Plant derived therapeutics for the treatment of Leishmaniasis

Diseases caused by insect borne trypanosomatid parasites are significant, yet remain a neglected public health problem. Leishmania, a unicellular protozoan parasite is the causative organism of Leishmaniasis and is transmitted by female phlebotamine sandflies affecting millions of people worldwide. In the wake of resistance to pentavalent antimonial drugs, new therapeutic alternatives are desirable. The plant kingdom has in the past provided several affordable compounds and this review aims to provide an overview of the current status of available leishmanicidal plant derived compounds that are effective singly or in combination with conventional anti-leishmanial drugs, yet are non toxic to mammalian host cells. Furthermore, delineation of the contributory biochemical mechanisms involved in mediating their effect would help develop new chemotherapeutic approaches.     

Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH₂O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC₅₀ value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.     

Antileishmanial evaluation of clubbed bis(indolyl)-pyridine derivatives: One-pot synthesis,in vitro biological evaluations and in silico ADME prediction

A new series of bis(indolyl)-pyridine derivatives 6(a–m) were synthesized by Chichibabin reaction process and evaluated for antileishmanial and antibacterial activities to establish structure–activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, and ammonium acetate in the presence of camphor-10-sulfonic acid as a catalyst. The compounds 6d (IC₅₀ = 102.47 μM) and 6f (IC₅₀ = 99.49 μM) had shown promising antileishmanial against L. donovani promastigotes when compared with standard sodium stibogluconate (IC₅₀ = 490.00 μM). All the synthesized compounds (MIC range = 41.35–228.69 μg/mL) had shown potent antibacterial activity than standard ampicillin (MIC range = 100.00–250.00 μg/mL) against all the tested bacterial strains. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives.     

Synthesis and systemic toxicity assessment of quinine-triazole scaffold with antiprotozoal potency

A series of hybrid antiprotozoal compounds with quinine-triazolyl scaffold were prepared by copper catalyzed Huisgen 1,3-dipolar cycloaddition via O-mesylation with mesyl chloride followed by azide displacement. The synthesized azide derivative was made to react with various aromatic and aliphatic alkynes. The triazolyl-linked quinine scaffolds were synthesized under solvent-free mechanochemical ball milling conditions. Products (6a-s) were screened for in-vitro antimalarial and antileishmanial activity. Screening results indicated that out of the synthesized series of 19 products, compounds 6d, 6h, 6l, 6m, and 6n showed significant antimalarial (P. falciparum) and antileishmanial activities (L. donavani) with IC₅₀ values 0.28, 0.28, 0.25, 0.33, 0.76 µM and 8.26, 4.4, 1.78, 3.95, and 4.06 µM, respectively. Further toxicological analysis established the Median lethal dose (LD₅₀), No observed adverse effect level (NOAEL) and human equivalent dose (HED) of the most potent compounds by acute and sub acute toxicity studies performed in rodent animal model. The studies revealed that compounds (6d, 6h, 6l and 6m) did not reveal any toxic manifestation at dose 1000 mg/Kg and from which the corresponding HED was calculated to be 13.84 mg/kg.     

New antileishmanial sesquiterpene coumarins from Ferula narthex Boiss

Two new sesquiterpene coumarins, fnarthexone (1) and fnarthexol (2), along with three known coumarin derivatives, conferol (3), conferone (4) and umbelliferone (5), were isolated from the plant Ferula narthex Boiss. The structures of the compounds 1–5 were elucidated using modern spectroscopic techniques. The structure of compound 3 was unambiguously deduced by the single-crystal X-ray diffraction technique. Compounds 1–4 were tested for in vitro leishmanicidal activity and promising results were obtained. Conferol (3) was found to be the most potent with IC₅₀ value of 11.51 ± 0.09 μg/mL.     

Essential‐Oil Composition,Antileishmanial, and Toxicity Study of Artemisia abyssinica and Satureja punctata ssp. punctata from Ethiopia

Essential oils of Artemisia abyssinica and Satureja punctata ssp. punctata from Ethiopia were analyzed by GC and GC/MS, and screened for leishmanicidal activity against promastigote and axenic amastigotes of Leishmania donovani and L. aethiopica, including toxicity studies on human monocytic leukemia cells (THP‐1) and erythrocytes in vitro. GC/MS of A. abyssinica oil revealed 67 compounds (99.94%) with the major constituents yomogi alcohol (38.47%), artemisyl acetate (24.88%), and artemisia alcohol (6.70%), and oxygenated monoterpenes (84.00%) as the dominant group. The oil of S. punctata contained 67 compounds (99.49%) with the main constituents geranial (27.62%), neral (21.72%), α‐bisabolol (13.62%), and (E)‐nerolidol (4.82%), of which oxygenated mono‐ and sesquiterpenes (58.39 and 26.91%, resp.) showed highest abundance. Both oils showed effect on promastigotes (MIC 76.5 to 312.5 nl/ml) and amastigotes (EC₅₀ 4.06 to 131.00 nl/ml) of L. donovani and L. aethiopica, and varying toxicities on THP‐1 cells (CC₅₀ 0.013 to 350 nl/ml with selectivity index between 0.001 and 28) and erythrocytes (with LC₅₀ 0.35 to 1.52 μl/ml). S. punctata oil exerted highest activity against both Leishmania sp. and toxicity. The revealed antileishmanial activities support further isolation and investigation of oil constituents for in vitro/in vivo evaluation.     

Leishmania donovani pteridine reductase 1: biochemical properties and structure-modeling studies

Pteridine reductase 1 (PTR1, EC 1.5.1.33) is a NADPH dependent short-chain reductase (SDR) responsible for the salvage of pterins in the protozoan parasite Leishmania. This enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Based on homology model drawn on recombinant pteridine reductase isolated from a clinical isolate of L. donovani, we carried out molecular modeling and docking studies with two compounds of dihydrofolate reductase specificity showing promising antileishmanial activity in vitro. Both the inhibitors appeared to fit well in the active pocket revealing the tight binding of the carboxylic acid ethyl ester group of pyridine moiety to pteridine reductase and identify the important interactions necessary to assist the structure based development of novel pteridine reductase inhibitors.     

Rothmanniamide and other constituents from the leaves of Rothmannia hispida (K.Schum.) fagerl. (Rubiaceae) and their chemophenetic significance

The chemical investigation of the CH₂Cl₂/MeOH (1:1) extract of the leaves of Rothmannia hispida (K. Schum.) Fagerl. (Rubiaceae) led to the isolation of a new ceramide rothmanniamide (1) and a naturally isolated alkyl cinnamate derivative n-heptadecyl-4-hydroxy-trans-cinnamate (2), along with fifteen known compounds including lupeol palmitate (3), lupeol (4), a mixture of uvaol (5) and erythrodiol (6), ursolic acid (7), 30-nor-2α,3β-dihydroxyurs-12-ene (8), hederagenin (9), stigmast-22-en-3-ol (10), a mixture of β-sitosterol (11) and stigmasterol (12), stigmast-4,22-dien-3-ol (13), stigmasterol 3-O-β-D-glucoside (14), triacontan-1-ol (15), kaempferol 3-O-β-D-glucopyranoside (16) and D-mannitol (17). Their structures were elucidated with the help of MS and NMR data. Compounds 8, 10 and 15 were isolated for the first time from the Rubiaceae family. The crude extract and the isolates were assessed in vitro for their antileishmanial activity against Leishmania donovani 1 S (MHOM/SD/62/1 S) promastigotes and cytotoxicity on RAW 264.7 macrophage cells. Compounds 7 and 8 exhibited a highly potent antileishmanial activity with IC₅₀ values of 0.88 and 1.75 μg/mL, respectively, with good selectivity indexes (SI > 57). The chemophenetic significance of these compounds is also discussed.     

Synthesis of 2-methoxybenzoylhydrazone and evaluation of their antileishmanial activity

Compounds 1–25 showed varying degree of antileishmanial activities with IC₅₀ values ranging between 1.95 and 88.56 μM. Compounds 2, 10, and 11 (IC₅₀ = 3.29 ± 0.07 μM, 1.95 ± 0.04 μM, and 2.49 ± 0.03 μM, respectively) were found to be more active than standard pentamidine (IC₅₀ = 5.09 ± 0.04 μM). Compounds 7 (IC₅₀ = 7.64 ± 0.1 μM), 8 (IC₅₀ = 13.17 ± 0.46 μM), 18 (IC₅₀ = 13.15 ± 0.02 μM), and 24 (IC₅₀ = 15.65 ± 0.41 μM) exhibited good activities. Compounds 1, 3, 4, 5, 9, 12, 15, 18, and 19 were found to be moderately active. Compounds 13, 14, 16, 17, 20–25 showed weak activities with IC₅₀ values ranging between 57 and 88 μM.     

Synthesis and activity of novel tetrazole compounds and their pyrazole-4-carbonitrile precursors against Leishmania spp

A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a–m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a–m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity of these compounds was evaluated on the RAW 264.7 cell line. The results showed that among the assayed compounds the substituted 3-chlorophenyl (4a) (IC₅₀/24 h = 15 ± 0.14 μM) and 3,4-dichlorophenyl tetrazoles (4d) (IC₅₀/24 h = 26 ± 0.09 μM) were the most potent against L. braziliensis promastigotes, as compared the reference drug pentamidine, which presented IC₅₀ = 13 ± 0.04 μM. In addition, 4a and 4d derivatives were less cytotoxic than pentamidine. However, these tetrazole derivatives (4) and pyrazole-4-carbonitriles precursors (3) differ against each of the tested species and were more effective against L.braziliensis than on L. amazonensis.