Synthesis, characterisation and anti-microbial studies of heterocyclic thiolato bismuth complexes

Abstract

This thesis deals with studies on the synthesis and characterisation of heteroleptic bismuth(V) and bismuth(III) and homoleptic bismuth(III) complexes of heterocyclic thiols/thiones. The anti-bacterial activity of the synthesised complexes and heterocyclic parent compounds were evaluated against on five bacterial strains Mycobacterium smegmatis (M. smegmatis), Staphylococcus aureus (S. aureus), Methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis (E. faecalis) and Escherichia coli (E. coli). The relevance of these complexes and corresponding thiols/thiones as anti-Leishmanial drugs have also been assessed and described. Chapter 2 describes synthesis and characterisation of 21 novel homo- and hetro-leptic bismuth thiolate complexes from a series of heterocyclic thiols:1-methyl-1H-tetrazole-5-thiol 1-MMTZ(H), 4-methyl-4H-1,2,4-triazole-3-thiole 4-MMT(H), 1-methyl-1H-imidazole-2-thiol 2-MMI(H), 5-methyl-1,3,4-thiadiazole-2-thiol 5-MMTD(H) and 1,3,4-thiadiazole-2-dithiol 2,5-MTD(H)₂. Three novel bismuth(V) thiolate complexes [BiPh(4-MTT)₄] 1 and [BiPh(2-MMI)₄] 2, [BiPh(1-MMTZ)₄] 3 were synthesised by the reaction of BiPh3 with 4-MTT(H), 2-MMI(H) and 1-MMTZ(H). Crystallization of complexes 1, 2 and 3 from DMSO over several weeks gave the daughter bismuth(III) thiolate complexes [BiPh(4-MTT)₂{4-MTT(H)}₂] 4, [BiPh(2-MMI)₂{2-MMI(H)₂}] 5 and [BiPh(1-MMTZ)₂{1-MMTZ(H)}₂] 6 respectively following reduction and ligand protonation in DMSO solution. Five bis-thiolato bismuth(III) complexes were also synthesised and the solid-state structures of complexes [BiPh(5-MMTD)₂] 10 and [BiPh{2,5-MTD(H)}₂(Me₂C=O)] 11 were authenticated by single crystal X-ray diffraction studies. In Chapter 3 the synthesis of a five tris-thiolato bismuth(III) complexes was investigated. Overall, it is seen that complexes of bismuth(III) with 4-methylthiazole-2-thiol 2-MTM(H); 3-amino-1H-1,2,4-triazole-5-thiol 5-MAT(H); 5-(methylthio)-1,3,4-thiadiazole-2-thiol 2-MTTD(H); 4-bromobenzene-1-thiol; 1-MBrB(H) and 1-(4-hydroxyphenyl)-1H-tetrazol-5-thiol 5-MBTZ(H) always yielded the tris-thiolato complexes of general form [BiL₃] (L= 2-MTM, 2-MTTD, 5-MAT, MBTZ and 5-MBTZ) 23-26 using BiCl₃ and Bi(OtBu)₃. Complex [Bi(5-MBTZ)₃] 26 was characterised by single crystal X-ray diffraction studies and proved to be a polymeric. Chapter 4 discusses synthesis and characterisation of four novel bis- and tris-thiolato complexes containing the thiazole moiety. A range of bismuth precursors involving BiPh₃, BiCl₃ and Bi(OtBu)3 were employed in their synthesis. The complex [Bi(MBT)₃] 27, [BiPh(MBT)₂] 28 and [Bi(BrMBT)₃] 29 (MBT = 4-phenylthiazole-2-thiol and BrMBT = 4-(4-bromophenyl)thiazole-2-thiol) were determined by single crystal X-ray studies. Chapter 5 discusses the synthesis and characterisation of seven novel 5-substituted-1,3,4-oxadiazole thiones and their bis- and tris-thiolato bismuth(III) complexes. Highlights include [BiPh(Cl-PTOT)₂] 35, [BiPh(Br-PTOT)₂] 36, [Bi(Cl-PTOT)₃] 42 and [Bi(Cl-PTOT)₃] 43 (Cl-PTOT = 5-(2-(4-chlorophenyl)thiazol-4-yl)-1,3,4-oxadiazole-2(3H)-thiolate and Br-PTOT = 5-(2-(4-bromophenyl)thiazol-4-yl)-1,3,4-oxadiazole-2(3H)-thiolate).The solid state structures of 35 and 36 were determined by X-ray crystallography. The synthesis and structural studies of novel mixed thiolato/thione bismuth(III) complexes are discussed in Chapter 6. Five new bismuth(III) complexes [BiPh(5-MMTD)₂{4-MMT(H)}] 45, [Bi(4-MTTZ)₂{(PYM)(PYM-H)₂}] 46, [Bi(MBT)₂{5-MMTD}] 47, [Bi(BrMBT)₃{2-MMI(H)}] 48 and [Bi(1-MTTZ)₂{1-MTTZ(H)}(2-MMI){2-MMI(H)₂}] 49 were synthesised and fully characterised. The solid state structures of all these complexes 45-49 were authenticated by X-ray crystallography. Chapter 7 explores the biological applications of the synthesised bismuth(III) complexes. Activity of bismuth(III) thiolate complexes was tested against L. major promastigotes and results were compared with the activity of commercial drug Amphotericin B. Many of free thiols/thiones and their bismuth(III) complexes showed promising anti-Leishmanial activity. The activity of the synthesised complexes was also assessed against M. smegmatis, S. aureus, MRSA, E. faecalis and E. coli. Most of the complexes proved to be highly active against these pathogens and gave significantly lower inhibitory concentration values (0.10-2.45 µM) than the commercially available drugs isoniazid and vancomycin. Mammalian cell toxicity tests were conducted against human fibroblast cells and COS-7 cell lines.