Department of Pharmacy

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Subject: search.filters.subject.Antimalarial

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Now showing 1 - 6 of 6
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    Pyrazole-pyrazoline as promising novel antimalarial agents: a mechanistic study
    (Elsevier, 2018-04) Kumar, Gautam
    A series of pyrazole-pyrazoline substituted with benzenesulfonamide were synthesized and evaluated for their antimalarial activity in vitro and in vivo. The compounds were active against both chloroquine (CQ) sensitive (3D7) and CQ resistant (RKL-9) strains of Plasmodium falciparum. Seven compounds (7e, 7i, 7j, 7l, 7m, 7o and 7p) exhibiting EC50 less than 2 μM. A mechanistic study of compound 7o revealed that these compound act through the inhibition of β-hematin. The study indicated that these compounds can serve as lead compounds for further development of potent antimalarial drugs.
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    Plants from Annonaceae family as antimalarials: An ethnopharmacology and phytochemistry review to identify potential lead molecules
    (Elsevier, 2023-04) Sundriyal, Sandeep
    Malaria is a life-threatening infectious disease, which affected more than 247 million people worldwide in 2021, causing close to 619,000 deaths. WHO recommends region-specific combination therapies based on the susceptibility of the parasite as the standard treatment for P. falciparum malaria. In recent years, the primary cause of concern is the upsurge of resistance against almost all clinically used antimalarial drugs. Herbal medicines have been reported to be therapeutically effective and have played an important role in the treatment of malaria since time immemorial. The discovery of quinine from the cinchona tree's bark and artemisinin from Artemisia annua L. are the leading examples of bioactive compounds used in modern medicine identified from plant-based traditional medicines. Several plants from the Annonaceae family are used traditionally as antimalarials in different parts of the world endemic to malaria.
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    Recent trends in the design of antimicrobial agents using Ugi-multicomponent reaction
    (Elsevier, 2021-08) Sundriyal, Sandeep
    Multi-drug resistant (MDR) forms of several bacteria, fungi, viruses, and parasites pose a serious challenge to human health and economy. Hence, the rise of antimicrobial resistance (AMR) requires the expedient discovery of novel antimicrobial agents with a unique mode of action. Ugi multicomponent reaction (Ugi-MCR) and its variants have proved to be an important tool in the hand of a medicinal chemist. Traditional Ugi reaction provides one-step access to peptide-like molecules. However, several modifications of Ugi products are now available, enabling the design of diverse molecular scaffolds. This has tremendously expanded the scope of Ugi-MCR in drug discovery. This review focuses on the recently reported application of Ugi reaction in the design of molecules against important pathogenic microbes and parasites. The design, synthesis, and bioactivities of important lead molecules from the literature is discussed. Towards the end, we also provide our perspective highlighting the overall trends in Ugi-MCR enabled antimicrobial drug design and future prospects.
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    Non-hydroxamate inhibitors of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR): A critical review and future perspective
    (Elsevier, 2021-03) Sundriyal, Sandeep
    1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) catalyzes the second step of the non-mevalonate (or MEP) pathway that functions in several organisms and plants for the synthesis of isoprenoids. DXR is essential for the survival of multiple pathogenic bacteria/parasites, including those that cause tuberculosis and malaria in humans. DXR function is inhibited by fosmidomycin (1), a natural product, which forms a chelate with the active site divalent metal (Mg2+/Mn2+) through its hydroxamate metal-binding group (MBG). Most of the potent DXR inhibitors are structurally similar to 1 and retain hydroxamate despite the unfavourable pharmacokinetic and toxicity profile of the latter. We provide our perspective on the lack of non-hydroxamate DXR inhibitors. We also highlight the fundamental flaws in the design of MBG in these molecules, primarily responsible for their failure to inhibit DXR. We also suggest that for designing next-generation non-hydroxamate DXR inhibitors, approaches followed for other metalloenzymes targets may be exploited.
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    Evaluation of Pharmacokinetics, Biodistribution, and Antimalarial Efficacy of Artemether-Loaded Polymeric Nanorods
    (ACS, 2023) Jindal, Anil B.
    Artemether oily injection is recommended for the treatment of severe malaria by the intramuscular route. The major limitations of the artemisinin combination therapy are erratic absorption from the injection site and high dosing frequency due to a very short elimination half-life of the drug. Advanced drug delivery systems have shown significant improvement in the current malaria therapy; the desired drug concentration within infected erythrocytes is yet the major challenge. Recently, we have reported the fabrication of artemether-loaded polymeric nanorods for intravenous malaria therapy which was found to be biocompatible with THP-1 monocytes and rat erythrocytes. The objective of the present study was the evaluation of pharmacokinetics, biodistribution, and antimalarial efficacy of artemether-loaded polymeric nanorods. Scanning electron microscopy and confocal microscopy studies revealed that both nanospheres and nanorods were adsorbed onto the surface of rat erythrocytes after an incubation of 10 min. After intravenous administration to rats, artemether nanorods showed higher plasma concentration and lower elimination rate of artemether when compared with nanospheres. The biodistribution studies showed that, at 30 min, the liver concentration of DiR-loaded nanospheres was higher than that of DiR-loaded nanorods after intravenous administration to BALB/c mice. The in vitro schizont inhibition study showed that both nanorods and nanospheres exhibited concentration-dependent parasitic inhibition, wherein at lower concentrations (2 ppm), nanorods were more effective than nanospheres. However, at higher concentrations, nanospheres were found to be more effective. Nanorods showed higher chemosuppression on day 5 and day 7 than nanospheres and free artemether when studied with the Plasmodium berghei mouse model. Moreover, the survival rate of P. berghei infected mice was also found to be higher after treatment with artemether nanoformulations when compared with free artemether. In conclusion, polymeric nanorods could be a promising next-generation delivery system for the treatment of malaria.
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    Insignificant in vitro falcipain‑2 inhibitory activity of novel 2‑(4‑(substituted benzoyl) piperazine‑1‑yl)‑N‑phenylacetamide derivatives
    (2015) Mahesh, R.
    The cysteine protease, falcipain‑2 (FP‑2) is an important drug target for the management of infection by the human malaria parasite Plasmodium falciparum. The rapid emergence of resistance is the main problem with all antimalarial agents. Hence, the discovery of novel, effective drugs to counter the spread of malaria parasites that are resistant toward existing agents, especially drugs that can act on new targets, is urgently necessary. Materials and Methods: A novel series of 2‑(4‑(substituted benzoyl) piperazine‑1‑yl)‑N‑phenylacetamide derivatives was designed using the ligand‑based approach, employing a three‑point pharmacophore model. It consists of an aromatic group (monocyclic/bicyclic), which is attached to the hydrophobic moiety; commonly an aromatic residue through hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) atom(s) acting as the linker. The new chemical entities were synthesized from the key intermediate N‑phenyl‑2‑(piperazine‑1‑yl) acetamide, by coupling it with various substituted acids in the presence of 1‑(3‑dimethylaminopropyl)‑3‑ethylcarbodiimide hydrochloride (EDC.HCl) and 1 hydroxybenzotriazole (HOBt). The obtained compounds’ structures were confirmed by 1H NMR and by mass spectral data. Results: All the synthesized compounds were evaluated for their in vitro FP‑2 inhibitory activity. Two compounds 5l and 5q showed very weak enzyme inhibition activities (3‑5%) and the remaining 15 compounds showed no inhibition at 10 μm concentrations. However, unlike other reported FP‑2 inhibitors, none of these molecules showed potent activity. Conclusion: This series of compounds did not have or had very less antimalarial activity. Key words: Antimalarial, falcipain‑2 (FP‑2), ligand‑based drug design