Drug Repurposing in the Chemotherapy of Infectious Diseases.

Repurposing is a universal mechanism for innovation, from the evolution of feathers to the invention of Velcro tape. Repurposing is particularly attractive for drug development, given that it costs more than a billion dollars and takes longer than ten years to make a new drug from scratch. The COVID-19 pandemic has triggered a large number of drug repurposing activities. At the same time, it has highlighted potential pitfalls, in particular when concessions are made to the target product profile. Here, we discuss the pros and cons of drug repurposing for infectious diseases and analyze different ways of repurposing. We distinguish between opportunistic and rational approaches, i.e., just saving time and money by screening compounds that are already approved versus repurposing based on a particular target that is common to different pathogens. The latter can be further distinguished into divergent and convergent: points of attack that are divergent share common ancestry (e.g., prokaryotic targets in the apicoplast of malaria parasites), whereas those that are convergent arise from a shared lifestyle (e.g., the susceptibility of bacteria, parasites, and tumor cells to antifolates due to their high rate of DNA synthesis). We illustrate how such different scenarios can be capitalized on by using examples of drugs that have been repurposed to, from, or within the field of anti-infective chemotherapy.

SARS-CoV-2 Antibody Prevalence and Population-Based Death Rates, Greater Omdurman, Sudan.

In a cross-sectional survey in Omdurman, Sudan, during March-April 2021, we estimated that 54.6% of the population had detectable severe acute respiratory syndrome coronavirus 2 antibodies. Overall population death rates among those >50 years of age increased 74% over the first coronavirus disease pandemic year.

HPLC-Based Activity Profiling for Antiprotozoal Compounds in Croton gratissimus and Cuscuta hyalina.

In a screening of Sudanese medicinal plants for antiprotozoal activity, the chloroform fractions obtained by liquid-liquid partitioning from ethanolic extracts of fruits of Croton gratissimus var. gratissimus and stems of Cuscuta hyalina Roth ex Schult. exhibited in vitro activity against axenically grown Leishmania donovani amastigotes. This antileishmanial activity was localized by HPLC-based activity profiling. Targeted preparative isolation afforded flavonoids 1-6, 3-methoxy-4-hydroxybenzoic acid (7), and benzyltetrahydroisoquinoline alkaloids laudanine (8) and laudanosine (9) from C. gratissimus, and pinoresinol (10), isorhamnetin (11), (-)-pseudosemiglabrin (12), and kaempferol (13) from C. hyalina. The antiprotozoal activity of 1-13 against L. donovani (axenic and intracellular amastigotes), Trypanosoma brucei rhodesiense (bloodstream forms), and Plasmodium falciparum (erythrocytic stages), and the cytotoxicity in L6 murine myoblast cells were determined in vitro. Quercetin-3,7-dimethylether (6) showed the highest activity against axenic L. donovani (IC50, 4.5 µM; selectivity index [SI], 12.3), P. falciparum (IC50, 7.3 µM; SI, 7.6), and T. b. rhodesiense (IC50, 2.4 µM; SI, 23.2). The congener ayanin (2) exhibited moderate antileishmanial (IC50, 8.2 µM; SI, 12.2), antiplasmodial (IC50, 7.8 µM; SI, 12.9), and antitrypanosomal activity (IC50, 11.2 µM; SI, 8.9). None of the compounds showed notable activity against the intramacrophage form of L. donovani.

Mining Sudanese Medicinal Plants for Antiprotozoal Agents.

Neglected tropical diseases are major health hazards in developing countries. Annually, up to 30 million people are affected by either Chagas disease, African trypansomiasis or leishmaniasis, and more than 200 million by malaria. Most of the currently available drugs have drawbacks in terms of toxicity, limited oral availability, development of resistance, or non-affordability. Tropical plants of the arid zones are a treasure chest for the discovery of bioactive secondary metabolites. This study aims to compile Sudanese medicinal plants, validate their antiprotozoal activities, and identify active molecules. We have performed a survey of medicinal plants of Sudan and selected 62 that are being used in Sudanese traditional medicine. From these, we collected materials such as leaves, stem, bark, or fruit. The plant materials were extracted in 70% ethanol and further fractionated by liquid-liquid partitioning using solvents of increasing polarity. This resulted in a library of 235 fractions. The library was tested in vitro against Plasmodium falciparum (erythrocytic stages), Trypanosoma brucei rhodesiense (bloodstream forms), Trypanosoma cruzi (intracellular amastigotes), and Leishmania donovani (axenic amastigotes). Active fractions were also tested for cytotoxicity. Of the 235 fractions, 125 showed growth inhibitory activity >80% at 10 µg/ml, and >50% at 2 µg/ml against at least one of the protozoan parasites. Plasmodium falciparum was the most sensitive of the parasites, followed by T. b. rhodesiense and L. donovani. Only few hits were identified for T. cruzi, and these were not selective. Contrary to expectation based on phylogeny, but in agreement with previous results, a large number of extracts displayed mutual activity against T. brucei and P. falciparum. HPLC-based activity profiling for selected active extracts was performed to identify the bioactive principles. Active compounds identified by dereplication were guieranone A from Guiera senegalensis J.F.Gmel.; pseudosemiglabrin from Tephrosia apollinea (Delile) DC; ellagic acid and quercetin from Terminalia leiocarpa (DC.) Baill.; and catechin, ethyl gallate, and epicatechin gallate from Vachellia nilotica (L.) P.J.H.Hurter & Mabb. Also the extracts of Croton gratissimus var. gratissimus and Cuscuta hyalina Roth ex Schult. exhibited promising antitrypanosomatid activity. This assessment provides a comprehensive overview of Sudanese medicinal plants and supports the notion that they are a potential source of bioactive molecules against protozoan parasites.

Lignans, Amides, and Saponins from Haplophyllum tuberculatum and Their Antiprotozoal Activity.

A screening of Sudanese medicinal plants for antiprotozoal activities revealed that the chloroform and water fractions of the ethanolic root extract of Haplophyllum tuberculatum exhibited appreciable bioactivity against Leishmania donovani. The antileishmanial activity was tracked by HPLC-based activity profiling, and eight compounds were isolated from the chloroform fraction. These included lignans tetrahydrofuroguaiacin B (1), nectandrin B (2), furoguaiaoxidin (7), and 3,3'-dimethoxy-4,4'-dihydroxylignan-9-ol (10), and four cinnamoylphenethyl amides, namely dihydro-feruloyltyramine (5), (E)-N-feruloyltyramine (6), N,N'-diferuloylputrescine (8), and 7'-ethoxy-feruloyltyramine (9). The water fraction yielded steroid saponins 11-13. Compounds 1, 2, and 5-13 are reported for the first time from Haplophyllum species and the family Rutaceae. The antiprotozoal activity of the compounds plus two stereoisomeric tetrahydrofuran lignans-fragransin B2 (3) and fragransin B1 (4)-was determined against Leishmania donovani amastigotes, Plasmodium falciparum, and Trypanosoma brucei rhodesiense bloodstream forms, along with their cytotoxicity to rat myoblast L6 cells. Nectandrin B (2) exhibited the highest activity against L. donovani (IC50 4.5 µM) and the highest selectivity index (25.5).