important class of compounds that have been extensively exploited in medicinal chemistry, [1][2][3] materials science [4][5][6][7][8][9][10] and organic synthesis. [11][12][13] Among them, chalcogenophenes have presented many promising applications as new materials due to their properties as organic semiconductors, which showed potential as organic field-effect transistors (OFET), [14][15][16][17][18][19] organic light-emitting diode (OLED), [20][21][22][23][24] and organic solar cells (OSC).…”