Quinazolinone Compounds Have Potent Antiviral Activity against Zika and Dengue Virus

Abstract

Dengue (DENV) and Zika (ZIKV) viruses are important human pathogens, causing ∼100 million symptomatic infections each year. These infections carry a 20-fold increased incidence of serious neurological diseases, such as microcephaly in newborns (for ZIKV) and Guillain-Barrésyndrome. Moreover, DENV can develop serious and possibly life-threatening dengue hemorrhagic fever in certain patients. Patients recovered from one of the four serotypes of DENV are still susceptible to other serotypes with a higher likelihood of serious disease because of antibody-dependent enhancement. Except for mosquito control, there have been no antiviral drugs to prevent and treat ZIKV/ DENV infections. Phenotypic screening found that 2,3,6-trisubstituted quinazolinone compounds are novel inhibitors of ZIKV replication. Fiftyfour analogues were synthesized, and their structure−activity relationships are discussed. Additional testing shows that compounds 22, 27, and 47 exhibited broad and potent activities against ZIKV and DENV with EC 50 values as low as 86 nM with no significant cytotoxicity to mammalian cells.

Target-based discovery of a broad spectrum flukicide

“…Ultimately, the analog possessing an unsubstituted phenyl ring (20) was the most potent agonist at both Sm.TRPM PZQ and Fh.TRPM PZQ , such that this analog was carried forward as the optimal Northern Hemisphere. Next, SAR of the Southern Hemisphere was investigated (Supplementary Table 1).…”

“…Next, SAR of the Southern Hemisphere was investigated (Supplementary Table 1). A total of 15 compounds were made but no improvements in potency were identified favoring retention of the 3-chlorophenyl Southern Hemisphere in (20). Finally, substitutions around the core ring were profiled (Supplementary Table 2).…”

“…This stringency likely reflects requirements for complementarity within the hydrophobic VSLD binding pocket. Quinazolinones have broadly reported biological activities, including antiparasitic [19] and antiviral activities [20]. Quinazolinone-type benzamides have been studied from a synthetic standpoint on account of their chirality and chiroptic properties [21,22].…”

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives Possessing a Trifluoromethyl Moiety as Potential Antitumor Agents

“…[9] This has made privileged scaffold-based drug discovery a popular strategy in the lead optimization stages of the anti-cancer drug discovery process. [10] The quinazoline [11,12] is a privileged scaffold that has been found in various biologically active natural products and is known to possess many medicinal properties, [13,14] such as antitumor, [15,16] antiviral, [17] antibacterial, [18] and anti-inflammatory [19] properties. In particular, in the field of anti-cancer drug research, the most renowned first and second-generation EGFR inhibitors such as Gefitinib, Erlotinib, and Vandetanib (Figure 1) have been developed and employed with quinazoline as the core skeleton.…”

Synthesis, molecular docking analysis and in vitro evaluation of new heterocyclic hybrids of 4-aza-podophyllotoxin as potent cytotoxic agents

“…Heterocycles, a class of cyclic organic compounds containing at least one ring hetero atom, have played an important role in pharmaceutical development due to their variety of biological activities such as anti-fungal, 1 antimicrobial, 2 anti-inflammatory, 3,4 anti-diabetic, 5 cytotoxic, 6,7 anti-tumor, anti-cancer, 8,9 anti-viral, 10 acetylcholinesterase inhibitory, 11 and SARS-CoV2 inhibitory activities. 12 To date, heterocycles have presented themselves as the basic core of most marketed drugs.…”