Iron mediated reductive cyclization/oxidation for the generation of chemically diverse scaffolds: An approach in drug discovery

• Published in: Bioorganic chemistry Vol. 139; p. 106698
• Main Authors: Karale, Uttam B., Shinde, Akash, Gaikwad, Vikas R., Kalari, Saradhi, Gourishetti, Karthik, Radhakrishnan, Mydhili, Poornachandra, Yedla, Amanchy, Ramars, Chakravarty, Sumana, Andugulapati, Sai Balaji, Rode, Haridas B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2023
• Subjects: Anti-inflammatory compounds; Chemically diverse compounds; Drug discovery; Heterocyclic compounds; Neurotropic compounds; Anti-inflammatory compounds; Chemically diverse compounds; AST; IL; NGF; LPS; PCA; RT q-PCR; NF-κB; TNF-α; Heterocyclic compounds; ANOVA; Neurotropic compounds; BUN; Drug discovery
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106698

[Display omitted] •Chemically diverse scaffolds serve as a major source of biologically significant starting points for the development of novel drugs.•Iron-mediated reductive cyclization/oxidation strategy generates chemically diverse compounds from nitroarene or nitro(hetero) arenes.•Tricyclic nitrogen-containing heterocycles exhibit significant neurotropic activity.•Quinoline fused oxadiazole showed prophylactic anti-inflammatory activity and improved the survival of rats in the sepsis model.•Principal component analysis provides chemical diversity of synthesized heterocycles. Chemically diverse scaffolds represent a main source of biologically important starting points in drug discovery. Herein, we report the development of such diverse scaffolds from nitroarene/ nitro(hetero)arenes using a key synthetic strategy. In a pilot-scale study, the synthesis of 10 diverse scaffolds was achieved. The 1,7-phenanthroline, thiazolo[5,4-f]quinoline, 2,3-dihydro-1H-pyrrolo[2,3-g]quinoline, pyrrolo[3,2-f]quinoline, 1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one, [1,2,5]oxadiazolo[3,4-h]quinoline, 7H-pyrido[2,3-c]carbazole, 3H-pyrazolo[4,3-f]quinoline, pyrido[3,2-f]quinoxaline were obtained from nitro hetero arenes in ethanol using iron-acetic acid treatment followed by reaction under oxygen atmosphere. This diverse library is compliant with the rule of five for drug-likeness. The mapping of chemical space represented by these scaffolds revealed a significant contribution to the underrepresented chemical diversity. Crucial to the development of this approach was the mapping of biological space covered by these scaffolds which revealed neurotropic and prophylactic anti-inflammatory activities. In vitro, neuro-biological assays revealed that compounds 14a and 15a showed excellent neurotropic potential and neurite growth compared to controls. Further, anti-inflammatory assays (in vitro and in vivo models) exhibited that Compound 16 showed significant anti-inflammatory activity by attenuating the LPS-induced TNF-α and CD68 levels by modulating the NFkB pathway. In addition, treatment with compound 16 significantly ameliorated the LPS-induced sepsis conditions, and pathological abnormalities (in lung and liver tissues) and improved the survival of the rats compared to LPS control. Owing to their chemical diversity along with bioactivities, it is envisaged that new quality pre-clinical candidates will be generated in the above therapeutic areas using identified leads.