Tetrahydrocarbazoles as Novel Class of DNA Biosynthesis Inhibitors in Bacteria

Abstract

Background: High-throughput screening (HTS) of large-compound libraries is a convenient and cost-effective tool for novel drug discovery. However, in many cases, HTS platforms are not well adapted to perform cell-based screening assay with simultaneous identification of the mechanism of action for active compounds. Methods: Previously, we have described a unique double-reporter system that can be used to reveal compounds having antibacterial activity. This construction is based on two genes of Katushka2S and RFP that encode proteins with different imaging signature. The upregulated expression of the first gene attributes directly to translation inhibition in prokaryotes while the high expression of the second one is unambiguously associated with DNA biosynthesis restriction (SOS-response). Results: In the current work, we have applied this system for the identification of novel smallmolecule compounds with antibacterial activity in HTS scale. Compounds were selected from the ChemDiv in-house collection (of total 47K molecules) following the maximum diversity in structure. Based on the obtained results, we have revealed a small series of tetrahydrocarbazole derivatives with antibacterial activity. The hit compound inhibited bacterial growth with a MIC value of 21 μg/ml and blocked DNA biosynthesis. No activity towards translation has been observed. In spite of a relatively moderate potency, as compared to the control sample (erythromycin, MIC=3 μg/ml), this molecule provides good selectivity index (SI>333, HEK239). Conclusion: Tetrahydrocarbazole derivatives can be properly regarded as an attractive starting point for further development and optimization.

Exploring the diastereoselectivity for Fischer indolization of L-menthone under different conditions, spectral characterization, and biological activities of new (2R,4aS)-2,3,4,4a-tetrahydro-1H-carbazole analogs

“…1 H NMR (400 MHz, CDCl3, δ, ppm): 7.48 (d, J8,7 = 7.7 Hz, 1H, H-8), 7.11-7.09 (s+d, J7,8 = 10.0 Hz, 2H, H-5, H-7), 2.74 (dd, J1-ax,1-eq = 13.0 Hz, J1-ax,2 = 6.1 Hz, 1H, 1-eq CH2), 2.61 (d, J1-eq,2 = 13.0 Hz, 1H, 1-eq CH2), 2.49-2.48 (m, 1H, 2-CH), 2.36 (s, 3H, 14-CH3), 2.34-2.29 (m, 2H, 4-eq CH2/11-CH), 2.07 (tt, J3-ax,(3-eq,4-ax) = 14.1 Hz, J3-ax,(2-eq,4-eq) = 4.0 Hz, 1H, 3-ax CH2), 1.34 (dm, J3-eq,3-ax = 14.1 Hz, 1H, 3-eq CH2), 1.24 (td, J4-ax,(3-ax,4-eq) = 14.1 Hz, J4-ax,3-eq = 3.7 Hz, 1H, 4-ax CH2), 1.21 (d, J12,11 = 6.8 Hz, 3H, 12-CH3), 0.81 (d, J10,2 = 7.2 Hz, 3H, 10-CH3), 0.25 (d, J13,11 = 6.7 Hz, 3H, 13-CH3). 13 (13), 182 (18), 168 (10), 157 (100), 144 (8), 128 (12), 115 (12), 91 (3), 89 (3). UV/Vis (CHCl3, λmax, nm, (ε)): 261 (2.09).…”

“…This class is widely distributed in nature and has gained immense attention of medicinal chemists as found as the main skeleton in many bioactive compounds [1]. These compounds showed biological properties such as P-type ATPase inhibitory activity as antifungal [2], DNA biosynthesis inhibitory activity as antibacterial [3], antiviral [4], neuroprotective [5], β-3-adrenoceptor agonist [6], antitumor [7], etc. (Figure 1).…”