Chemical synthesis, crystal structure, versatile evaluation of their biological activities and molecular simulations of novel pyrithiobac derivatives

Abstract

a b s t r a c tSince pyrithiobac (PTB) is a successful commercial herbicide with very low toxicity against mammals, it is worth exploring its derivatives for an extensive study. Herein, a total of 35 novel compounds were chemically synthesized and single crystal of 6e6 was obtained to confirm the molecular structure of this family of compounds. The novel PTB derivatives were fully evaluated against various biological platforms. From the bioassay results, the best AHAS inhibitor 6e22 displayed weaker herbicidal activity but stronger anti-Candida activity than PTB did. For plant pathogenic fungi, 6e26 showed excellent activity at 50 mg/L dosage. Preliminary insecticidal activity and antiviral activity were also observed for some title compounds. Strikingly, 6e5 exhibited a promising inhibitory activity against SARS-CoV M pro with IC 50 of 4.471 mM and a low cellular cytotoxicity against mammalian 293 T cells. Based on the results of molecular modeling, HOMO-1 was considered to be a factor that affects AHAS inhibition and a possible binding mode of 6e5 with SARS-CoV M pro was predicted. This is the first time that PTB derivatives have been studied as biological agents other than herbicides. The present research hence has suggested that more attentions should be paid to compounds belonging to this family to develop novel agrochemicals or medicines.

Potential of coronavirus 3C-like protease inhibitors for the development of new anti-SARS-CoV-2 drugs: Insights from structures of protease and inhibitors

“…Compound 19 formed hydrophobic interactions with Phe140, Leu141, His163, Glu166 and His172, whilst the 1,3,4-oxadiazole group formed multiple H-bonds with Asn142, Gly143 and Cys145. As part of an ongoing investigation of novel inhibitors [35] , a new class of 55 pyrithiobac derivatives were synthesised and evaluated for their inhibitory activities. Among these synthetic compounds, sulfide 20 , with a 1,3,5-triazin ring and a phenyl ring, exhibited promising inhibitory activity with an IC 50 value of 4.47 μM ( Fig.…”

Discovery and structural optimization of 3-O-β-chacotriosyl oleanane-type triterpenoids as potent entry inhibitors of SARS-CoV-2 virus infections

“…As with other well-known coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new enveloped positive-stranded RNA virus [ [1] , [2] , [3] , [4] ]. SARS-CoV-2 is able to cause high pathogenic and apathogenic human infections because of the possibility of an aerosol mode of transmission, the high fatality rate, as well as the unpredictable nature of the outbreaks, posing a serious threaten to public health and the global economy [ [5] , [6] , [7] ].…”

Human coronaviruses and therapeutic drug discovery

“…Drugs targeting Mpro include peptidomimetic inhibitors of enterovirus 3Cpro (6b, 6c and 6d) [ 39 ], a novel series of fused 1,2,3-triazoles [ 40 ], lopinavir/ritonavir, [ 30 , 41 ], Ti-containing polyoxometalates (POMs) [ 42 ], compounds 6–5 derived from pyrithiobac (PTB) [ 43 ], some molecules such as N3 [ 44 ], and synthesized compounds (derived from isatin, piperazine, piperidine and phenylisoserine) [ 45 – 47 ]. According to a randomized control trial published in The Lancet , lopinavir–ritonavir was not associated with survival improvement or mortality reduction [ 48 , 49 ], so the World Health Organization (WHO) terminated related experiments.…”