Total Synthesis of the Natural Chalcone Lophirone E, Synthetic Studies toward Benzofuran and Indole-Based Analogues, and Investigation of Anti-Leishmanial Activity.

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure-activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC50 = 15.3, 27.2, 15.9 µM, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation.

Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1.

In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 µM; 21, IC50 = 3.05 µM; and 27, IC50 = 3.34 µM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 µM), while 7 showed the most potent CD value of 1.12 µM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 µM) as well as QR1 induction (CD = 5.76 µM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3'-nitrogen coordinating with the heme group.

2-Arylindoles: Concise Syntheses and a Privileged Scaffold for Fungicide Discovery.

Indole is a popular and functional scaffold existing widely in the fields of medicine, pesticides, spices, food and feed additives, dyes, and many others. Among indoles, 2-arylindole represents a particular and interesting subset but has attracted less attention for drug discovery. In this study, we report a general, practical one-pot assembly of a variety of 2-arylindole derivatives. To develop novel fungicide scaffolds, their fungicide activity was also evaluated. The bioassay results showed that many of the synthesized 2-arylindoles exhibited considerable fungicidal activities especially toward Rhizoctonia cerealis, and several demonstrated an inhibition rate of more than 90%. Notably, 4-fluoro-2-phenyl-1H-indole 6e was obtained with a broad spectrum of fungicidal activities, which showed excellent growth inhibition activities against R. cerealis, Rhizoctonia solani, Botrytis cinerea, Magnaporthe oryza, and Sclerotinia sclerotiorum with EC50 values of 2.31, 4.98, 6.78, 10.57, and 17.80 µg/mL, respectively. Preliminary fungicidal mode of action of 6e showed a significant inhibition effect on mycelial growth and spore germination. These results indicated that 2-arylindoles as privileged scaffolds exhibited potential fungicidal activities that deserve further study.