In continuation to our search for new amino acid and peptide based anti-inflammatory agents, the suggestion, synthesis, structure elucidation of some Nα -bis-dipicolinoyl amino acids, linear tetra and cyclic octa bridged peptides 1-9, of which four are new compounds 6-9, were herein realized. Accordingly, Nα -bis-dipicolinoyl-L-leucine methyl ester 1, the corresponding acid 2, its bis-DL-norvalyl methyl ester homologue 3, the acid 4 and hydrazide 5 analogues were conventionally prepared.The tetrachlorophthalic acid hydrazine conjugate 6, anisaldehyde hydrazone 7, the benzenetetracarboxylic acid and naphthalenetetracarboxylic acid bis-L-leucyl-DL-norvalyl cyclic octa bridged peptides 8 and 9 respectively, were newly synthesized via condensation of the hydrazide 5 with the corresponding aldehyde or anhydride.The chromatographic, IR, NMR and mass spectral analysis confirmed the identities of the synthesized compounds.Comparable to the two reference antiinflammatory drugs indomethacin® and voltaren® (100%), the determined antiinflammatory potency of the candidates (carrageenan® induced paw edema in rats) revealed a general significant activity (66 - 94%), except for the practically inactive 6 (∼1.5 % activity).In particular, the potency of the (Nα -dipicolinoyl)-bis-L-leucyl-DL-norvalyl anisaldehyde hydrazone 7 was of 94 and 87%, comparable to the reference drugs. However, 7 also showed 58% protection against ulcer formation, comparable to null for indomethacin®. Additionally, an acceptable acute toxicity was observed (LD50: 2833 mg/kg, comparable to 2700 and 2850 for indomethacin® and voltaren® respectively).

In continuation to our search for new chiral macrocyclic peptide-based anti-inflammatories, the suggestion, synthesis, structure elucidation of some Nalpha-bis-dipicolinoyl amino acids, linear, tetra and cyclic (penta and octa)-bridged peptides 3-10, were realized herein. The newly synthesized compounds showed potent anti-inflammatory activity with low toxicity (LD50) comparable to indomethacin and diclofenac as reference anti-inflammatory drugs.

A series of heterocyclic derivatives was synthesized using (3-benzoyl-4,5-dioxo-2-phenyl-pyrrolidin-1-yl)acetic acid ethyl ester 1 as starting material. Treatment of 1 with 1 N NaOH or hydrazine hydrate afford the corresponding acid 2 and acid hydrazides 4 and 5, which were reacted with several reagents to produce some new peptido hetero-organic derivatives 6-12. The pharmacological screening showed that many of these newly synthesized compounds have good anti-inflammatory and analgesic activities comparable to diclofenac potassium and valdecoxib as reference drugs.

Novel macrocyclic dipicolinic acid acylated peptides based on upper rim bridged peptidocalix[4]arenes, peptido-pyridines or hybrid structures of both, were synthesized as potential molecular metallacages and chemosensors. While conventional azide or mixed anhydride (ethyl chloroformate) peptide couplings served well for assembling the L-tyrosine or L-ornithine peptide backbones, the acid chloride of pyridine-2,6-dicarboxylic acid (dipicolinic acid) acid served as the complementary acylating agent. The structure assignment of the new compounds was based on chemical and spectroscopic evidences. Some of these compounds exhibit antimicrobial activities.