Designed, synthesis and antibacterial evolution of piperazine hybrids.

Abstract

Piperazine is a kind of azacycloalkane that has two nitrogen atoms at1-4 places on a six-membered ring. It is well known that molecules with the piperazine ring, a key component of the N-heterocyclicfamily of bioactive natural products, are often prevalent in biologically active substances. There are many antitumor, antibacterial, antiinflammatory, antipsychotic, antifungal, and anti-diabetic compounds based on the piperazine scaffold, which has been recognized as an active structure in drug discovery. Piperazine hybrids with different moieties such as isoniazid, coumarin, benzothiazinones, isoquinoline, triazole,pyrrole, and oxazolidinone showed good activity against mycobacterium tuberculosis and microbial strains. In this thesis we have demonstrated the synthesis of piperazine hybrid with hydrazides, hydrazines, and coumarines and tested their activity against mycobacterium tuberculosis, gram positive and gram negative microbial strains. In Chapter 2, we have covered topics related to the analogues of piperazine that have anti-tubercular efficacy. This chapter we have published as a review article in European Journal of Medicinal Chemistry. In this review, we have made a concerted effort to trace the development of anti-mycobacterial compounds during the past 50 years (1971-2019), focusing on instances where piperazine has been utilized as a key building block. In depth discussion of the design, rationale, and structure-activity relationship (SAR) of the reported potent piperazine-based anti-TB molecules will help medicinal chemists fill in the blanks, capitalize on the reported strategies, and create more effective, selective, and less hazardous anti-mycobacterial drugs. In chapter 3, we have developed and synthesized a new class of hybrids between phenylpiperazine and hydrazides (c1-c15). During the synthesis of phenyl piperazines, the formylation of piperazine was observed, a phenomenon on which we have developed a different methodology discussed in chapter 5. All of the derivatives have been tested in vitro against H37Rv, a strain of mycobacterium. In addition, we have analysed the zone of inhibition against eight different bacterial strains, including both gram-positive (methicillin resistant staphylococcus aureus (MRSA), Streptococcus pyrogens, Bacillus subtilis, Enterococcus faecium, and Staphylococcus aureus), and gram-negative (Enterobacter hormaechei, Pseudomonas aeruginosa, and Escherichia coli) bacteria. Among the derivatives tested, only compound c8 showed action against the mycobacterium strain H37Rv (MIC value of 0.39-0.78 g/ml). No zone of inhibition was seen for any of the microbiological strains when exposed to any of the synthesized compounds. The hybrids between phenylpiperazine sulphonamide and phenyl hydrazide (E1-E6) and phenylpiperazine sulphonamide and phenyl hydrazine (F7-F19) were proposed and synthesized in chapter 4. All substances were evaluated against mycobacterium tuberculosis, five gram-positive and three gram-negative bacterial strains in vitro. Derivatives E1 and E2 with an isoniazid moiety were the most effective in inhibiting the growth of the H37Rv strain of tuberculosis, with an IC50 value of 3.125 M. Of the derivatives tested, F10 showed significant action against the gram-positive bacteria Enterococcus faecium (7.81 μg/mL), whereas the others (E2, E6, F7, F9, F14) were only moderately active (250-62.5 μg/mL). Using a the molecular hybridization strategy, we were enabled to create novel analogues of coumarin-(phenylsulfonyl)piperazine and 4-methyl coumarin-(phenylsulfonyl)piperazine in chapter 5.All synthesised compounds were evaluated for their in vitro anti-mycobacterial and antimicrobial activity against H37Rvand a variety of antimicrobial gram-positive and gram-negative strains.The Compounds 6G, 6H, 10D and 10E displayed moderate inhibition against gram positive and gram negative strains with MIC values in the range of 62.5-250 (table 1) against MRSA, Bacillus subtilis, and Enterococcus faecium, and gram negative strains Enterobacter hormaechei, Pseudomonas aeruginosa, and Escherichia coli.In addition, the Structure-Activity Relationship (SAR) analysis showed that phenyl ring substituents could enhance antibacterial activity. Chapter 6 came from the process of synthesizing phenyl piperazine in chapter 1. This chapter disclosed a method for efficient synthesis of transamidation in the presence of Iodine and NH2OH.HCl which published in Chemistry Select. This method is efficient for a broad range of primary, secondary, and tertiary amides, and it enables the formylation, acylation, and benzoylation of a number of different amines. The key benefits of the present technique are that it is easy to follow, quick, does not need a metal catalyst, uses a starting material that is inexpensive, and has a low effect on the environment when the synthesis process is carried out. All of the chapters in this thesis are written in thesis by publication style, rather than the conventional style.