Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties

Abstract

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2′-pyrrolidine-3′,3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

Bioassay-Guided Isolation of Antimicrobial Components and LC/QToF Profile of Plumeria obtusa: Potential for the Treatment of Antimicrobial Resistance

“…Meanwhile, peak # 5 was identified as the dehydro derivative of plumeridoid A, a plumeiride-type iridoid previously isolated from the stem bark of P. rubra L. 27 However, its dehydro derivative (5) was identified here from P. obtusa for the first time.…”

“…coli (STEC)], methicillin-resistant Staphylococcus aureus (MRSA), and Bacillus cereus have been identified as causes of nosocomial (hospital-acquired) infections. These strains are among the most critical MDR bacteria in the recently published WHO list of antibiotic-resistant priority pathogens. − Although Escherichia coli (E. coli) is a common natural flora of humans, its strains may cause enteric diseases; others may colonize the urinary tract or cause other extraintestinal infections, such as septicemia and meningitis .…”

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…SARS-CoV-2 is the virus which caused a global pandemic (at the end of 2019), affecting and threatening millions of human lives. Intensive research studies for effective drugs are still one of the hot topics of scientific society [ 27 ].…”

“…Dual inhibitory properties of spirooxindoles bearing sulfonyl function 58 were revealed against VEGFR2 and EGFR [ 27 ]. Multi-targeted inhibitors have recently attracted great attention for cancer chemotherapy.…”

Potential RNA-dependent RNA polymerase (RdRp) inhibitors as prospective drug candidates for SARS-CoV-2

“…The new Omicron variant indicates that the epidemic/pandemic is far from its end due to its efficient human-to-human transmission [ 12 ]. The main symptoms due to the infection from this variant are fever, dry cough, diarrhea, and shortness of breath besides blood clotting and stroke in severe conditions [ 10 , 13 ]. Repurposed drugs and vaccination substantially helped to overcome the pandemic and retain the socioeconomic status and human life to normal [ 14 ].…”