Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3, 1] is an active form of vitamin D3 and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1α,25(OH)2D3, (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3.

Design, Synthesis of Amide Derivatives of Scutellarin And Their Anti-Leukemia And Neuroprotective Activities

A unique series of amide-scutellarin derivatives were designed and synthesized in order to develop the function of scutellarin further. The antiproliferative activity of all target compounds against two human leukaemia cell lines were evaluated. Among them, compounds 6g and 7c displayed the most antitumor activities against HL-60 and THP-1. Moreover, all compounds were also assayed for their neuroprotective activity against hydrogen peroxide (H2O2)-induced PC-12 cell injury, and the majority of the compounds had moderate to good neuroprotective properties. These findings confirmed that these target compounds could be used as anti-leukaemia and neuroprotective candicates in the future.

Synthesis of Functionalized Thiophene Based Pyrazole Amides via Various Catalytic Approaches: Structural Features through Computational Applications and Nonlinear Optical Properties

In the present study, pyrazole-thiophene-based amide derivatives were synthesized by different methodologies. Here, 5-Bromothiophene carboxylic acid (2) was reacted with substituted, unsubstituted, and protected pyrazole to synthesize the amide. It was observed that unsubstituted amide (5-bromo-N-(5-methyl-1H-pyrazol-3-yl)thiophene-2-carboxamide (7) was obtained at a good yield of about 68 percent. The unsubstituted amide (7) was arylated through Pd (0)-catalyzed Suzuki–Miyaura cross-coupling, in the presence of tripotassium phosphate (K3PO4) as a base, and with 1,4-dioxane as a solvent. Moderate to good yields (66–81%) of newly synthesized derivatives were obtained. The geometry of the synthesized compounds (9a–9h) and other physical properties, like non-linear optical (NLO) properties, nuclear magnetic resonance (NMR), and other chemical reactivity descriptors, including the chemical hardness, electronic chemical potential, ionization potential, electron affinity, and electrophilicity index have also been calculated for the synthesized compounds. In this study, DFT calculations have been used to investigate the electronic structure of the synthesized compounds and to compute their NMR data. It was also observed that the computed NMR data manifested significant agreement with the experimental NMR results. Furthermore, compound (9f) exhibits a better non-linear optical response compared to all other compounds in the series. Based on frontier molecular orbital (FMO) analysis and the reactivity descriptors, compounds (9c) and (9h) were predicted to be the most chemically reactive, while (9d) was estimated to be the most stable among the examined series of compounds.

Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.

Research on Crystal Structure and Fungicidal Activity of the Amide Derivatives Based on the Natural Products Sinapic Acid and Mycophenolic Acid

Structural optimization based on natural products is an important and effective way to discover new green pesticides. Here, two series of amide derivatives based on sinapic acid and mycophenolic acid were designed in combination with the fungicidal natural product piperlongumine and synthesized by preparing the carboxylic acid into acyl chloride and then reacting with the corresponding aromatic amines, respectively. The resulting structures were successively characterized by 1H NMR, 13 C NMR, and HRMS. The crystal structures of molecules I-4 and II-5 were analyzed for structure validation. The in vitro inhibitory activity indicated that most of the target products exhibited fungicidal activity equivalent to or even better than fluopyram against Physalospora piricola. The in vivo fungicidal activity demonstrated that the compounds I-5 and II-4 displayed almost the same preventative activity as carbendazim and fluopyram at 200 μg mL−1. The TEM observation revealed that the fungicidal activity of the target molecules against Physalospora piricola may be due to the influence on the mitochondria in the cell structure. These results will provide valuable theoretical guidance for developing the new green fungicides.