Therefore the rational design of target compounds is based o

Therefore, the rational design of target compounds is based on the hybrid of attractive phenotypic bis-indole (5, Fig. 1) and sulfonamide moieties, in which the indole core might anticipate in hydrophobic interaction, and the functionality of sulfonamide group may involve in H-bonding with the site of action. Structural feature of both indole and sulfonamide moieties was modified using many substitution patterns and substituents. In this study, various hybrids of indole-sulfonamide derivatives were synthesized (Scheme 1) and evaluated for their aromatase inhibitory activities. Molecular docking and QSAR modeling were also performed to provide insights into the important interaction of compounds and target site as well as useful structure-activity relationship (SAR) information.
Results and discussion
Conclusions A series of indole-based sulfonamides (11–44) have been synthesized using the alkylation reaction. Their aromatase inhibitory activities, molecular docking, and QSAR were studied. It was observed that all indoles exerted aromatase inhibitory activity (IC50 = 0.8–15.3 μM). Particularly, the bis-indoles 28 and 34 were shown to be the most potent inhibitors (IC50 of 0.7 and 0.8 μM, respectively) without affecting the normal cell line. Molecular docking results revealed that the top three ranked indoles possessing the most potent aromatase inhibitory activities (compounds 28, 30 and 34) could occupy at the same binding site of the natural substrate ASD on the aromatase pocket, and share the same binding residues with those of the ASD (i.e. MET374, VAL370, VAL373, and PHE134). These suggested that the investigated indole derivatives may elicit their aromatase inhibitory activities via acting as competitive inhibitors. The QSAR study demonstrated MATS6e, Mor28u, E2m, and nArOH as a set of influential descriptors. The most potent inhibitors with para- and ortho-phenoxy groups (R) had high value of electronegativity (MATS6e) in which the value of para-OH Pyocyanin (28) was greater than that of ortho-OH compound (34). The QSAR results are well correlated with the molecular docking that the most potent compound (28) could tightly bind the cavity of the aromatase enzyme to mimic H-bonding of C-17 and C-3 keto functions (via MET374 and ASP309, respectively) as well as to mimic hydrophobic interactions of the natural substrate. In summary, the study highlighted a series of indole derivatives as potential compounds to be further developed as novel aromatase inhibitors for therapeutic applications.
Experimental section
Acknowledgments This project is financially supported by Srinakharinwirot University (grant no. 055/2560). Great supports from the office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative are appreciated. We are also indebted to Chulabhorn Research Institute for recording mass spectra and bioactivity testing.
Introduction Ziram is a dithiocarbamate fungicide (A). It forms a complex with zinc (A). It is widely used to treat many fungal diseases in crops such as nuts, some fruits, potatoes, and grain [1]. Ziram is also used in the industry for an accelerating agent in latex rubber production. Therefore, ziram can be absorbed into human body [1]. Ziram has been found to cause health problems in animal models and humans. Ziram has toxicity in the immune system [2], [3], [4], [5]. For example, ziram promoted the concanavalin-stimulated production of interferon gamma and interleukin 4 in murine vascular lymph node cells [6]. It also has toxicity in the nerve system [7], [8]. Recently, we identified that ziram could be an endocrine disruptor. For example, it was found to potently inhibit 11β-hydroxysteroid dehydrogenase 2, thus interfering with the glucocorticoid metabolism [3]. However, whether it interferes with placental function is still unclear. Placenta is an active steroid-producing organ. Placenta primarily produces progesterone and estradiol (B). In human placenta, the trophoblast cells express 3β-hydroxysteroid dehydrogenase 1 (HSD3B1, encoded by HSD3B1). This enzyme is located in the mitochondria of placenta cells, where it catalyzes pregnenolone to synthesize progesterone (B).