Exploration of Structural & Biological Aspects of Bismuth Complexes and Synthetic Application of Organogermanium Carboxylates

Abstract

In a quest to discover new formulations for the treatment of various parasitic diseases, a series of triorganobismuth(v) biscarboxylates of type [R3Bi(O2CR′)2] have been synthesized, characterized and evaluated for their biological potential. The organic moiety R in the organometallics represents Ph for (1-10) and CH3-Ph for (11-22) whereas R′ represent the respective carboxylate ligands used. All the synthesized complexes were fully characterized by elemental analysis, FT-IR, multinuclear (1H, 13C) NMR spectroscopy and single crystal Xray analysis. The crystal structures for (1-6, 8, 10, 18) have been ascertained and confirmed distorted trigonal bipyramidal geometry, being monomeric with seven/five coordinated bismuth center as predicted by IR data. The synthesized complexes (1-21) when screened for antibacterial, antifungal and antileishmanial activity, demonstrated a moderate to significant potential against these microorganisms. Enzyme inhibition data for these complexes also proved to be convincing enough to signify the biological importance of these compounds. A limited Structure Activity Relationship (SAR) has been developed, demonstrating that triphenylbismuth derivatives exhibit higher biological activities in general as compared to tritolyl bismuth derivatives. Two new bismuth-oxido Carboxylate clusters (23, 24) have been synthesized including the outcome of a structurally unprecedented Bi12 Carboxylate cluster that is the first of its own kind. Both these were fully characterized by elemental analysis, FT-IR, multinuclear(1H, 13C) NMR spectroscopy and X-ray crystallography. The triphenylbismuth(III) and trifluoroacetic acid (TFAH) were reacted in toluene in the presence of Ag2O to generate the hetronuclear compound with formulation as; {[Bi4(μ3- O)2(TFA)9Ag(tol)2]2} (25) (tol = PhMe). Similarly, BiPh3, TFAH, PPh3, and Ag2O were reacted in hexane to form [Bi4(μ3-O)2(TFA)10(AgPPh3)2]n (26). Both are comprised of {Bi4(μ3-O)2} units that have been previously observed with a variety of carboxylate ligands in neutral compounds and anionic compounds. In contrast to other anionic [Bi4(μ3- O)2(TFA)N](N-8)- with metal-based counter cations, the Ag+ ions in (25) and (26) are directly attached to oxygen atoms of the TFA- ligands bonded to the bismuth core. A crystallographic evolution was observed for (25). Solvent-rich orthorhombic crystals grew initially upon standing. However, by three weeks all crystals had converted to a triclinic unit cell that contained no free solvent. Therefore molecular volume decreased from 3146.11 Å3 (orthorhombic) to 2954.06 Å3 (triclinic) resulting in formation of (25). The latter (25) possessed an intermolecular π- π stacking system between silver- and bismuth-bound toluene molecules, which explains the reorganization to a non-solvated morphology. The compound (26) crystallizes in the triclinic space group P-1 as a coordination polymer through bridging xiv carboxylates. The presence of the PPh3 ligands on Ag+ results in a higher Ag:Bi stoichiometry than for (25). The importance of the Ag2O in generating the oxido ligands was confirmed by the isolation of {[Bi2(TFA)6(TFAH)(tol)]2}n (27) from the reaction of BiPh3 with TFAH in toluene in absence of the metal oxide. A unique and previously unknown hexanitratobismuth(III) anion, [Bi(NO3)6]3− is reported for 28; [Co{HC(MeCO)2(MeCNH)}2][Bi(NO3)6]. To further explore the potential application of another main group metal, germanium, a series of substituted dihydropyrimidin-2(1H)-thione derivatives (29-36) have been synthesized using a facile and modified procedure with triphenylgermyl propionate as a catalyst. In comparison with the classical Biginelli reaction, this new protocol has the advantages of excellent yield and shorter reaction times. The synthesized compounds have been characterized by various spectroscopic techniques such as FT-IR, multinuclear (1H/13C) NMR spectroscopy and single crystal XRD analysis. Molecular docking studies were performed to identify the probable binding modes of potent inhibitors in the active site of the enzymes human topoisomerase II alpha (4FM9) and Helicobacter pylori urease (1E9Y). The compound (31) was evaluated to be the most potent inhibitor according to the molecular docking scores and molecular dynamic simulations which suggest it can be further processed as a lead molecule to interpret the pharmacological properties of such type of compounds.