Design, Synthesis, and Biological Evaluation of Novel Hybrid Dicaffeoyltartaric/Diketo Acid and Tetrazole-Substitutedl-Chicoric Acid Analogue Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

Abstract

Fourteen analogues of the anti-HIV-1 integrase (IN) inhibitor L-chicoric acid (L-CA) were prepared. Their IC(50) values for 3'-end processing and strand transfer against recombinant HIV-1 IN were determined in vitro, and their cell toxicities and EC(50) against HIV-1 were measured in cells (ex vivo). Compounds 1-6 are catechol/β-diketoacid hybrids, the majority of which exhibit submicromolar potency against 3'-end processing and strand transfer, though only with modest antiviral activities. Compounds 7-10 are L-CA/p-fluorobenzylpyrroloyl hybrids, several of which were more potent against strand transfer than 3'-end processing, a phenomenon previously attributed to the β-diketo acid pharmacophore. Compounds 11-14 are tetrazole bioisosteres of L-CA and its analogues, whose in vitro potencies were comparable to L-CA but with enhanced antiviral potency. The trihydroxyphenyl analogue 14 was 30-fold more potent than L-CA at relatively nontoxic concentrations. These data indicate that L-CA analogues are attractive candidates for development into clinically relevant inhibitors of HIV-1 IN.

Mechanism and color modulation of fungal bioluminescence

“…Compound 2 was then synthesized in two steps from 3,4-dimethoxybenzalacetone ( 17 ), and its chromatographic profile and fluorescence spectrum were compared with those acquired during the study of the bioluminescent reaction. The retention time and absorption maxima matched those of the unknown product of the enzymatic oxidation of 1 (Fig.…”

Evaluation of Hepatocyteprotective and Anti-hepatitis B Virus Properties of Cichoric Acid from <i>Cichorium intybus</i> Leaves in Cell Culture

“…10) What is more important is that chicoric acid also exhibits significant antiviral effects against human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus (HSV-I). [11][12][13][14][15] It is well known that some classical anti-HIV drugs such as interferon-α and lamivudine often possess potent anti-HBV effect in clinical practice. Furthermore, coinfection with HBV and HIV is common due to shared routes of transmission, with 70-90% of HIV-infected individuals having evidence of past or active infection with HBV.…”

Characterization of Nine Compounds Isolated from the Acid Hydrolysate of Lonicera fulvotomentosa Hsu et S. C. Cheng and Evaluation of Their In Vitro Activity towards HIV Protease

“…Lonicera species possess antiviral activities [22]. Triterpene derivatives, caffeoylquinic acid derivatives, and flavonoids isolated from Lonicera species exhibit potent inhibitory effects against human immunodeficiency virus (HIV)-1 integrase and prevented HIV-1 replication in tissue culture [15][16][17][18][19]. However, there is also evidence showing that strong binding to HIV-1 integrase does not always translate into potent antiviral activity [20,21].…”

“…Various active ingredients, such as caffeoylquinic acid, secoiridoids, flavonoids, cerebrosides, nitrogen-containing iridoid glycosides, and triterpene glycosides, have been isolated and characterized from Lonicera species [9][10][11][12][13][14]. In addition, a number of triterpene derivatives, caffeoylquinic acid derivatives, and flavonoids have exhibited potent inhibitory effects against human immunodeficiency virus (HIV)-1 integrase and prevented HIV-1 replication in tissue culture [15][16][17][18][19]. However, in vitro binding and inhibition of HIV-1 integrase does not always translate into potency against HIV replication [20,21].…”