Abstract
Erythromycin A is an established anti-bacterial agent against Gram-positive bacteria, but it is unstable to acid. This led to an evaluation of erythromycin B and its derivatives because these have improved acid stability. These compounds were investigated for their anti-malarial activities, by their in silico molecular docking into segments of the exit tunnel of the apicoplast ribosome from Plasmodium falciparum. This is believed to be the target of the erythromycin A derivative, azithromycin, which has mild anti-malarial activity. The erythromycin B derivatives were evaluated on the multi-drug (chloroquine, pyrimethamine, and sulfadoxine)-resistant strain K1 of P. falciparum for asexual growth inhibition on asynchronous culture. The erythromycin B derivatives were identified as active in vitro inhibitors of asexual growth of P. falciparum with low micro-molar IC50 values after a 72 h cycle. 5-Desosaminyl erythronolide B ethyl succinate showed low IC50 of 68.6 µM, d-erythromycin B 86.8 µM, and erythromycin B 9-oxime 146.0 µM on the multi-drug-resistant K1 of P. falciparum. Based on the molecular docking, it seems that a small number of favourable interactions or the presence of unfavourable interactions of investigated derivatives of erythromycin B with in silico constructed segment from the exit tunnel from the apicoplast of P. falciparum is the reason for their weak in vitro anti-malarial activities.
Highlights
Malaria remains a huge health problem worldwide with 229 million cases and409,000 registered deaths reported in 2019 [1]
Based on the molecular docking, it seems that a small number of favourable interactions or the presence of unfavourable interactions of investigated derivatives of erythromycin B with in silico constructed segment from the exit tunnel from the apicoplast of P. falciparum is the reason for their weak in vitro anti-malarial activities
The pdb files of the ligand molecules consisted of folded-out structures obtained in the unconstrained conformational search for all investigated erythromycin B derivatives, except erythromycin B 2 -[3-(dimethylaminomethyl)benzoate], where we used the global minimum of the constrained conformational search
Summary
409,000 registered deaths reported in 2019 [1]. Due to the growing resistance from Southeast Asia to Africa to almost all anti-malarial drugs, it is clear that new therapeutic strategies are essential. Erythromycin A possesses in vitro and in vivo anti-malarial activity [6]. Its anti-malarial action is improved in combination with chloroquine; its modulating effect is important in chloroquine resistance [3]. Anti-malarial activity has been described for other antibiotics such as co-trimoxazole, quinolones, tigecycline, mirincamycin, ketolides, fusidic acid, and thiopeptides [7]. Based on studies in Africa, co-trimoxazole can be used as an alternative in malaria prophylaxis, for children and adults, HIV (human immunodeficiency viruses) positive or negative patients. Materials 2021, 14, 6980 on studies in Africa, co-trimoxazole can be used as an alternative in malaria prophylaxis, for children and adults, HIV (human immunodeficiency viruses) positive or negative patients and pregnant women [8,9,10,11]. TThheerreefoforree, ,ddeevveellooppiinngg aa mmoorreeeefffefectcitviveeanadndsasfearfearnatin-mti-amlaarliaarlifarlomfrotmhe tchlaesscloafssmoafcmroalcirdoelsidiessthisetahiemaiomf tohfisthreisseraersceha.rcHhe. rHe,etrhee, tihneviintrvoitarnotia-nmtia-lmaraialalraiacltiavcittyivoitfysoyfnsthyenstihsee-d sdiseerdivdaetriviveastiovfeseroyftehrryotmhryocminycBin(eBry(ethryrothmroymciyncBin9B-o9x-oimxiem, e5,-d5-edseossoasmaminiynlyel reyrtyhthroronnoolildideeB Betehthylysluscuccicniantaet,ee,ryerthyrthomroymcyinciBn2B′-[23--([m3-o(mrpohroplhinoolimnoetmhyetl)hbyeln)bzeonazteo]a, teer]y,tehrryotmhryocminyBci2n′-[B32(d-[i3m-(edtihmyelathmyilnaommineothmyel)tbheynl)zboeantzeo],aaten]d, a8n-dd-8e-rdy-tehrryotmhryocminycBi)n(BF)ig(uFirgeu1r)e, 1a)n, aancidac-sidta-sbtlaebdleedreivriavtaivtieveofofereyryththrorommyycicninAA[[1177]]hhaavvee bbeeeenn iinnvveessttiiggaatteedd,, iinncclluuddiinngg tthheeuusseeooffmmoolelceuculalarr ddoocckkininggtotoggiviveeininsisgighht trereggaardrdininggththeemmecehchananisimsmoof facatcitoionn
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