Studies towards the Design and Synthesis of Novel 1,5-Diaryl-1H-imidazole-4-carboxylic Acids and 1,5-Diaryl-1H-imidazole-4-carbohydrazides as Host LEDGF/p75 and HIV-1 Integrase Interaction Inhibitors

Abstract

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target scaffolds in the AlphaScreenTM HIV-1 IN-LEDGF/p75 inhibition assay identified seventeen compounds exceeding the pre-defined 50% inhibitory threshold at 100 µM concentration. Further evaluation of these compounds in the HIV-1 IN strand transfer assay at 100 μM showed that none of the compounds (with the exception of 10a, 10l, and 11k, with marginal inhibitory percentages) were actively bound to the active site, indicating that they are selectively binding to the LEDGF/p75-binding pocket. In a cell-based HIV-1 antiviral assay, compounds 11a, 11b, 11g, and 11h exhibited moderate antiviral percentage inhibition of 33–45% with cytotoxicity (CC50) values of >200 µM, 158.4 µM, >200 µM, and 50.4 µM, respectively. The antiviral inhibitory activity displayed by 11h was attributed to its toxicity. Upon further validation of their ability to induce multimerization in a Western blot gel assay, compounds 11a, 11b, and 11h appeared to increase higher-order forms of IN.

Synthesis of esters and amides of 2-aryl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acids and study of their antiviral activity against orthopoxviruses

“…Imidazole-containing molecules demonstrate a wide variety of antiviral activities. Only recently papers on antiviral activity of imidazole derivatives against Hepatitis C virus 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , Hepatitis B virus [38] , influenza A virus 39 , 40 , dengue virus 41 , 42 , Chikungunya virus [43] , rhabdoviridae 44 , 45 , 46 , 47 , 48 , herpesviridae [49] , Human Cytomegalovirus [50] , HIV-1 [51] and coronaviruses [52] have been published.…”

GC–MS analysis, cytotoxicity, and molecular docking studies of bioactive alkaloids extracted from tomato leaves inoculated with endophytic fungus Beauveria sp. AUMC 15401

“…The biological activities of some alkaloidal compounds extracted from fungus‐treated leaves are summarized in Table 2. Among the identified compounds, there are various compounds that exhibited wide biological activities such as 2,5‐Difluoro‐1‐(tri‐acetyl ribo‐furanosyl) imidazole‐4‐carboxylic acid, ethyl ester (Narasimhan et al, 2011; Rashamuse et al, 2021), Estra‐1,3,5(10)‐trien‐17.beta.‐ol (Al‐Gara et al, 2019), Cholestan‐6‐one, 3‐(acetyloxy)‐, (3.beta.,5.alpha.) (Jegadeeswari et al, 2012), 3‐(3‐Fluoroanilino)‐1‐(3‐nitrophenyl)‐1‐propanone (Eswaraiah et al, 2020), and Quinoline, 2‐(4‐methylphenyl) (Matada et al, 2021).…”

“…The biological activities of some alkaloidal compounds extracted from fungus-treated leaves are summarized in Table 2. Among the identified compounds, there are various compounds that exhibited wide biological activities such as 2,5-Difluoro-1-(tri-acetyl ribo-furanosyl) imidazole-4-carboxylic acid, ethyl ester (Narasimhan et al, 2011;Rashamuse et al, 2021), Beauveria sp. AUMC 15401 colonization into tomatoes could stimulate the secretion of other important biologically active metabolites that showed a promising cytotoxic effect.…”

Systematic Review on Thiazole Compounds as Nanoparticles: Chemistry, Synthesis, Antimicrobial Activities, Therapeutic Investigation

“…Alvarez Ibarra et al [48] have further reported the synthesis of 2-etylthio-4-carbethoxy-5-alkyl/arylaminothiazoles by treatment of EMIC in the presence of potassium t-butoxide with isothiocyanate in THF: Takeda et al [49] have devised an ingenious method of synthesizing 2-amino-5-arylthiazole-4-carboxylates by the following:…”