MS Thesis Defense by Nikhil Bhagavatula
VRB-210
Rachel White
508-999-8232
rwhite@umassd.edu
Title: Synthesis of 2,3-Disubstituted Imidazo[1,2-a] pyrimidines as Versatile Intermediates Toward Oroidin and Modified CK-666 Analogues
Advisor/Committee Members:
- Dr. Sivappa Rasapalli, Associate Professor, Chemistry/Biochemistry Dept., UMass Dartmouth, Thesis Advisor and Committee Chair
- Dr. Shuowei Cai, Chemistry/Biochemistry Dept., UMassD, Thesis Committee Member
- Dr. Wei-Shun Chang, Chemistry/Biochemistry Dept., UMassD, Thesis Committee Member
Abstract:
Nitrogen-rich heterocycles constitute privileged structural motifs in natural products and pharmaceuticals, forming the core architecture of numerous bioactive alkaloids, antibiotics, and approved drugs through their selective interactions with diverse biological targets. Among these, the imidazo[1,2-a]pyrimidine scaffold is particularly valued for its recurrence in marine alkaloid synthesis in our research program and others, exemplified by oroidin, clathroidin, and hymenidin synthesis, and its proven utility in cytoskeletal inhibitor design, notably CK-666.
Herein, we describe the synthesis of 2,3-disubstituted imidazo[1,2-a]pyrimidines toward two complementary objectives: (i) the total synthesis of oroidin, a pyrrole-2-aminoimidazole alkaloid isolated from marine sponges of the genus Agelas possessing notable antimicrobial, anti-fouling, and anti-biofilm properties, along with its structural analogues; and (ii) the design of modified CK-666 analogues through strategic functionalization of the imidazo[1,2-a]pyrimidine core. CK-666 inhibits the Arp2/3 complex—a seven-subunit assembly that nucleates branched actin filaments essential for cell motility—yet exhibits only moderate potency and modest binding affinity, providing a clear impetus for structure-based optimization toward more efficacious derivatives.