Malaria prevention is key for protecting high-risk groups, such as children and pregnant women. Existing approaches, including insecticide-based vector control, infant vaccination, and targeted chemoprevention are successful in some contexts. However, new tools are needed to broaden the scope and enhance the effectiveness of preventive strategies, particularly in high transmission areas. This paper examines emerging modalities for malaria chemoprevention beyond vaccination, illustrating advances toward long-acting interventions that can provide sustained protection with fewer doses. The pharmacological rationale and essential considerations for the clinical development and deployment of monoclonal antibodies, long-acting oral agents, and long-acting injectable small-molecule formulations are explored with examples. These innovations represent a step-change in malaria prevention, improving operational feasibility and long-term impact in endemic settings. They also have the potential to transform malaria prevention from a disease control tool in high-burden settings to a strategy capable of accelerating malaria elimination.

Focused structure-activity-relationship studies of MMV020136, 1, a whole-cell phenotypic screening hit originating from the Pathogen Box against the human malaria parasite, Plasmodium falciparum, led to the identification of compound 15 (MMV1581361). Compound 15 retained nanomolar activity against drug-sensitive, drug-resistant, and field isolates of Plasmodium falciparum blood-stage parasites. It was found to display a moderate rate-of-kill profile similar to pyrimethamine in vitro and efficacy in the humanized P. falciparum Pf3D70087/N9 NODscidIL2Rγnull mouse model at a single dose of 25 mg/kg, with similar kinetics to chloroquine. Furthermore, compound 15 demonstrated significant transmission-blocking potential, achieving 90% inhibition of male gamete exflagellation, a 98% reduction in mean oocyst intensity, and an 88% block in transmission. Mechanism-of-action studies revealed that compound 15 disrupts Na+ ion homeostasis in P. falciparum, indicating that it functions as a PfATP4 inhibitor. However, due to the resistance risk associated with the PfATP4 target and the presence of more advanced clinical candidates, further development of 15 into a viable antimalarial drug is currently deprioritised.

The current therapeutic agents for the treatments of visceral leishmaniasis are ineffective, and cytotoxic. Therefore, there is the urgent need for new chemotypes for the treatment of the disease with novel mechanisms of action. In our previous investigation, we identified the triazolopyridazine, STOCK6S-84928 as a potential inhibitor of Leishmania donovani sterol methyltransferase (LdSMT) with IC50 value of 118.3 µM. To improve the biological activity of the initial hit compound, we hereby describe the results of structural-activity relationship studies on STOCK6S-84928 via chemical modifications on the scaffold and virtually screening of 250 compounds obtained against the Modeller generated LdSMT structure. A total of 21 compounds were found to have binding energies ranging from − 7.0 to − 9.2 kcal/mol lower or comparable to the 22,26-azasterol (− 7.6 kcal/mol), the known inhibitor of the target. Molecular docking and molecular dynamics simulations revealed Ile272 and Tyr275 to be pivotal for ligand binding. The compounds were predicted to possess leishmanicidal activities with good drug-like properties. Significantly, the compounds 8, 9, 21, and 23 were predicted to possess antineoplastic, anti-inflammatory, analgesics, protein and MAP kinase inhibitory activities with probability of activity (Pa) > 0.2 and probability of inactivity (Pi) < 0.16. Through the applications of cyclization, amination, Williamson’s ether synthesis, and Suzuki cross-coupling reactions, the selected analogues of STOCK6S-84928 were synthesised in moderate to high yields and characterized by FTIR, LC–MS, and NMR spectroscopy methods. In vitro antileishmanial evaluation of the synthesized compounds identified 23 as the most potent, exhibiting L. donovani promastigotes inhibitory activities with IC50 value of (1.9 ± 0.1) µM. The ortho-difluoropheneyl group as well as the triazolopyridine moieties were suspected to be responsible for the observed activity. Similarly, the compounds 10 and 16 required (0.8 ± 0.1) µM and (0.6 ± 0.0) µM, respectively to eliminate 50

The Hosomi–Sakurai allylation reaction has been widely applied in the total synthesis of biologically active natural products, especially in synthesising complex polycyclic compounds containing multi-stereogenic centres since its discovery in 1976. The Hosomi-Sakurai allylation is the allylation of ketones and aldehyde with nucleophilic allylsilanes catalyzed with Lewis acid mainly used to extend the C-C bond in a molecule and also create a new site for manipulation due to the facile transformation of the pi (π) bond at the end of its chain. This review highlights only portions of natural product synthetic works that feature the Hosomi-Sakurai allylation reaction or its modification as a key transformation in the synthetic route.

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities. The review focuses on pioneering studies of Kishi which elaborate first-, second-, and third-generation approaches to the synthesis of mycolactones A/B. The three generations focused on the construction of the key intermediates required for the mycolactone synthesis. Synthesis of the first generation involves assignment of the relative and absolute stereochemistry of the mycolactones A and B. This was accomplished by employing a linear series of 17 chemical steps (1.3% overall yield) using the mycolactone core. The second generation significantly improved the first generation in three ways: (1) by optimizing the selection of protecting groups; (2) by removing needless protecting group adjustments; and (3) by enhancing the stereoselectivity and overall synthetic efficiency. Though the synthetic route to the mycolactone core was longer than the first generation, the overall yield was significantly higher (8.8%). The third-generation total synthesis was specifically aimed at an efficient, scalable, stereoselective, and shorter synthesis of mycolactone. The synthesis of the mycolactone core was achieved in 14 linear chemical steps with 19% overall yield. Furthermore, a modular synthetic approach where diverse analogues of mycolactone A/B were synthesized via a cascade of catalytic and/or asymmetric reactions as well as several Pd-catalyzed key steps coupled with hydroboration reactions were reviewed. In addition, the review discusses how mycolactone is employed in the diagnosis of Buruli ulcer with emphasis on detection methods of mass spectrometry, immunological assays, RNA aptamer techniques, and fluorescent-thin layer chromatography (f-TLC) methods as diagnostic tools. We examined studies of the structure–activity relationship (SAR) of various analogues of mycolactone. The paper highlights the multiple biological consequences associated with mycolactone such as skin ulceration, host immunomodulation, and analgesia. These effects are attributed to various proposed mechanisms of actions including Wiskott–Aldrich Syndrome protein (WASP)/neural Wiskott–Aldrich Syndrome protein (N-WASP) inhibition, Sec61 translocon inhibition, angiotensin II type 2 receptor (AT2R) inhibition, and inhibition of mTOR. The possible application of novel mycolactone analogues produced based on SAR investigations as therapeutic agents for the treatment of inflammatory disorders and inflammatory pain are discussed. Additionally, their therapeutic potential as anti-viral and anti-cancer agents have also been addressed.

The mortalities and morbidities of leishmaniasis are high and the disease is under reported globally. The absence of vaccines coupled with chemotherapeutic challenges including chemoresistance, scarcity and toxicity have made the fight against leishmaniasis an arduous one. Furthermore, the treatment options currently available for leishmaniasis are long and sometimes require hospitalization. There is therefore the need to explore novel pathways to identify new compounds with alternative mechanisms of action. A pharmacophore-based screening was employed in identifying new potential inhibitors with unique scaffolds targeting Leishmania donovani sterol methyltransferase (LdSMT), a key enzyme for ergosterol biosynthesis. To accomplish this, 22,26-azasterol, a known inhibitor of this target and five other derivatives with IC50 less than 10 μM were used to generate a robust 3D pharmacophore model via LigandScout with a score of 0.9144. The validated model was used as a query to screen a library of 69034 natural products obtained from the InterBioScreen Limited. Compounds with pharmacophore fit scores above 50 were docked against the modelled structure of LdSMT. Altogether, ten molecules with binding energies between −7 and −11 kcal/mol were identified as potential bioactive molecules. The molecular dynamics simulation and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations reinforced the results from the docking studies suggesting the selected hits bind effectively at the active sites of the target protein. The compounds were observed to bind in the S-adenosine-L-homocysteine binding pocket of the modelled LdSMT with Trp208 and Val330 predicted as key residues critical for ligand binding. Prediction of biological activity with probability of activity (Pa) greater than probability of inactivity (Pi) revealed that seven compounds (STOCKIN-54848, STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, STOCKIN-76694, STOCKIN-47277 and STOCKIN-95708) possessed antileishmanial properties. STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, and STOCKIN-47277 were predicted to be membrane permeability inhibitors, while all ten hit compounds possessed antineoplastic activity. The compounds have the propensity of disrupting ergosterol biosynthesis leading to the suppression of growth in Leishmania donovani. The compounds were predicted to have good absorption, distribution, metabolism, excretion and toxicity profiles, hence their potential antileishmanial activity can be exploited upon experimental corroboration.

The recent outlook of leishmaniasis as a global public health concern coupled with the reportage of resistance and lack of efficacy of most antileishmanial drugs calls for a concerted effort to find new leads. The study combined In silico and in vitro approaches to identify novel potential synthetic small-molecule inhibitors targeting the Leishmania donovani sterol methyltransferase (LdSMT). The LdSMT enzyme in the ergosterol biosynthetic pathway is required for the parasite’s membrane fluidity, distribution of membrane proteins, and control of the cell cycle. The lack of LdSMT homologue in the human host and its conserved nature among all Leishmania parasites makes it a viable target for future antileishmanial drugs. Initially, six known inhibitors of LdSMT with IC50 < 10 μM were used to generate a pharmacophore model with a score of 0.9144 using LigandScout. The validated model was used to screen a synthetic library of 95,630 compounds obtained from InterBioScreen limited. Twenty compounds with pharmacophore fit scores above 50 were docked against the modelled three-dimensional structure of LdSMT using AutoDock Vina. Consequently, nine compounds with binding energies ranging from −7.5 to −8.7 kcal/mol were identified as potential hit molecules. Three compounds comprising STOCK6S-06707, STOCK6S-84928, and STOCK6S-65920 with respective binding energies of −8.7, −8.2, and −8.0 kcal/mol, lower than 22,26-azasterol (−7.6 kcal/mol), a known LdSMT inhibitor, were selected as plausible lead molecules. Molecular dynamics simulation studies and molecular mechanics Poisson–Boltzmann surface area calculations showed that the residues Asp25 and Trp208 were critical for ligand binding. The compounds were also predicted to have antileishmanial activity with reasonable pharmacological and toxicity profiles. When the antileishmanial activity of the three hits was evaluated in vitro against the promastigotes of L. donovani, mean half-maximal inhibitory concentrations (IC50) of 21.9 ± 1.5 μM (STOCK6S-06707), 23.5 ± 1.1 μM (STOCK6S-84928), and 118.3 ± 5.8 μM (STOCK6S-65920) were obtained. Furthermore, STOCK6S-84928 and STOCK6S-65920 inhibited the growth of Trypanosoma brucei, with IC50 of 14.3 ± 2.0 μM and 18.1 ± 1.4 μM, respectively. The identified compounds could be optimised to develop potent antileishmanial therapeutic agents.

Mortalities associated with leishmaniasis are skyrocketing at an alarming rate. Lack of vaccine for leishmaniasis treatment is making the fight against the disease an arduous one. Interestingly, apart from the expensive nature of leishmaniasis treatments, the mono- and combinational chemotherapeutic agents suffer drawbacks such as resistance, synergism resistance, systemic toxicity, and ineffectiveness. Due to this, the new paradigm proposed for combating this canker is an efficient therapeutic antileishmanial agent with multitarget inhibitory properties. Though natural products and their derivatives have long been known for their medicinal properties for treating various ailments, little is known for their multimodality antileishmanial effects. A plethora of structurally diverse natural products, their IC50, and their biological targets of inhibition are, therefore, discussed in this book chapter. Structural modifications of these natural products based on pharmacophoric analysis leading to the semi-synthesis of their derivatives are also presented. Additionally, a view on metallodrugs using these versatile natural products and their derivatives coordinated to transition metals geared toward leishmaniasis treatment is proposed.

Background Mycobacterium ulcerans is the causative agent of Buruli ulcer. The pathology of M. ulcerans disease has been attributed to the secretion of a potent macrolide cytotoxin known as mycolactone which plays an important role in the virulence of the disease. Mycolactone is a biomarker for the diagnosis of BU that can be detected using the fluorescent-thin layer chromatography (f-TLC) technique. The technique relies on the chemical derivatization of mycolactone A/B with 2-naphthylboronic acid (BA) which acts as a fluorogenic chemosensor. However, background interferences due to co-extracted human tissue lipids, especially with clinical samples coupled with the subjectivity of the method call for an investigation to find an alternative to BA. Methods Twenty-six commercially available arylboronic acids were initially screened as alternatives to BA using the f-TLC experiment. UV–vis measurements were also conducted to determine the absorption maximum spectra of mycolactone A/B and myco-boronic acid adducts followed by an investigation of the fluorescence-enhancing ability of the boronate ester formation between mycolactone A/B and our three most promising boronic acids (BA15, BA18, and BA21). LC–MS technique was employed to confirm the adduct formation between mycolactone and boronic acids. Furthermore, a comparative study was conducted between BA18 and BA using 6 Polymerase Chain Reaction (PCR) confirmed BU patient samples. Results Three of the boronic acids (BA15, BA18, and BA21) produced fluorescent band intensities superior to BA. Complexation studies conducted on thin layer chromatography (TLC) using 0.1 M solution of the three boronic acids and various volumes of 10 ng/µL of synthetic mycolactone ranging from 1 µL – 9 µL corresponding to 10 ng – 90 ng gave similar results with myco-BA18 adduct emerging with the most visibly intense fluorescence bands. UV–vis absorption maxima (λ max ) for the free mycolactone A/B was observed at 362 nm, and the values for the adducts myco-BA15, myco-BA18, and myco-BA21 were at 272 nm, 270 nm, and 286 nm respectively. The comparable experimental λ max of 362 nm for mycolactone A/B to the calculated Woodward-Fieser value of 367 nm for the fatty acid side chain of mycolactone A/B demonstrate that even though 2 cyclic boronates were formed, only the boronate of the southern side chain with the chromophore was excited by irradiation at 365 nm. Fluorescence experiments have demonstrated that coupling BA18 to mycolactone A/B along the 1,3-diols remarkably enhanced the fluorescence intensity at 537 nm. High-Resolution Mass Spectrometer (HR-MS) was used to confirm the formation of the myco-BA15 adduct. Finally, f-TLC analysis of patient samples with BA18 gave improved BA18-adduct intensities compared to the original BA-adduct. Conclusion Twenty-six commercially available boronic acids were investigated as alternatives to BA, used in the f-TLC analysis for the diagnosis of BU. Three (3) of them BA15, BA18, and BA21 gave superior fluorescence band intensity profiles. They gave profiles that were easier to interpret after the myco-boronic acid adduct formation and in experiments with clinical samples from patients with BA18 the best. BA18, therefore, has been identified as a potential alternative to BA and could provide a solution to the challenge of background interference of co-extracted human tissue lipids from clinical samples currently associated with the use of BA.

The therapeutic challenges pertaining to leishmaniasis due to reported chemoresistance and toxicity necessitate the need to explore novel pathways to identify plausible inhibitory molecules. Leishmania donovani 24-sterol methyltransferase (LdSMT) is vital for the synthesis of ergosterols, the main constituents of Leishmania cellular membranes. So far, mammals have not been shown to possess SMT or ergosterols, making the pathway a prime candidate for drug discovery. The structural model of LdSMT was elucidated using homology modeling to identify potential novel 24-SMT inhibitors via virtual screening, scaffold hopping, and de-novo fragment-based design. Altogether, six potential novel inhibitors were identified with binding energies ranging from −7.0 to −8.4 kcal/mol with e-LEA3D using 22,26-azasterol and S1–S4 obtained from scaffold hopping via the ChEMBL, DrugBank, PubChem, ChemSpider, and ZINC15 databases. These ligands showed comparable binding energy to 22,26-azasterol (−7.6 kcal/mol), the main inhibitor of LdSMT. Moreover, all the compounds had plausible ligand efficiency-dependent lipophilicity (LELP) scores above 3. The binding mechanism identified Tyr92 to be critical for binding, and this was corroborated via molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The ligand A1 was predicted to possess antileishmanial properties with a probability of activity (Pa) of 0.362 and a probability of inactivity (Pi) of 0.066, while A5 and A6 possessed dermatological properties with Pa values of 0.205 and 0.249 and Pi values of 0.162 and 0.120, respectively. Structural similarity search via DrugBank identified vabicaserin, daledalin, zanapezil, imipramine, and cefradine with antileishmanial properties suggesting that the de-novo compounds could be explored as potential antileishmanial agents.

Malaria and tuberculosis (TB) though curable and preventable, remain serious public health problems globally, with devastating consequences. Co-infection of these two deadly diseases worsens the situation and particularly makes treatment very difficult. The current mainstay for malaria treatment is gradually losing their potency due to the development of resistance. Macobacterium tuberculosis (MTB) has developed Multi-drug Resistance (MDR) and Extensive Drug Resistance (XDR) to current antitubercular drugs due to patient incompliance resulting from long treatment regimen. A small library of isonicotinohydrazide were synthesised by incorporating 1,2,4,5- tetraoxane and hydrazine moieties. Evaluation of the compounds gave antimalarial activities in the range 0.060 ± 0.033–0.491 ± 0.012 µM against 3D7 strain of Plasmodium falciparum. We assessed antimycobacterial activity of selected compounds against the standard Mycobacterium tuberculosis reference strain H37Rv and M. aurum (a non-tuberculous mycobacteria) using the microplate Alamar blue (MABA) assay and found four compounds to be very potent against H37Rv but largely inactive against Macobacterium aurum. We followed up to estimate the minimum inhibitory concentrations of these active compounds and tested them against clinical M. tuberculosis strains resistant to isoniazid (INH) and rifampicin (RIF). The MICs of the active compounds against H37Rv were between 0.003 and 0.5 mg/mL however, they were largely inactive against drug resistant clinical strains except for the INH mono-resistant resistant strain which was very active with compounds 5 and 8 possessing MICs of 0.125 mg/mL.

Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc1 complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc1. Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalian’s equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and P. falciparum Qi sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite bc1 with improved antimalarial properties.

Buruli ulcer is a necrotizing skin infection caused by Mycobacterium ulcerans. BU lesions may start with characteristic painlessness but most often, the typical presentations of the disease are characterized by large ulcers with undermined edges. If left untreated, BU lesions may result in extensive ulceration that can cover 15% of the body. Even though public sensitization and education have resulted in sufficient and improved knowledge about the etiology of the disease in Ghana, patients still report to health facilities with advanced forms of the disease.

Background Buruli ulcer is a tissue necrosis infection caused by an environmental mycobacterium called Mycobacterium ulcerans (MU). The disease is most prevalent in rural areas with the highest rates in West and Central African countries. The bacterium produces a toxin called mycolactone which can lead to the destruction of the skin, resulting in incapacitating deformities with an enormous economic and social burden on patients and their caregivers. Even though there is an effective antibiotic treatment for BU, the control and management rely on early case detection and rapid diagnosis to avert morbidities. The diagnosis of Mycobacterium ulcerans relies on smear microscopy, culture histopathology, and PCR. Unfortunately, all the current laboratory diagnostics have various limitations and are not available in endemic communities. Consequently, there is a need for a rapid diagnostic tool for use at the community health centre level to enable diagnosis and confirmation of suspected cases for early treatment. The present study corroborated the diagnostic performance and utility of fluorescent-thin layer chromatography (f-TLC) for the diagnosis of Buruli ulcer. Methodology/Principal findings The f-TLC method was evaluated for the diagnosis of Buruli ulcer in larger clinical samples than previously reported in an earlier preliminary study Wadagni et al. (2015). A total of 449 patients suspected of BU were included in the final data analysis out of which 122 (27.2%) were positive by f-TLC and 128 (28.5%) by PCR. Using a composite reference method generated from the two diagnostic methods, 85 (18.9%) patients were found to be truly infected with M. ulcerans, 284 (63.3%) were uninfected, while 80 (17.8%) were misidentified as infected or noninfected by the two methods. The data obtained was used to determine the discriminatory accuracy of the f-TLC against the gold standard IS2404 PCR through the analysis of its sensitivity, specificity, positive (+LR), and negative (–LR) likelihood ratio. The positive (PPV) and negative (NPV) predictive values, area under the receiver operating characteristic curve Azevedo et al. (2014), and diagnostic odds ratio were used to assess the predictive accuracy of the f-TLC method. The sensitivity of f-TLC was 66.4% (85/128), specificity was 88.5% (284/321), while the diagnostic accuracy was 82.2% (369/449). The AUC stood at 0.774 while the PPV, NPV, +LR, and–LR were 69.7% (85/122), 86.9% (284/327), 5.76, and 0.38, respectively. The use of the rule-of-thumb interpretation of diagnostic tests suggests that the method is good for use as a diagnostic tool. Conclusions/Significance Larger clinical samples than previously reported had been used to evaluate the f-TLC method for the diagnosis of Buruli ulcer. A sensitivity of 66.4%, a specificity of 88.5%, and diagnostic accuracy of 82.2% were obtained. The method is good for diagnosis and will help in making early clinical decisions about the patients as well as patient management and facilitating treatment decisions. However, it requires a slight modification to address the challenge of background interference and lack of automatic readout to become an excellent diagnostic tool.

We have a long-term vision to develop drug discovery research capacity within Ghana, to tackle unmet medical needs in Ghana and the wider West African region. However, there are several issues and challenges that need to be overcome to enable this vision, including training, human resource, equipment, infrastructure, procurement, and logistics. We discuss these challenges from the context of Ghana in this review. An important development is the universities and research centres within Ghana working together to address some of these challenges. Therefore, while there is a long way to go to fully accomplish our vision, there are encouraging signs.

By means of thin layer chromatography coupled to a fluorescence enhancer, a highly sensitive and operationally simple method to detect the mycolactones stemming from the human pathogen Mycobacterium ulcerans was developed and applied to various sample sources.

Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative targets including vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known about such compounds and their multimodal anticancer properties. A compendium of heterocyclic synthetic and natural product multitarget anticancer compounds, their IC50, and biological targets of inhibition are therefore presented in this review.

The mortality rate of leishmaniasis is increasing at an alarming rate and is currently second to malaria amongst the other neglected tropical diseases. Unfortunately, many governments and key stakeholders are not investing enough in the development of new therapeutic interventions. The available treatment options targeting different pathways of the parasite have seen inefficiencies, drug resistance, and toxic side effects coupled with longer treatment durations. Numerous studies to understand the biochemistry of leishmaniasis and its pathogenesis have identified druggable targets including ornithine decarboxylase, trypanothione reductase, and pteridine reductase, which are relevant for the survival and growth of the parasites. Another plausible target is the sterol biosynthetic pathway; however, this has not been fully investigated. Sterol biosynthesis is essential for the survival of the Leishmania species because its inhibition could lead to the death of the parasites. This review seeks to evaluate how critical the enzymes involved in sterol biosynthetic pathway are to the survival of the leishmania parasite. The review also highlights both synthetic and natural product compounds with their IC50 values against selected enzymes. Finally, recent advancements in drug design strategies targeting the sterol biosynthesis pathway of Leishmania are discussed.

Despite advancements in the areas of omics and chemoinformatics, potent novel biotherapeutic molecules with new modes of actions are needed for leishmaniasis. The socioeconomic burden of leishmaniasis remains alarming in endemic regions. Currently, reports from existing endemic areas such as Nepal, Iran, Brazil, India, Sudan and Afghanistan, as well as newly affected countries such as Peru, Bolivia and Somalia indicate concerns of chemoresistance to the classical antimonial treatment. As a result, effective antileishmanial agents which are safe and affordable are urgently needed. Natural products from both flora and fauna have contributed immensely to chemotherapeutics and serve as vital sources of new chemical agents. This review focuses on a systematic cross-sectional view of all characterized anti-leishmanial compounds from natural sources over the last decade. Furthermore, IC50/EC50, cytotoxicity and suggested mechanisms of action of some of these natural products are provided. The natural product classification includes alkaloids, terpenes, terpenoids, and phenolics. The plethora of reported mechanisms involve calcium channel inhibition, immunomodulation and apoptosis. Making available enriched data pertaining to bioactivity and mechanisms of natural products complement current efforts geared towards unraveling potent leishmanicides of therapeutic relevance.

Background Ghana is endemic for some neglected tropical diseases (NTDs) including schistosomiasis, onchocerciasis and lymphatic filariasis. The major intervention for these diseases is mass drug administration of a few repeatedly recycled drugs which is a cause for major concern due to reduced efficacy of the drugs and the emergence of drug resistance. Evidently, new treatments are needed urgently. Medicinal plants, on the other hand, have a reputable history as important sources of potent therapeutic agents in the treatment of various diseases among African populations, Ghana inclusively, and provide very useful starting points for the discovery of much-needed new or alternative drugs. Methodology/Principal findings In this study, extracts of fifteen traditional medicines used for treating various NTDs in local communities were screened in vitro for efficacy against schistosomiasis, onchocerciasis and African trypanosomiasis. Two extracts, NTD-B4-DCM and NTD-B7-DCM, prepared from traditional medicines used to treat schistosomiasis, displayed the highest activity (IC50 = 30.5 μg/mL and 30.8 μg/mL, respectively) against Schistosoma mansoni adult worms. NTD-B2-DCM, also obtained from an antischistosomal remedy, was the most active against female and male adult Onchocera ochengi worms (IC50 = 76.2 μg/mL and 76.7 μg/mL, respectively). Antitrypanosomal assay of the extracts against Trypanosoma brucei brucei gave the most promising results (IC50 = 5.63 μg/mL to 18.71 μg/mL). Incidentally, NTD-B4-DCM and NTD-B2-DCM, also exhibited the greatest antitrypanosomal activities (IC50 = 5.63 μg/mL and 7.12 μg/mL, respectively). Following the favourable outcome of the antitrypanosomal screening, this assay was selected for bioactivity-guided fractionation. NTD-B4-DCM, the most active extract, was fractionated and subsequent isolation of bioactive constituents led to an eupatoriochromene-rich oil (42.6%) which was 1.3-fold (IC50 <0.0977 μg/mL) more active than the standard antitrypanosomal drug, diminazene aceturate (IC50 = 0.13 μg/mL). Conclusion/Significance These findings justify the use of traditional medicines and demonstrate their prospects towards NTDs drug discovery.