Synthesis, in-vitro biological evaluation, and molecular docking study of novel spiro-β-lactam-isatin hybrids

Abstract

In our ongoing search for bioactive compounds, a class of novel spiro-β-lactam isatin hybrids has been synthesized through a [2+2] cycloaddition reaction from 1-allyl-3-(arylimino)indolin-2-one, ketenes and various aryloxy acetic acids. The formation of all cycloadducts was confirmed by FTIR, 1 H NMR, 13 C NMR, and mass spectroscopy as well as elemental analyses. The new βlactams were subsequently evaluated for their biological activities demonstrating moderate to good activities against P. falciparum K1 strain. Among them, 4b and 4e lead to the best results with IC 50 of 5.04 and 7.18 µM, respectively. The molecular docking simulation of 4b with P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site presented several important intermolecular interactions. All the synthesized β-lactams were also evaluated for their antimicrobial activities against both Gram-positive (S. aureus ATCC 25923) and Gram-negative bacteria (E. coli ATCC 28922, P. aeruginosa ATCC 27853) but unfortunately MICs up to 200 µg/mL were encountered in all cases.

Antineoplastic indole-containing compounds with potential VEGFR inhibitory properties

“…Spiroindoles occupy a unique place in heterocyclic chemistry due to the versatile bio-properties of their natural and synthetic analogs 146 (exemplied by antibacterial, antifungal, [147][148][149][150][151] antimycobacterial, [152][153][154] antiviral, 19,155 anticancer, [156][157][158][159][160] antimalarial, 161,162 anti-inammatory 163 and antihyperglycemic 164,165 ). [3 + 2]-Dipolar cycloaddition of azomethine ylides derived from isatin derivatives with a-amino acids to the exocyclic olenic linkage derived from alicycles or heterocycles is an accessible synthetic approach successfully used for the construction of various spiroindoles with regio-and stereoselectivity.…”

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…Spiro-β-lactam-oxindoles 31 were obtained through [2+2] cycloaddition of isatin-imines with aryloxy acetic acid ( Scheme 4 ). All the synthesized agents revealed weak antibacterial properties (>200 μM) against E. coli , P. aeruginosa , and S. aureus [ 17 ].…”

“…Anti-mycobacterial properties by spiro[indoline-3,2′-[ 1 , 3 , 4 ]oxadiazols] 30 ( Scheme 3 ) against M. tuberculosis were also noticed. The most promising are those with halogen-substituted indolyl heterocycle (R = Br and Cl, IC 50 = 6.25 μg/mL) relative to Ciprofloxacin (IC 50 = 3.12 μg/mL) [ 17 ].…”

Stereoselective synthesis of β-lactams: recent examples

“…3 But the development of new synthetic methodologies has allowed to obtain these bioactive molecules in several ways. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Progress in the preparation of β-lactams ran parallel with the development of stereoselective synthetic methodologies, allowing to access to the different isomers (cis or trans) and also to obtain enantioenriched products. [22][23][24][25][26] This review is focused on recent advances towards the stereoselective synthesis of β-lactams, dividing the manuscript into three main sections: (i) metal-free cycloaddition reactions; (ii) transition metal-catalysis; and (iii) base-promoted synthesis.…”

“…3 But the development of new synthetic methodologies has allowed to obtain these bioactive molecules in several ways. 4–21…”