Current Topics in Medicinal Chemistry - Volume 19, Issue 14, 2019

Background: Lymphatic filariasis is one of the chronic diseases in many parts of the tropics and sub-tropics of the world despite the use of standard drugs diethylcarbamazine and ivermectin because they kill microfilaries and not the adult parasites. Therefore, new leads with activity on adult parasites are highly desirable. Objective: Anti-filarial lead optimization by semi-synthetic modification of glycyrrhetinic acid (GA). Methods: The GA was first converted into 3-O-acyl derivative, which was further converted into 12 amide derivatives. All these derivatives were assessed for their antifilarial potential by parasite motility assay. The binding affinity of active GA derivatives on trehalose-6-phosphate phosphatase (Bm-TPP) was assessed by molecular docking studies. Results: Among 15 GA derivatives, GAD-2, GAD-3, and GAD-4 were found more potent than the GA and standard drug DEC. These derivatives reduced the motility of Brugia malayi adult worms by up to 74% while the GA and DEC reduced only up to 49%. Further, GA and most of its derivatives exhibited two times more reduction in MTT assay when compared to the standard drug DEC. These derivatives also showed 100% reduction of microfilariae and good interactions with Bm-TPP protein. Conclusion: The present study suggests that 3-O-acyl and linear chain amide derivatives of glycyrrhetinic acid may be potent leads against B. malayi microfilariae and adult worms. These results might be helpful in developing QSAR model for optimizing a new class of antifilarial lead from a very common, inexpensive, and non toxic natural product.

The significant spread of helminth and protozoan infections, the uncontrolled intake of the known drugs by a large population, the emergence of resistant forms of pathogens have prompted people to search for alternative drugs. In this review, we have focused attention on structures and synthesis of peroxides active against parasites causing neglected tropical diseases and toxoplasmosis. To date, promising active natural, semi-synthetic and synthetic peroxides compounds have been found.

Human lymphatic filariasis (LF), a parasitic infection caused by the nematodes Wuchereria bancrofti, Brugia malayi and B. timori, and transmitted by mosquito, results in a debilitating disease commonly identified as ‘elephantiasis’. LF affects millions of people in India and several other tropical and sub-tropical countries imposing a huge economic burden on governments due to disability associated loss of man-hours and for disease management. Efforts to control the infection by WHO’s mass drug administration (MDA) strategy using three antifilarials diethylcarbamazine, albendazole and ivermectin are only partly successful and therefore, there is an immediate need for alternative strategies. Some of the alternative strategies being explored in laboratories are: enhancing the immune competence of host by immunomodulation, combining immunomodulation with antifilarials, identifying immunoprophylactic parasite molecules (vaccine candidates) and identifying parasite molecules that can be potential drug targets. This review focuses on the advances made in this direction.

Background: Schistosomiasis is a neglected disease, which affects millions of people in developing countries. Its treatment relies on a single therapeutic alternative, the praziquantel. This situation may lead to drug resistance which, in turn, made urgent the need for new antischistosomal agents. Nacylhydrazones are usually explored as good antimicrobial agents, but the vanillin-related N-acylhydrazones have never been tested by their antiparasitic potential. Objective: Herein, we report the synthesis of seven analogues, three of them unpublished, their biological investigation against Schistosoma mansoni and Target Fishing studies. Methods: The compounds were synthesized following classical synthetical approaches. The anthelmintic potential was assessed as well as their cytotoxicity profile. Confocal laser scanning microscopy and target fishing study were performed to better understand the observed antischistosomal activity. Results: Compound GPQF-407 exhibited good antischistosomal activity (47.91 μM) with suitable selectivity index (4.14). Confocal laser scanning microscopy revealed that it triggered severe tegumental destruction and tubercle disintegration. Target fishing studies pointed out some probable targets, such as the serine-threonine kinases, dihydroorotate dehydrogenases and carbonic anhydrase II. Conclusion: The GPQF-407 was revealed to be a promising antischistosomal agent which, besides presenting the N-acylhydrazone privileged scaffold, also could be easily synthesized on large scales from commercially available materials.

Background: Lymphatic filariasis (LF) is a parasitic disease that causes permanent disability (elephantiasis). Currently used antifilarial drugs are failing to control LF and there is resurgence in some areas. Looking for new antifilarial leads, we found that Calotropis procera plant parts have been used in traditional medicine for alleviating elephantiasis but the antifilarial activity is not known. Objective: In the present study, the antifilarial activity of ethanolic extract (A001) and its hexane fraction (F001) of C. procera flowers was investigated using the human filarial parasite Brugia malayi. Methods: A001 and F001 were tested for antifilarial activity using motility and 3-(4,5-dimethylthiazol-2- yl)-2,5 diphenyltetrazolium bromide (MTT) assays (in vitro) and in the rodent models B. malayi- Meriones unguiculatus and B. malayi-Mastomys coucha. In the rodent models, A001 and F001 were administered orally for 5 consecutive days, and the adult worm burden and course of microfilaraemia were determined. Results: Both A001 and F001 showed microfilaricidal and macrofilaricidal activity in vitro. In animal models, A001 killed ~49-54% adult worms. In M. coucha model, F001 killed 12-60% adult worms in a dose (125-500 mg/kg) dependent manner; A001 and F001 suppressed microfilaraemia till days 91 and 35 post initiation of treatment, respectively. HPTLC revealed 0.61% lupeol, 0.50% β-sitosterol and 1.50% triacontanol in F001. Conclusion: Flowers of C. procera have definite microfilaricidal and macrofilaricidal activities. Whether this activity is due to lupeol, β-sitosterol and triacontanol found in the hexane fraction remains to be investigated. This is the first report on the antifilarial efficacy of flowers of the plant C. procera.

Background: Filariasis affects millions of people in tropical and subtropical regions of the world and is caused by nematode roundworm. In order to develop a vaccine and specific diagnostic tests, it is important to characterize different stages of the filarial worms. Microfilariae (Mf) stage of the roundworm is found in host’s blood or lymph vessels and can be important not only for developing better immunodiagnostics but also for understanding immune recognition and its relevance to immunepathogenesis and protective immunity. Objective: The present study aimed to immunocharacterize Mf and adult worm antigens that could be helpful in future diagnostic tests. Methods: Four different immune sera against Setaria cervi intact live, intact live with adjuvant, intact glutaraldehyde fixed with adjuvant and total somatic Mf were prepared and used for the immunocharacterization of Mf antigens. Results: Our study results suggest that compared to fixed intact Mf, live intact Mf are more immunogenic, as the immune sera generated against intact live Mf showed high ELISA reactivity with Setaria cervi Mf and adult worm antigens. All the four immune sera IgG fractions had surface specificity as determined through considerable ELISA reactivity with S. cervi intact Mf. When tested under native conditions (immunoelectrophoresis and crossed immunoelectrophoresis), all the four immune rabbit sera were able to detect antigens of S. cervi Mf and adult stages. Conclusion: These results can be useful in detailed understanding of the complex nature of the Mf and adult antigens, which are prerequisites in the development of vaccine and more specific diagnostic tests.