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  1. Applications of medicinal chemistry for drug discovery against Acanthamoeba infections
    Ahmed U, Anwar A, Ong SK, Anwar A, Khan NA
    Med Res Rev, 2021 Sep 02.
    PMID: 34472107 DOI: 10.1002/med.21851
    Acanthamoeba is a genus of free-living amoebae, pervasively found in the environment. Most of its pathogenic species are the causative agent of sight-threatening Acanthamoeba keratitis and fatal granulomatous amoebic encephalitis. Despite the advancements in the field of chemotherapy, treating Acanthamoeba infections is still challenging due to incomplete knowledge of the complicated pathophysiology. In case of infection, the treatment regimen for the patients is often ineffective due to delayed diagnosis, poor specificity, and side-effects. Besides the resistance of Acanthamoeba cysts to most of the drugs, the recurrence of infection further complicates the recovery. Thus, it is necessary to develop an effective treatment which can eradicate these rare, but serious infections. Based on various computational and in vitro studies, it has been established that the synthetic scaffolds such as heterocyclic compounds may act as potential drug leads for the development of antiamoebic drugs. In this review, we report different classes of synthetic compounds especially heterocyclic compounds which have shown promising results against Acanthamoeba. Moreover, the antiamoebic activities of synthetic compounds with their possible mode of actions against Acanthamoeba, have been summarized and discussed in this review.
  2. Potent antibacterial activity of MXene-functionalized graphene nanocomposites
    Salmi MS, Ahmed U, Aslfattahi N, Rahman S, Hardy JG, Anwar A
    RSC Adv, 2022 Nov 15;12(51):33142-33155.
    PMID: 36425203 DOI: 10.1039/d2ra04944a
    Two dimensional (2D) nanomaterials display properties with significant biological utility (e.g., antimicrobial activity). In this study, MXene-functionalized graphene (FG) nanocomposites with Ti3C2T x in varying ratios (FG : Ti3C2T x , 25 : 75%, 50 : 50%, and 75 : 25%) were prepared and characterized via scanning electron microscopy, scanning electron microscopy-energy dispersive X-ray (SEM-EDX), high-resolution transmission electron microscopy (HRTEM), and zeta potential analysis. Their cytotoxicity was assessed using immortalized human keratinocytes (HaCaT) cells at three different timepoints, and antibacterial activity was assessed using Gram-positive Methicillin resistant Staphylococcus aureus, MRSA, and Gram-negative neuro-pathogenic Escherichia coli K1 (E. coli K1) in vitro. The nanomaterials and composites displayed potent antibacterial effects against both types of bacteria and low cytotoxicity against HaCaT cells at 200 μg mL-1, which is promising for their utilization for biomedical applications.
  3. Comparison of activated carbon and low-cost adsorbents for removal of 2,4-dichlorophenol from wastewater using Aspen Adsorption and response surface methodology
    Yasir HA, Zein SH, Holliday MC, Jabbar KJ, Ahmed U, Jalil AA
    Environ Technol, 2023 Apr 14.
    PMID: 37057364 DOI: 10.1080/09593330.2023.2202829
    AbstractIn this paper, the adsorption of the chlorinated organic compound, 2,4-dichlorophenol, using activated carbon (AC), bagasse fly ash (BFA) and rice husk fly ash (RHFA) in a packed bed column was simulated using Aspen Adsorption software. The purpose of this study was to demonstrate the effectiveness of simulation software for identifying alternative low-cost adsorbents and optimising the adsorption process. The effect of process parameters such as initial concentration, bed height and inlet feed flow rate were evaluated using breakthrough curves. It was shown that the longest breakthrough times were at a higher bed height of 3 m and lower flow rate of 2 m3/hr and concentration had no effect on breakthrough time. After optimisation using response surface methodology, the AC, BFA and RHFA had a breakthrough time of 534 s, 426 s and 209 s, respectively. This shows the potential of BFA as a potential alternative for AC for the adsorption of 2,4-dichlorophenol and shows RHFA to be a relatively poor adsorbent in comparison. The economic evaluation illustrates that the overall cost of wastewater treatment with BFA and RHFA is lower than AC. The cost for the BFA and RHFA adsorbents is only a handling charge, but the cost for using AC adsorbent is £10,603/year. Therefore, the company can produce 17,520 m3/year of fresh water from the adsorbent and save £87,600/year. Therefore, it was concluded that BFA had a slightly weaker adsorption efficiency than AC but was more cost effective, allowing it to be more affordable and increasing its availability.
  4. Natural Terpenes Inhibit the Cytopathogenicity of Naegleria fowleri Causing Primary Amoebic Meningoencephalitis in the Human Cell Line Model
    Rajendran K, Ahmed U, Meunier AC, Shaikh MF, Siddiqui R, Anwar A
    ACS Chem Neurosci, 2023 Dec 06;14(23):4105-4114.
    PMID: 37983556 DOI: 10.1021/acschemneuro.3c00258
    Naegleria fowleri is one of the free-living amoebae and is a causative agent of a lethal and rare central nervous system infection called primary amoebic meningoencephalitis. Despite the advancement in antimicrobial chemotherapy, the fatality rate in the reported cases is more than 95%. Most of the treatment drugs used against N. fowleri infection are repurposed drugs. Therefore, a large number of compounds have been tested against N. fowleri in vitro, but most of the compounds showed high toxicity. To overcome this, we evaluated the effectiveness of naturally occurring terpene compounds against N. fowleri. In this study, we evaluated the antiamoebic potential of natural compounds including Thymol, Borneol, Andrographolide, and Forskolin againstN. fowleri. Thymol showed the highest amoebicidal activity with IC50/24 h at 153.601 ± 19.6 μM. Two combinations of compounds Forskolin + Thymol and Forskolin + Borneol showed a higher effect on the viability of trophozoites as compared to compounds alone and hence showed a synergistic effect. The IC50 reported for Forskolin + Thymol was 81.30 ± 6.86 μM. Borneol showed maximum cysticidal activity with IC50/24 h at 192.605 ± 3.01 μM. Importantly, lactate dehydrogenase release testing revealed that all compounds displayed minimal cytotoxicity to human HaCaT, HeLa, and SH-SY5Y cell lines. The cytopathogenicity assay showed that Thymol and Borneol also significantly reduced the host cell cytotoxicity of pretreated amoeba toward the human HaCaT cell line. So, these terpene compounds hold potential as therapeutic agents against infections caused by N. fowleri and are potentially a step forward in drug development against this deadly pathogen as these compounds have also been reported to cross the blood-brain barrier. Therefore, an in vivo study using animal models is necessary to assess the efficacy of these compounds and the need for further research into the intranasal route of delivery for the treatment of these life-threatening infections.
  5. Fulltext Potential anti-amoebic effects of synthetic 1,4-benzothiazine derivatives against Acanthamoeba castellanii
    Alishba, Ahmed U, Taha M, Khan NA, Salar U, Khan KM, et al.
    Heliyon, 2024 Jan 15;10(1):e23258.
    PMID: 38205285 DOI: 10.1016/j.heliyon.2023.e23258
    A rare but lethal central nervous system disease known as granulomatous amoebic encephalitis (GAE) and potentially blinding Acanthamoeba keratitis are diseases caused by free-living Acanthamoeba. Currently, no therapeutic agent can completely eradicate or prevent GAE. Synthetic compounds are a likely source of bioactive compounds for developing new drugs. This study synthesized seventeen 1,4-benzothiazine derivatives (I -XVII) by a base-catalyzed one-pot reaction of 2-amino thiophenol with substituted bromo acetophenones. Different spectroscopic techniques, such as EI-MS, 1H-, and 13C NMR (only for the new compounds), were used for the structural characterization and conformation of compounds. These compounds were assessed for the first time against Acanthamoeba castellanii. All compounds showed anti-amoebic potential in vitro against A. castellanii, reducing its ability to encyst and excyst at 100 μM. Compounds IX, X, and XVI showed the most potent activities among all derivatives and significantly reduced the viability to 5.3 × 104 (p 
  6. Lactase can target cellular differentiation of Acanthamoeba castellanii belonging to the T4 genotype
    Simau FA, Ahmed U, Khan KM, Khan NA, Siddiqui R, Alharbi AM, et al.
    Parasitol Res, 2024 Jan 31;123(2):117.
    PMID: 38294565 DOI: 10.1007/s00436-024-08131-2
    The free living Acanthamoeba spp. are ubiquitous amoebae associated with potentially blinding disease known as Acanthamoeba keratitis (AK) and a fatal central nervous system infection granulomatous amoebic encephalitis (GAE). With the inherent ability of cellular differentiation, it can phenotypically transform to a dormant cyst form from an active trophozoite form. Acanthamoeba cysts are highly resistant to therapeutic agents as well as contact lens cleaning solutions. One way to tackle drug resistance against Acanthamoeba is by inhibiting the formation of cysts from trophozoites. The biochemical analysis showed that the major component of Acanthamoeba cyst wall is composed of carbohydrate moieties such as galactose and glucose. The disaccharide of galactose and glucose is lactose. In this study, we analyzed the potential of lactase enzyme to target carbohydrate moieties of cyst walls. Amoebicidal assessment showed that lactase was ineffective against trophozoite of A. castellanii but enhanced amoebicidal effects of chlorhexidine. The lactase enzyme did not show any toxicity against normal human keratinocyte cells (HaCaT) at the tested range. Hence, lactase can be used for further assessment for development of potential therapeutic agents in the management of Acanthamoeba infection as well as formulation of effective contact lens disinfectants.
  7. Fulltext Nanoparticle-Terpene Fusion: A Game-Changer in Combating Primary Amoebic Meningoencephalitis Caused by Naegleria fowleri
    Rajendran K, Ahmed U, Meunier AC, Shaikh MF, Siddiqui R, Anwar A
    ACS Omega, 2024 Mar 12;9(10):11597-11607.
    PMID: 38497026 DOI: 10.1021/acsomega.3c08844
    Pathogenic Naegleria fowleri (N. fowleri) are opportunistic free-living amoebae and are the causative agents of a very rare but severe brain infection called primary amoebic meningoencephalitis (PAM). The fatality rate of PAM in reported cases is more than 95%. Most of the drugs used againstN. fowleri infections are repurposed drugs. Therefore, a large number of compounds have been tested againstN. fowleri in vitro, but most of the tested compounds showed high toxicity and an inability to cross the blood-brain barrier. Andrographolide, forskolin, and borneol are important natural compounds that have shown various valuable biological properties. In the present study, the nanoconjugates (AND-AgNPs, BOR-AgNPs, and FOR-AgNPs) of these compounds were synthesized and assessed against both stages (trophozoite and cyst) ofN. fowleri for their antiamoebic and cysticidal potential in vitro. In addition, cytotoxicity and host cell pathogenicity were also evaluated in vitro. FOR-AgNPs were the most potent nanoconjugate and showed potent antiamoebic activity againstN. fowleriwith an IC50 of 26.35 μM. Nanoconjugates FOR-AgNPs, BOR-AgNPs, and AND-AgNPs also significantly inhibit the viability of N. fowleri cysts. Cytotoxicity assessment showed that these nanoconjugates caused minimum damage to human keratinocyte cells (HaCaT cells) at 100 μg/mL, while also effectively reducing the cytopathogenicity of N. fowleri trophozoites to the HaCaT cells. The outcomes of our experiments have unveiled substantial potential for AND-AgNPs, BOR-AgNPs, and FOR-AgNPs in the realm of developing innovative alternative therapeutic agents to combat infections caused by N. fowleri. This study represents a significant step forward in the pursuit of advanced strategies for managing such amoebic infections, laying the foundation for the development of novel and more effective therapeutic modalities in the fight against free-living amoebae.
  8. Metal Oxide Nanoparticles Exhibit Anti-Acanthamoeba castellanii Properties by Inducing Necrotic Cell Death
    Ahmed U, Gew LT, Siddiqui R, Khan NA, Alharbi AM, Alhazmi A, et al.
    Acta Parasitol, 2024 Sep;69(3):1717-1723.
    PMID: 39153011 DOI: 10.1007/s11686-024-00891-2
    PURPOSE: The treatment of amoebic infections is often problematic, largely due to delayed diagnosis, amoebae transformation into resistant cyst form, and lack of availability of effective chemotherapeutic agents. Herein, we determined anti-Acanthamoeba castellanii properties of three metal oxide nanoparticles (TiO2, ZrO2, and Al2O3).

    METHODS: Amoebicidal assays were performed to determine whether metal oxide nanoparticles inhibit amoebae viability. Encystation assays were performed to test whether metal oxide nanoparticles inhibit cyst formation. By measuring lactate dehydrogenase release, cytotoxicity assays were performed to determine human cell damage. Hoechst 33342/PI staining was performed to determine programmed cell death (apoptosis) and necrosis in A. castellanii.

    RESULTS: TiO2-NPs significantly inhibited amoebae viability as observed through amoebicidal assays, as well as inhibited their phenotypic transformation as evident using encystation assays, and showed limited human cell damage as observed by measuring lactate dehydrogenase assays. Furthermore, TiO2-NPs altered parasite membranes and resulted in necrotic cell death as determined using double staining cell death assays with Hoechst33342/Propidium iodide (PI) observed through chromatin condensation. These findings suggest that TiO2-NPs offers a potential viable avenue in the rationale development of therapeutic interventions against Acanthamoeba infections.

  9. Anti-amoebic effects of synthetic acridine-9(10H)-one against brain-eating amoebae
    Ahmed U, Manzoor M, Qureshi S, Mazhar M, Fatima A, Aurangzeb S, et al.
    Acta Trop, 2023 Mar;239:106824.
    PMID: 36610529 DOI: 10.1016/j.actatropica.2023.106824
    Pathogenic A. castellanii and N. fowleri are opportunistic free-living amoebae. Acanthamoeba spp. are the causative agents of granulomatous amebic encephalitis (GAE) and amebic keratitis (AK), whereas Naegleria fowleri causes a very rare but severe brain infection called primary amebic meningoencephalitis (PAM). Acridinone is an important heterocyclic scaffold and both synthetic and naturally occurring derivatives have shown various valuable biological properties. In the present study, ten synthetic Acridinone derivatives (I-X) were synthesized and assessed against both amoebae for anti-amoebic and cysticidal activities in vitro. In addition, excystation, encystation, cytotoxicity, host cell pathogenicity was also performed in-vitro. Furthermore, molecular docking studies of these compounds with three cathepsin B paralogous enzymes of N. fowleri were performed in order to predict the possible docking mode with pathogen. Compound VII showed potent anti-amoebic activity against A. castellanii with IC50 53.46 µg/mL, while compound IX showed strong activity against N. fowleri in vitro with IC50 72.41 µg/mL. Compounds II and VII showed a significant inhibition of phenotypic alteration of A. castellanii, while compound VIII significantly inhibited N. fowleri cysts. Cytotoxicity assessment showed that these compounds caused minimum damage to human keratinocyte cells (HaCaT cells) at 100 µg/mL, while also effectively reduced the cytopathogenicity of Acanthamoeba to HaCaT cells. Moreover, Cathepsin B protease was investigated in-silico as a new molecular therapeutic target for these compounds. All compounds showed potential interactions with the catalytic residues. These results showed that acridine-9(10H)-one derivatives, in particular compounds II, VII, VIII and IX hold promise in the development of therapeutic agents against these free-living amoebae.
  10. Malabaricones from the fruit of Myristica cinnamomea King as potential agents against Acanthamoeba castellanii
    Ahmed U, Sivasothy Y, Khan KM, Khan NA, Wahab SMA, Awang K, et al.
    Acta Trop, 2023 Dec;248:107033.
    PMID: 37783284 DOI: 10.1016/j.actatropica.2023.107033
    Acanthamoeba castellanii is an opportunistic free-living amoeba (FLA) pathogen which can cause fatal central nervous system (CNS) infection, granulomatous amoebic encephalitis (GAE) and potentially blinding ocular infection, Acanthamoeba keratitis (AK). Acanthamoeba species remain a challenging protist to treat due to the unavailability of safe and effective therapeutic drugs and their ability to protect themselves in the cyst stage. Natural products and their secondary metabolites play a pivotal role in drug discovery against various pathogenic microorganisms. In the present study, the ethyl acetate extract of Myristica cinnamomea King fruit was evaluated against A. castellanii (ATCC 50492), showing an IC50 of 45.102 ± 4.62 µg/mL. Previously, the bio-guided fractionation of the extract resulted in the identification of three active compounds, namely Malabaricones (A-C). The isolated and thoroughly characterized acylphenols were evaluated for their anti-amoebic activity against A. castellanii for the first time. Among tested compounds, Malabaricone B (IC50 of 101.31 ± 17.41 µM) and Malabaricone C (IC50 of 49.95 ± 6.33 µM) showed potent anti-amoebic activity against A. castellanii trophozoites and reduced their viability up-to 75 and 80 %, respectively. Moreover, both extract and Malabaricones also significantly (p < 0.05) inhibit the encystation and excystation of A. castellanii, while showed minimal toxicity against human keratinocyte cells (HaCaT cells) at lower tested concentrations. Following that, the explanation of the possible mechanism of action of purified compounds were assessed by detection of the state of chromatin. Hoechst/PI 33342 double staining showed that necrotic cell death occurred in A. castellanii trophozoites after 8 h treatment of Malabaricones (A-C). These findings demonstrate that Malabaricones B and C could serve as promising therapeutic options against A. castellanii infections.
  11. Alpha-Mangostin and its nano-conjugates induced programmed cell death in Acanthamoeba castellanii belonging to the T4 genotype
    Ahmed U, Ong SK, Tan KO, Khan KM, Khan NA, Siddiqui R, et al.
    Int Microbiol, 2023 Nov 28.
    PMID: 38015290 DOI: 10.1007/s10123-023-00450-1
    Acanthamoeba are free living amoebae that are the causative agent of keratitis and granulomatous amoebic encephalitis. Alpha-Mangostin (AMS) is a significant xanthone; that demonstrates a wide range of biological activities. Here, the anti-amoebic activity of α-Mangostin and its silver nano conjugates (AMS-AgNPs) were evaluated against pathogenic A. castellanii trophozoites and cysts in vitro. Amoebicidal assays showed that both AMS and AMS-AgNPs inhibited the viability of A. castellanii dose-dependently, with an IC50 of 88.5 ± 2.04 and 20.2 ± 2.17 μM, respectively. Both formulations inhibited A. castellanii-mediated human keratinocyte cell cytopathogenicity. Functional assays showed that both samples caused apoptosis through the mitochondrial pathway and reduced mitochondrial membrane potential and ATP production, while increasing reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) cytochrome-c reductase in the cytosol. Whole transcriptome sequencing of A. castellanii showed the expression of 826 genes, with 447 genes being up-regulated and 379 genes being down-regulated post treatment. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the majority of genes were linked to apoptosis, autophagy, RAP1, AGE-RAGE and oxytocin signalling pathways. Seven genes (PTEN, H3, ARIH1, SDR16C5, PFN, glnA GLUL, and SRX1) were identified as the most significant (Log2 (FC) value 4) for molecular mode of action in vitro. Future in vivo studies with AMS and nanoconjugates are needed to realize the clinical potential of this work.
  12. Self-assembled micelles loaded with itraconazole as anti-Acanthamoeba nano-formulation
    Rao K, Abdullah M, Ahmed U, Wehelie HI, Shah MR, Siddiqui R, et al.
    Arch Microbiol, 2024 Mar 04;206(4):134.
    PMID: 38433145 DOI: 10.1007/s00203-024-03854-3
    Acanthamoeba castellanii are opportunistic pathogens known to cause infection of the central nervous system termed: granulomatous amoebic encephalitis, that mostly effects immunocompromised individuals, and a sight threatening keratitis, known as Acanthamoeba keratitis, which mostly affects contact lens wearers. The current treatment available is problematic, and is toxic. Herein, an amphiphilic star polymer with AB2 miktoarms [A = hydrophobic poly(ℇ-Caprolacton) and B = hydrophilic poly (ethylene glycol)] was synthesized by ring opening polymerization and CuI catalyzed azide-alkyne cycloaddition. Characterization by 1H and 13C NMR spectroscopy, size-exclusion chromatography and fluorescence spectroscopy was accomplished. The hydrophobic drug itraconazole (ITZ) was incorporated in self-assembled micellar structure of AB2 miktoarms through co-solvent evaporation. The properties of ITZ loaded (ITZ-PCL-PEG2) and blank micelles (PCL-PEG2) were investigated through zeta sizer, scanning electron microscopy and Fourier-transform infrared spectroscopy. Itraconazole alone (ITZ), polymer (DPB-PCL), empty polymeric micelles (PCL-PEG2) alone, and itraconazole loaded in polymeric micelles (ITZ-PCL-PEG2) were tested for anti-amoebic potential against Acanthamoeba, and the cytotoxicity on human cells were determined. The polymer was able to self-assemble in aqueous conditions and exhibited low value for critical micelle concentration (CMC) 0.05-0.06 µg/mL. The maximum entrapment efficiency of ITZ was 68%. Of note, ITZ, DPB, PCL-PEG2 and ITZ-PCL-PEG2 inhibited amoebae trophozoites by 37.34%, 36.30%, 35.77%, and 68.24%, respectively, as compared to controls. Moreover, ITZ-PCL-PEG2 revealed limited cytotoxicity against human keratinocyte cells. These results are indicative that ITZ-PCL-PEG2 micelle show significantly better anti-amoebic effects as compared to ITZ alone and thus should be investigated further in vivo to determine its clinical potential.
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