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The development of resistance to conventional antimalarial therapies, along with the unfavorable impact of the COVID-19 pandemic on the global malaria fight, necessitates a greater focus on the search for more effective antimalarial drugs. Targeting a specific enzyme of the malaria parasite to alter its metabolic pathways is a reliable technique for finding antimalarial drug candidates. In this study, we used an in silico technique to test four novel imidazoles and an oxazole derivative for inhibitory potential against Plasmodium lactate dehydrogenase (pLDH), a unique glycolytic enzyme necessary for parasite survival and energy production. The promising imidazole compounds and the oxazole derivative were then tested for anti-plasmodial efficacy in Plasmodium berghei -infected mice. With a binding energy of -6.593 kcal/mol, IM-3 had the best docking score against pLDH, which is close to that of NADH (-6.758 kcal/mol) and greater than that of chloroquine (-3.917 kcal/mol). The test compounds occupied the enzyme's NADH binding site, with IM-3 forming four hydrogen bonds with Thr-101, Pro-246, His-195 and Asn-140. Infected mice treatment with IM-3, IM-4 and OX-1 exhibited significantly reduced parasitemia over a four-day treatment period when compared to the infected untreated animals. At 5, 10 and 20 mg/kg, IM-3 demonstrated the highest anti-plasmodial activity, suppressing parasitemia by 86.13, 97.71 and 94.11%, respectively. PCV levels were restored by IM-3 and IM-4, and the three selected compounds reduced the lipid peroxidation induced by P. berghei infection in mice. Thus, these compounds may be considered for further development as antimalarial medicines.Communicated by Ramaswamy H. Sarma.

Background: Therapeutic options for toxoplasmosis are limited. This fact underscores ongoing research efforts to identify and develop better therapy. Previously, we reported the anti-parasitic potential of a new series of derivatives of imidazole., Objective: In the current investigation, we attempted the investigation of the possible action mechanism of few promising anti-parasite imidazole derivatives namely C1 (bis-imidazole), C2 (phenyl-substituted 1H-imidazole) and C3 (thiophene-imidazole) METHODS: We evaluated if oxidative stress, hypoxia as well as metabolic reprogramming of host l-tryptophan pathway form part of the parasite growth inhibition by imidazoles. Anti-parasite assay was performed for imidazoles at concentrations ranging from 0 to 10 μM, while pyrimethamine was used as reference drug to validate assay., Results: Imidazole compounds restricted parasite growth dose-dependently. However, in the presence of an antioxidant (Trolox), l-tryptophan and/or CoCl 2 (chemical inducer of hypoxia), the growth inhibitory efficacy of imidazoles was appreciably abolished. Further, imidazole treatment led to elevated level of reactive oxygen species, while reducing parasite mitochondrial membrane potential compared with control. In contrast, imidazole had no effect on host HIF-1α level suggesting its exclusion in the anti-parasite action., Conclusion: Taken together, imidazole-based compounds might restrict parasite growth by causing oxidative stress. The findings provide new insight on the likely biochemical mechanisms of imidazoles as prospective anti-parasite therapy. Data gives new perspective that not only underscores the anti-parasite prospects of imidazoles, but implicates the host l-tryptophan pathway as a feasible treatment option for T. gondii infections., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The Trypanosoma spp. cause animal and human trypanosomiasis characterized with appreciable health and economic burden mostly in developing nations. There is currently no effective therapy for this parasitic disease, due to poor drug efficacy, drug resistance, and unwanted toxicity, etc. Therefore, new anti- Trypanosoma agents are urgently needed. This study explored new series of imidazoles for anti- Trypanosoma properties in vitro and in vivo . The imidazoles showed moderate to strong and specific action against growth of T. congolense . For example, the efficacy of the imidazole compounds to restrict Trypanosoma growth in vitro was ≥ 12-fold specific towards T. congolense relative to the mammalian cells. Additionally, the in vivo study revealed that the imidazoles exhibited promising anti- Trypanosoma efficacy corroborating the in vitro anti-parasite capacity. In particular, three imidazole compounds (C1, C6, and C8) not only cleared the systemic parasite burden but cured infected rats after no death was recorded. On the other hand, the remaining five imidazole compounds (C2, C3, C4, C5, and C7) drastically reduced the systemic parasite load while extending survival time of the infected rats by 14 days as compared with control. Untreated control died 3 days post-infection, while the rats treated with diminazene aceturate were cured comparable to the results obtained for C1, C6, and C8. In conclusion, this is the first study demonstrating the potential of these new series of imidazoles to clear the systemic parasite burden in infected rats. Furthermore, a high selectivity index of imidazoles towards T. congolense in vitro and the oral LD 50 in rats support anti-parasite specific action. Together, findings support the anti-parasitic prospects of the new series of imidazole derivatives., (Copyright ©2021, Yale Journal of Biology and Medicine.)

Background: Our previous reports demonstrated the prospects of a new series of imidazoles as a source of alternative anti-parasite treatments, thus warranting further studies that include toxicity profiling., Objective: In this study, we evaluated three imidazoles: bis-imidazole (compound 1), phenyl-substituted 1H-imidazole (compound 2), and thiopene-imidazole (compound 3) for cellular toxicity and possible mechanisms., Methods: The three (3) compounds were assessed for in vitro cytotoxic action. Additionally, we probed likely mechanistic actions of these imidazoles. Findings showed dose-dependent cellular toxicity by these imidazoles., Results: In the presence of antioxidant (Trolox), cytotoxicity was improved for compounds 2 and 3 but not for compound 1. Meantime, compound 7 promoted reactive oxygen species (ROS) production, which was abated in the presence of a standard antioxidant (Trolox). Additionally, the three (3) imidazoles impaired mitochondrial membrane potential (MMP). While MMP was not restored after treatment removal, the addition of antioxidant (Trolox) improved MMP for compounds 2 and 3 treatment. Additionally, compound 1 elevated expression of hypoxia-inducing factor 1-alpha (HIF-1α). This may not be unconnected with the capacity of compound 1 to cause oxidative stress., Conclusion: We show evidence that supports the cytotoxic action of imidazoles involves likely impairment to redox balance and mitochondrial membrane potential. The findings help our understanding of the mechanistic action of these imidazoles in living cells, and altogether may boost their prospects as new and alternative anti-protozoans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Toxoplasmosis is a common parasitic disease caused by Toxoplasma gondii. Limitations of available treatments motivate the search for better therapies for toxoplasmosis. In this study, we synthesized a series of new imidazole derivatives: bis-imidazoles (compounds 1-8), phenyl-substituted 1H-imidazoles (compounds 9-19), and thiopene-imidazoles (compounds 20-26). All these compounds were assessed for in vitro potential to restrict the growth of T. gondii. To explore the structure-activity relationships, molecular analyses and bioactivity prediction studies were performed using a standard molecular model. The in vitro results, in combination with the predictive model, revealed that the imidazole derivatives have excellent selectivity activity against T. gondii versus the host cells. Of the 26 compounds screened, five imidazole derivatives (compounds 10, 11, 18, 20, and 21) shared a specific structural moiety and exhibited significantly high selectivity (> 1176 to > 27,666) towards the parasite versus the host cells. These imidazole derivatives are potential candidates for further studies. We show evidence that supports the antiparasitic action of the imidazole derivatives. The findings are promising in that they reinforce the prospects of imidazole derivatives as alternative and effective antiparasitic therapy as well as providing evidence for a probable biological mechanism.

Background: Current drugs available for the treatment of Chagas disease are fraught with several challenges including severe toxicity and limited efficacy. These factors coupled with the absence of effective drugs for treating the chronic stage of the disease have rendered the development of new drugs against Chagas disease a priority., Objective: This study screened several imidazole-based compounds for anti-Trypanosoma potential., Method: Using an in vitro experimental infection model, several imidazole-based compounds were screened for anti-proliferative effect on Trypanosoma cruzi epimastigotes. Additionally, all test compounds were evaluated for unspecific cytotoxicity on L929 murine fibroblasts. Benznidazole (BZN) served as reference drug., Results: All test compounds demonstrated interesting trypanocidal potential with IC50 values in the μM range (1< 1C50 <8 μM). The activities of the test compounds compared favorably with BZN, which had an IC50 value ca. 30 μM. Conversely, most of the test compounds were highly cytotoxic, resulting in selectivity lower than that of BZN (SI > 9.42)., Conclusion: We provide evidence which implicate the imidazole-based compounds as potential prototypes for the development of anti-parasitic agents. Findings have far-reaching relevance to drug discovery efforts for trypanosomiasis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

New 2-(1H-imidazol-2-yl)phenols (L1Et-L8tBuPt) bearing a phenolic proton in the vicinity of the imidazole base were prepared and characterized. Experimental studies of the dependence of their protonation/deprotonation equilibrium on substituent identities and intramolecular hydrogen bonding tendencies were carried out using electronic absorption spectroscopy at varying pH values. In order to make comparison, 2-(anthracen-10-yl)-4,5-diphenyl-1H-imidazole (L9Anthr) bearing no phenolic proton and 4,5-diphenyl-2-(4,5-diphenyl-1H-imidazol-2-yl)-1H-imidazole (L10BisIm) bearing two symmetrical imidazole base fragments were also prepared and experimentally investigated. DFT calculations were carried out to study frontier orbitals of the investigated molecules. While electron-releasing substituents produced increase in protonation-deprotonation pK(a)s for the hydroxyl group, values for the imidazole base were mainly affected by polarization of the imidazole ring aromaticity across the 2-imidazole carbon and the 4,5-imidazole carbons axis of the imidazole ring. It was concluded that electron-releasing substituents on the phenol ring and/or electron-withdrawing substituents on 4,5-imidazole carbons negatively affects donor strengths/coordination chemistries of 2-(1H-imidazol-2-yl)phenols, and vice versa. Change of substituents on the phenol ring significantly altered the donor strength of the imidazole base. The understanding of pK(a) variation on account of electronic effects of substituents in this work should aid the understanding of biochemical properties and substituent environments of imidazole-containing biomacromolecules., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

A series of 2-(imidazole-2-yl)phenol ligands L1-L6 with the general composition 4-R(4)-5-R(3)-6-R(2)-2-(4,5-R(1),R(1)-1H-imidazole-2-yl)phenol (L1: R(1) = C(2)H(5), R(2) = R(3) = R(4) = H; L2: R(1) = C(6)H(5), R(2) = R(3) = R(4) = H; L3: R(1) = C(6)H(5), R(3) = OCH(3), R(2) = R(4) = H; L4: R(1) = C(6)H(5), R(4) = OCH(3), R(2) = R(3) = H; L5: R(1) = C(6)H(5), R(3) = H, R(2) = R(4) = CH(3); L6: R(1) = C(6)H(5), R(3) = H, R(2) = R(4) = t-Bu) and L7 (2,4-di-tert-butyl-6-(1H-phenanthro[9,10-d]imidazol-2-yl)phenol) and their neutral Zn(II) complexes (Z1-Z7) were synthesized and characterized by spectroscopic and elemental analyses. Molecular structures of L1, L5, Z1, and Z2 were confirmed by single-crystal X-ray diffraction. L1 crystallized in the monoclinic Cc space group, while L5, Z1, and Z2 all crystallized in the triclinic P1 space group. One-dimensional arrays based on continuous pi-pi stacking interactions and hydrogen bonding were observed for L1 and Z1, while L5 existed as discrete dimeric stack units. Z2 formed hydrogen-bonded 1D network structures but was completely devoid of pi-pi stacking interactions. Emission processes were found to be more dependent on the substituents on phenol as well as condensed media. In contrast to general conclusions on closely related systems in the literature, significant photorelaxation from the excited enol state was observed in the cases of L1 in methanol and L4 in both THF and methanol. Therefore, there exists a certain unusual hindering factor to keto-enol phototautomerism in the ligand-solvent systems. The sensing property of zinc(II) complexes was explored regarding the effects of substituents in their ligands. It was observed that coordination to the zinc(II) ion led to emission quenching for L1 and L2 while causing an enhancement of fluorescent intensity for L3, L4, L5, and L6. A linear relationship was observed between the emission intensity and the concentration of the zinc ion at the 10(-8) M level. Compared to other zinc compounds in this work, fluorescence enhancement in Z3 and Z4 showed that the methoxyl substituent is favorable for fluorescent enhancement.