Pyrroloimidazolediones Derived from Aminomalonates and Benzaldehydes

Bicyclic lactams can be prepared from diethyl aminomalonate and substituted benzaldehydes by formation of a dimerised imidazolidine cycloadduct followed by a Dieckmann ring closure. The resulting N,N-heterocycles are metal-chelating but show no antibacterial activity.

Crystal structures, packing features, Hirshfeld surface analyses and DFT calculations of hydrogen-bond energy of two homologous 8a-aryl-2,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidin-6(1H)-ones

The crystal structures and packing features of two homologous Meyer's bicyclic lactams with fused pyrrolidone and medium-sized perhydropyrimidine rings, namely, 8a-phenyl-2,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidin-6(1H)-one, C13H16N2O (1), and 8a-(4-methylphenyl)-2,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidin-6(1H)-one, C14H18N2O (2), were elucidated, and Hirshfeld surface plots were calculated and drawn for visualization and a deeper analysis of the intermolecular noncovalent interactions. Molecules of 1 and 2 are weakly linked by intermolecular C=O...H—N hydrogen bonds into chains, which are in turn weakly linked by other C=O...H—Car interactions. The steric volume of the substituent significantly affects the crystal packing pattern.

Bicyclic Lactams Derived from Serine or Cysteine and 2-Methylpropanal

Bicyclic lactams may be prepared from serine or cysteine and 2-methylpropanal; the resulting S,N-heterocycles are more stable than the corresponding O,N-heterocycles but both are synthetic intermediates capable of further elaboration.

Synthesis of β- and γ-lactam fused dihydropyrazinones from Ugi adducts via a sequential ring construction strategy

An efficient and novel method for the synthesis of bicyclic lactams is reported via post-Ugi functionalization.

Organocatalytic Michael Addition to (D)-Mannitol-Derived Enantiopure Nitroalkenes: A Valuable Strategy for the Synthesis of Densely Functionalized Chiral Molecules

Carbohydrates are abundant renewable resources and are a feedstock for green chemistry and sustainable synthesis of the future. Among the hexoses and the pentoses present in biomass, mannitol was selected in the present project as a valuable platform, directly available from the chiral pool, to build highly functionalized molecules. Starting from (R)-2,3-O-cyclohexylidene glyceraldehyde, which is easily prepared in a large scale from D-mannitol, an enantiopure chiral nitro alkene was prepared by reaction with nitromethane, and its reactivity studied. Organocatalytic Michael addition of dimethyl malonate, β-keto esters, and other nucleophiles on the nitro alkene afforded high stereoselectivity and densely functionalized chiral molecules, which were further synthetically developed, leading to five-membered lactones and bicyclic lactams. Preliminary studies showed that the metal-free catalytic reaction on the chiral nitro alkene can be performed under continuous flow conditions, thus enabling the use of (micro)mesofluidic systems for the preparation of enantiomerically pure organic molecules from the chiral pool.

Natural Product Inspired Novel Indole based Chiral Scaffold Kills Human Malaria Parasites via Ionic Imbalance Mediated Cell Death

Natural products offer an abundant source of diverse novel scaffolds that inspires development of next generation anti-malarials. With this vision, a library of scaffolds inspired by natural biologically active alkaloids was synthesized from chiral bicyclic lactams with steps/scaffold ratio of 1.7:1. On evaluation of library of scaffolds for their growth inhibitory effect against malaria parasite we found one scaffold with IC50 in low micro molar range. It inhibited parasite growth via disruption of Na+ homeostasis. P-type ATPase, PfATP4 is responsible for maintaining parasite Na+ homeostasis and is a good target for anti-malarials. Molecular docking with our scaffold showed that it fits well in the binding pocket of PfATP4. Moreover, inhibition of Na+-dependent ATPase activity by our potent scaffold suggests that it targets parasite by inhibiting PfATP4, leading to ionic imbalance. However how ionic imbalance attributes to parasite’s death is unclear. We show that ionic imbalance caused by scaffold 7 induces autophagy that leads to onset of apoptosis in the parasite evident by the loss of mitochondrial membrane potential (ΔΨm) and DNA degradation. Our study provides a novel strategy for drug discovery and an insight into the molecular mechanism of ionic imbalance mediated death in malaria parasite.