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Öğe Anti-amoebic activity of a series of benzofuran/benzothiophene derivatives against acanthamoeba castellanii belonging to the T4 genotype(2022) Akbar, Noor; El-Gamal, Mohammed, I; Zaraei, Seyed-Omar; Saeed, Balsam Qubais; Khan, Naveed Ahmed; Siddiqui, RuqaiyyahAims: To determine the anti-amoebic activity of benzofuran/benzothiophene-possessing compounds against Acanthamoeba castellanii of the T4 genotype. Method and results: A series of benzofuran/benzothiophene-possessing compounds were tested for their anti-amoebic activities, in particular, to block encystation and excystation processes in amoebae. Cytotoxicity of the compounds were evaluated using lactate dehydrogenase (LDH) assays. The amoebicidal assay results revealed significant anti-amoebic effects against A. castellanii. Compounds 1p and 1e showed the highest amoebicidal activity, eliminating 68% and 64% of the amoebae, respectively. These compounds remarkably repressed both the encystation and excystation processes in A. castellanii. Furthermore, the selected compounds presented minimal cytotoxic properties against human cells, as well as considerably abridged amoeba-mediated cytopathogenicity when compared to the amoebae alone. Conclusions: Our findings show that benzofuran/benzothiophene derivatives depict potent anti-amoebic activities; thus these compounds should be used as promising and novel agents in the rationale development of therapeutic strategies against Acanthamoeba infections.Öğe The anti-amoebic potential of carboxamide derivatives containing sulfonyl or sulfamoyl moieties against brain-eating Naegleria fowleri(Springer, 2023) Akbar, Noor; Siddiqui, Ruqaiyyah; El-Gamal, Mohammed I.; Zaraei, Seyed-Omar; Alawfi, Bader S.; Khan, Naveed AhmedNaegleria fowleri is a free-living thermophilic flagellate amoeba that causes a rare but life-threatening infection called primary amoebic meningoencephalitis (PAM), with a very high fatality rate. Herein, the anti-amoebic potential of carboxamide derivatives possessing sulfonyl or sulfamoyl moiety was assessed against pathogenic N. fowleri using amoebicidal, cytotoxicity and cytopathogenicity assays. The results from amoebicidal experiments showed that derivatives dramatically reduced N. fowleri viability. Selected derivatives demonstrated IC50 values at lower concentrations; 1j showed IC50 at 24.65 mu M, while 1k inhibited 50% amoebae growth at 23.31 mu M. Compounds with significant amoebicidal effects demonstrated limited cytotoxicity against human cerebral microvascular endothelial cells. Finally, some derivatives mitigated N. fowleri-instigated host cell death. Ultimately, this study demonstrated that 1j and 1k exhibited potent anti-amoebic activity and ought to be looked at in future studies for the development of therapeutic anti-amoebic pharmaceuticals. Further investigation is required to determine the clinical relevance of our findings.Öğe Novel Anti-Acanthamoebic Activities of Irosustat and STX140 and Their Nanoformulations(Mdpi, 2023) Siddiqui, Ruqaiyyah; Rawas-Qalaji, Mutasem; El-Gamal, Mohammed I.; Sajeev, Sreedevi; Jagal, Jayalakshmi; Zaraei, Seyed-Omar; Sbenati, Rawan M.Pathogenic Acanthamoeba produce keratitis and fatal granulomatous amoebic encephalitis. Treatment remains problematic and often ineffective, suggesting the need for the discovery of novel compounds. For the first time, here we evaluated the effects of the anticancer drugs Irosustat and STX140 alone, as well as their nanoformulations, against A. castellanii via amoebicidal, excystment, cytopathogenicity, and cytotoxicity assays. Nanoformulations of the compounds were successfully synthesized with high encapsulation efficiency of 94% and 82% for Irosustat and STX140, respectively. Nanoparticles formed were spherical in shape and had a unimodal narrow particle size distribution, mean of 145 and 244 nm with a polydispersity index of 0.3, and surface charge of -14 and -15 mV, respectively. Irosustat and STX140 exhibited a biphasic release profile with almost 100% drug released after 48 h. Notably, Irosustat significantly inhibited A. castellanii viability and amoebae-mediated cytopathogenicity and inhibited the phenotypic transformation of amoebae cysts into the trophozoite form, however their nanoformulations depicted limited effects against amoebae but exhibited minimal cytotoxicity when tested against human cells using lactate dehydrogenase release assays. Accordingly, both compounds have potential for further studies, with the hope of discovering novel anti-Acanthamoeba compounds, and potentially developing targeted therapy against infections of the central nervous system.Öğe Novel anti-Acanthamoebic properties of raloxifene sulfonate/sulfamate derivatives(Elsevier, 2023) Siddiqui, Ruqaiyyah; El-Gamal, Mohammed I.; Sajeev, Sreedevi; Zaraei, Seyed-Omar; Khan, Naveed AhmedAcanthamoeba are known to cause a vision threatening eye infection typically due to contact lens wear, and an infection of the central nervous system. The ability of these amoebae to switch phenotypes, from an active trophozoite to a resistant cyst form is not well understood; the cyst stage is often resistant to chemotherapy, which is of concern given the rise of contact lens use and the ineffective disinfectants available, versus the cyst stage. Herein, for the first time, a range of raloxifene sulfonate/sulfamate derivatives which target nucleotide pyrophosphatase/phosphodiesterase enzymes, were assessed using amoebicidal and excystation tests versus the trophozoite and cyst stage of Acanthamoeba. Moreover, the potential for cytopathogenicity inhibition in amoebae was assessed. Each of the derivatives showed considerable anti-amoebic activity as well as the ability to suppress phenotypic switching (except for compound 1a). Selected raloxifene derivatives reduced Acanthamoeba-medi-ated host cell damage using lactate dehydrogenase assay. These findings suggest that pyrophosphatase/phosphodiesterase enzymes may be valuable targets against Acanthamoeba infections.Öğe Potential anti-amoebic activity of sulfonate- and sulfamate-containing carboxamide derivatives against pathogenic Acanthamoeba castellanii belonging to the genotype T4(Elsevier Ireland Ltd, 2024) Akbar, Noor; Siddiqui, Ruqaiyyah; El-Gamal, Mohammed I.; Zaraei, Seyed-Omar; Saeed, Balsam Qubais; Alawfi, Bader Saleem; Khan, Naveed AhmedAcanthamoeba are ubiquitously distributed in the environment and can cause infection of the central nervous system as well a sight-threatening eye infection. Herein, the potential anti-amoebic activity of a series of sulfonate/sulfamate derivatives against pathogenic A. castellanii was evaluated. These compounds were tested using several assays namely amoebicidal, adhesion, excystation, cytotoxic, and cytopathogenicity. Amoebicidal assays revealed that the selected compounds reduced amoebae viability significantly (P < 0.05), and exhibited IC50 values at two-digit micromolar concentrations. Sulfamate derivatives 1j & 1k inhibited 50% of amoebae at 30.65 mu M and 27.21 mu M, respectively. The tested compounds blocked amoebae binding to host cells as well as inhibited amoebae excystation. Notably, the selected derivatives exhibited minimal human cell cytotoxicity but reduced parasite-mediated host cell damage. Overall, our study showed that sulfamate derivatives 1j & 1k have anti-amoebic potential and offer a promising avenue in the development of potential anti-amoebic drug candidates.
