Eco-friendly approach to indenodiazepinones from o-formylynones and o-phenylenediamines: Novel pharmacophoric constructs and their anti-bacterial activity

Abstract

We have conceptualised and executed an efficient, eco-friendly, one-flask, synthetic approach of general applicability to functionally enriched and potentially pharmacophoric tetracyclic indenodiazepinones through a base-mediated reaction cascade between a multifunctional o-formylynones and commercial o-phenylenediamines. The pertinence of this operationally simple, no-waste protocol, embodying many green and sustainable features, has been scoped with 26 variegated examples. This controlled one-pot assembly of novel tetracyclic indenodiazepinones with an unusual placement of an olefin through a reaction cascade involving Schiff base formation, intramolecular aza-Michael addition and a Mannich reaction between o-formylynones and o-phenylenediamines rapidly generates a diverse library poised for exploring their therapeutic potential and medicinal chemistry applications. The newly accessed indenodiazepinones exhibit promising antibacterial activities against many microorganisms and are non-cytotoxic even at higher concentrations. Interestingly, one of the compounds, 3v did not develop resistance in Salmonella Typhimurium (STM) upon repeated exposure to sub-lethal doses up to the 160th cycle, whereas resistance against clinically used antibacterial ciprofloxacin was attained at the 128th cycle. These preliminary findings open avenues towards the development of novel antimicrobial agents with enhanced durability against drug resistance and these efforts are disclosed in this report. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/697289v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1d1d9beorg.highwire.dtl.DTLVardef@2e8560org.highwire.dtl.DTLVardef@36742eorg.highwire.dtl.DTLVardef@105ae7c_HPS_FORMAT_FIGEXP M_FIG C_FIG