Design, Synthesis, and Structure–Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility

Abstract

Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.

Ravuconazole self-emulsifying delivery system: in vitro activity against <em>Trypanosoma cruzi</em> amastigotes and in vivo toxicity

“…As discussed herein, at intestinal pH, the solubility of RAV is expected to be ,1 µg/mL. 16 A surfactant concentration-dependent increase in RAV solubility in PBS (pH 6.8) was observed ( Figure 3). Labrasol produced a significant (P,0.05) and linear (r 2 =0.9818) increase in RAV solubility in aqueous medium.…”

“…At pH 1.2, .50% is ionized and positively charged. 16 In aqueous HCl (pH 1.2), there was a reduction of negative surface charges (Table 4). This could be explained by the ionization of RAV in the acidic medium, producing positively charged groups.…”

“…14 However, in vivo studies in murine and canine models have shown limitations in the effectiveness of RAV, probably due to inadequate pharmacokinetic profile, mainly related to relatively short terminal plasma half-life of RAV in these animal models. 14,15 As a Biopharmaceutics Classification System (BCS) Class II drug, RAV possesses low aqueous solubility (,1 µg/mL in phosphate-buffered saline [PBS] pH 7.4 at 30°C), 16 has high lipophilicity (calculated logarithmic partition coefficient [clogP]: 3.477; Advanced Chemistry Development, Inc. [ACD/Labs]), and can be associated with lipid excipients. 17,18 Thus, the evaluation of RAV in new formulations that are able to improve its biopharmaceutical properties could turn it into a more promising alternative for the etiological treatment of experimental and human Chagas disease.…”

Antimicrobial evaluation, QSAR and docking studies of amide-linked 1,4-disubstituted 1,2,3-bistriazoles

“…This reaction leads to regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles and can also be performed in aqueous medium at room temperature. 1,2,3-Triazoles-containing compounds display fascinating biological activities such as anticancer (Singh et al, 2012), antitubercular (Patpi et al, 2012, Surineni et al, 2015, antimicrobial (Genin et al, 2000, Cao et al, 2014, anti-HIV (Whitting et al, 2006), antimalarial activities (Bakunov et al, 2010).…”

Design, synthesis, and structure–activity relationship studies of novel thienopyrrolidone derivatives with strong antifungal activity against Aspergillus fumigates

“…In this line, we have recently reported the discovery and development of several series of novel fused heterocycles-linked azoles (depicted by general formula I, the most potent compound from each classes of azoles, 19, 20, 21 and 22 were taken as examples) with high potency against Candida and Cryptococcus spp. Unfortunately, almost all of the target compounds discussed above showed only moderate or low potency (MIC = 2.0 µg/ml to 32.0 µg/ml) against Aspergillus fumigatus compared with albaconazole (MIC = 0.25 µg/ml), the highly potent lead compound [11]. Thus, this has prompted us to continue to undertake structural modification of potent original compounds in search of novel azoles with improved anti-Aspergillus efficacy.…”