Antiplasmodial activity, structure-activity relationship and studies on the action of novel benzimidazole derivatives.

Malaria cases and deaths keep being excessively high every year. Some inroads gained in the last two decades have been eroded especially due to the surge of resistance to most antimalarials. The search for new molecules that can replace the ones currently in use cannot stop. In this report, the synthesis of benzimidazole derivatives guided by structure-activity parameters is presented. Thirty-six molecules obtained are analyzed according to their activity against P. falciparum HB3 strain based on the type of substituent on rings A and B, their electron donor/withdrawing, as well as their dimension/spatial properties. There is a preference for electron donating groups on ring A, such as Me in position 5, or better, 5, 6-diMe. Ring B must be of the pyridine type such as picolinamide, other modifications are generally not favorable. Two molecules, 1 and 33 displayed antiplasmodial activity in the high nanomolar range against the chloroquine sensitive strain, with selectivity indexes above 10. Activity results of 1, 12 and 16 on a chloroquine resistance strain indicated an activity close to chloroquine for compound 1. Analysis of some of their effect on the parasites seem to suggest that 1 and 33 affect only the parasite and use a route other than interference with hemozoin biocrystallization, the route used by chloroquine and most antimalarials.

Structure modification, antialgal, antiplasmodial, and toxic evaluations of a series of new marine-derived 14-membered resorcylic acid lactone derivatives.

Marine natural products play critical roles in the chemical defense of many marine organisms and are essential, reputable sources of successful drug leads. Sixty-seven 14-membered resorcylic acid lactone derivatives 3-27 and 30-71 of the natural product zeaenol (1) isolated from the marine-derived fungus Cochliobolus lunatus were semisynthesized by chlorination, acylation, esterification, and acetalization in one to three steps. The structures of these new derivatives were established by HRESIMS and NMR techniques. All the compounds (1-71) were evaluated for their antialgal and antiplasmodial activities. Among them, 14 compounds displayed antifouling activities against adhesion of the fouling diatoms. In particular, 9 and 34 exhibited strong and selective inhibitory effects against the diatoms Navicula laevissima and Navicula exigua (EC50 = 6.67 and 8.55 µmol/L), respectively, which were similar in efficacy to those of the positive control SeaNine 211 (EC50 = 2.90 and 9.74 µmol/L). More importantly, 38, 39, and 69-71 showed potent antiplasmodial activities against Plasmodium falciparum with IC50 values ranging from 3.54 to 9.72 µmol/L. Very interestingly, the five antiplasmodial derivatives displayed non-toxicity in the cytotoxicity assays and the zebrafish embryos model, thus, representing potential promising antiplasmodial drug agents. The preliminary structure-activity relationships indicated that biphenyl substituent at C-2, acetonide at positions C-5' and C-6', and tri- or tetra-substituted of acyl groups increased the antiplasmodial activity. Therefore, combining evaluation of chemical ecology with pharmacological models will be implemented as a systematic strategy, not only for environmentally friendly antifoulants but also for structurally novel drugs. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-021-00103-0.

Semisynthesis, Antiplasmodial Activity, and Mechanism of Action Studies of Isocoumarin Derivatives.

In this study, eight natural isocoumarins (1-8) were isolated from a marine-derived Exserohilum sp. fungus. To explore their structure-activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a-1n, 2a, 3a-3c, 4a-4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC50 values of 1.1, 0.8, 0.4, and 2.6 µM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC50/IC50 = 675), high selectivity, and a notable drug-like profile.

Discovery, Semisynthesis, Antiparasitic and Cytotoxic Evaluation of 14-Membered Resorcylic Acid Lactones and Their Derivatives.

Ten antifouling 14-membered resorcylic acid lactones 1-10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1-6 and a series of derivatives 11-27 of compounds 7 and 8 with high yields (65-95%). Compounds 11-13 showed strong antiplasmodial activity against Plasmodium falciparum with IC50 values of 1.84, 8.36, and 6.95 µM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC50/IC50 > 180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC50 value of 9.22 µM. Compounds 11 and 12 showed the values of IC50 at 11.9 and 17.2 µM against neglected Chagas' disease causing Trypanosoma cruzi, respectively.