Thiazolidin-2,4-Dione Scaffold: An Insight into Recent Advances as Antimicrobial, Antioxidant, and Hypoglycemic Agents.

Heterocyclic compounds containing nitrogen and sulfur, especially those in the thiazole family, have generated special interest in terms of their synthetic chemistry, which is attributable to their ubiquitous existence in pharmacologically dynamic natural products and also as overwhelmingly powerful agrochemicals and pharmaceuticals. The thiazolidin-2,4-dione (TZD) moiety plays a central role in the biological functioning of several essential molecules. The availability of substitutions at the third and fifth positions of the Thiazolidin-2,4-dione (TZD) scaffold makes it a highly utilized and versatile moiety that exhibits a wide range of biological activities. TZD analogues exhibit their hypoglycemic activity by improving insulin resistance through PPAR-γ receptor activation, their antimicrobial action by inhibiting cytoplasmic Mur ligases, and their antioxidant action by scavenging reactive oxygen species (ROS). In this manuscript, an effort has been made to review the research on TZD derivatives as potential antimicrobial, antioxidant, and antihyperglycemic agents from the period from 2010 to the present date, along with their molecular mechanisms and the information on patents granted to TZD analogues.

Triazoles and Their Derivatives: Chemistry, Synthesis, and Therapeutic Applications.

Among the nitrogen-containing heterocyclic compounds, triazoles emerge with superior pharmacological applications. Structurally, there are two types of five-membered triazoles: 1,2,3-triazole and 1,2,4-triazole. Due to the structural characteristics, both 1,2,3- and 1,2,4-triazoles are able to accommodate a broad range of substituents (electrophiles and nucleophiles) around the core structures and pave the way for the construction of diverse novel bioactive molecules. Both the triazoles and their derivatives have significant biological properties including antimicrobial, antiviral, antitubercular, anticancer, anticonvulsant, analgesic, antioxidant, anti-inflammatory, and antidepressant activities. These are also important in organocatalysis, agrochemicals, and materials science. Thus, they have a broad range of therapeutic applications with ever-widening future scope across scientific disciplines. However, adverse events such as hepatotoxicity and hormonal problems lead to a careful revision of the azole family to obtain higher efficacy with minimum side effects. This review focuses on the structural features, synthesis, and notable therapeutic applications of triazoles and related compounds.

Novel mannopyranoside esters as sterol 14α-demethylase inhibitors: Synthesis, PASS predication, molecular docking, and pharmacokinetic studies.

Direct unimolar one-step valeroylation of methyl α-d-mannopyranoside (MDM) furnished mainly 6-O-valeroate. However, similar reaction catalyzed by DMAP resulted 3,6-di-O-valeroate (21%) and 6-O-valeroate (47%) indicating reactivity sequence as 6-OH>3-OH>2-OH,4-OH. To get potential antimicrobial agents, 6-O-valeroate was converted into four 2,3,4-di-O-acyl esters, and 3,6-di-O-valeroate was converted into 2,4-di-O-acetate. Direct tetra-O-valeroylation of MDM gave a mixture of 2,3,4,6-tetra-O-valeroate and 2,3,6-tri-O-valeroate indicating that the C2-OH is more reactive than the equatorial C4-OH. The activity spectra analysis along with in vitro antimicrobial evaluation clearly indicated that these novel MDM esters had better antifungal activities over antibacterial agents. In this connection, molecular docking indicated that these MDM esters acted as competitive inhibitors of sterol 14α-demethylase (CYP51), an essential enzyme for clinical target to cure several infectious diseases. Furthermore, pharmacokinetic studies revealed that these MDM esters may be worth considering as potent candidates for oral and topical administration. Structure activity relationship (SAR) affirmed that saturated valeric chain (C5) in combination with caprylic (C8) chains was more promising CYP51 inhibitor over conventional antifungal antibiotics.

Synthesis, PASS predication, in vitro antimicrobial evaluation and pharmacokinetic study of novel n-octyl glucopyranoside esters.

Octyl ß-d-glucopyranoside (OBG), prepared from d-glucose and octan-1-ol employing MW method, was subjected to direct dimolar valeroylation in pyridine at room temperature (25 °C) with valeroyl chloride. This mainly furnished the corresponding 3,6-di-O-valeroate in 57% yield indicating the regioselectivity at C-6 and C-3 positions. For structural elucidation and to get newer glucopyranosides of potential antimicrobial 3,6-di-O-valeroate was further converted into four novel 2,4-di-O-acyl esters reasonably in good yields. Per-O-acetate and per-O-benzoate of OBG were also prepared for SAR study. PASS predication and in vitro antimicrobial studies established them as better antifungal agent than that of antibacterial. SAR study along with AdmetSAR and SwissADME suggested that incorporation of alkanoyl and aromatic ester groups on octyl glucopyranoside core increase antimicrobial potentiality in very low concentration (10 µgmL-1). Molecular docking revealed that novel 2,4-di-O-tosyl ester and 2,3,4,6-tetra-O-benzoyl ester may act as competitive inhibitors of lanosterol 14-alpha demethylase.

Synthesis and evaluation of the glycosidase inhibitory activity of 5-hydroxy substituted isofagomine analogues.

An efficient strategy for the synthesis of 5-hydroxy substituted isofagomine analogues and , having both -CH2OH/CH3 and -OH functionality at the C-5 position, and evaluation of their inhibitory potency is reported. The synthetic methodology involves the aldol-Cannizzaro reaction of easily available alpha-d-xylopentodialdose followed by hydrogenolysis to afford the triol . Selective amidation of the alpha- and beta-hydroxymethyl group at C-4, deprotection of the 1,2-acetonide group and hydrogenation gave the target molecules, which were found to be potent against beta-glycosidases with IC50 values in the micro molar range. Compound showed excellent potency against glycosidases and human salivary amylase.

Synthesis and evaluation of glycosidase inhibitory activity of octahydro-2H-pyrido[1,2-a]pyrimidine and octahydro-imidazo[1,2-a]pyridine bicyclic diazasugars.

An efficient chiron approach for the synthesis of bicyclic diazasugars 4a and 4b having both -CH(2)OH and -OH functionality at the same carbon atom (C-6) is reported. Thus, easily available alpha-D-xylo-pentodialdo-1,4-furanose 5, obtained from D-glucose, on aldol-crossed Cannizzaro reaction followed by hydrogenolysis afforded 7. The regio-selective beta- and alpha-sulfonylation of hydroxymethyl groups in 7 afforded 8a (beta-sulfonylation) and 11 (alpha-sulfonylation) in good yields. The cleavage of the 1,2-acetonide functionality, individually in 8a and 11, followed by reaction with ethylenediamine gave in situ formation of sugar aminals that undergo concomitant nucleophilic displacement of the sulfonyloxy group, by amino functionality, to give hitherto unknown bicyclic diazasugars 4a and 4b, respectively. The inhibitory potency of the earlier reported bicyclic diazasugars 3a,b and 4a,b was evaluated against alpha- and beta-glycosidases and they were found to be potent and specific against the beta-glycosidases with IC(50) and K(1) values in the micro molar range.

N-hydroxyethyl-piperidine and -pyrrolidine homoazasugars: preparation and evaluation of glycosidase inhibitory activity.

An efficient and practical strategy for the synthesis of N-hydroxyethyl-1-deoxy-homonojirimycins 4 and 5 and N-hydroxyethyl-pyrrolidine homoazasugars 6 and 7 with full stereocontrol is being reported. The key step involved is the intermolecular Michael addition of benzylamine to D-glucose derived alpha,beta-unsaturated ester 8 followed by N-alkylation with ethyl bromoacetate. Reduction with LAH, acetylation, hydrogenation and protection with -Cbz group afforded compounds 14a and 14b. Removal of 1,2-acetonide functionality, hydrogenation and deacetylation afforded N-hydroxyethyl-D-gluco-1-deoxyhomonojirimycin (4) and N-hydroxyethyl-L-ido-1-deoxyhomonojirimycin (5), respectively. Compounds 14a and 14b on acetylation followed by removal of 1,2-acetonide functionality, sodium metaperiodate oxidation, hydrogenation and deacetylation gave 1,4,5-trideoxy-1,4-imino-N-hydroxyethyl-D-arabino-hexitol (6) and 1,4,5-trideoxy-1,4-imino-N-hydroxyethyl-L-xylo-hexitol (7), respectively. The glycosidase inhibition activity of compounds 4, 5, 6, 7, 16a and 16b was evaluated using sweet almond seed as a rich source of different glycosidases.