الفهرس 
Chapter (1) IntroductionOnly 14 pages are availabe for public view
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Abstract
The continued emergence of antimicrobial resistance is a major global
concern. The rapid development of resistance mechanisms by bacteria, as well
as the lack of new structurally and mechanistically distinct classes of antibiotics,
means that new antibiotics and antibiotic targets are desperately needed. In view
of this, development of effective antimicrobial agents continues to be a great
challenge, particularly due to the increasing resistance of superbugs and frequent
hospital breakouts. There is an urgent need for more potent and safer antibiotics
with novel scaffolds. In light of the above-mentioned considerations, the
objective of this study was to synthesize potential antimicrobial lead compounds
based on 2,4-thiazolidinedione and/or rhodanine scaffolds. Literature survey
showed amongst all heterocyclic rings, 2,4-thiazolidinedione and Rhodanine
surrogates play an important role in many dysfunctions of body like diabetes,
cancer, viral and bacterial diseases. Furthermore, hybridization of two or more
bioactive molecules often leads to increase activity due to synergistic effects To examine this proposal, modifications were made at the
thiazolidinedione skeleton to allow the installation of rhodanine
pharmacophore as one of the 4-thiazolidinones subtype. Our objective was to
synthesize thiazolidinedione- rhodanine hybrids with the aim to fulfill the
structure activity relationships as well as to establish how this modification
affects antimicrobial activity.
The starting key compound, thiazolidine-2, 4-dione-5-acetic acid (3) was prepared from maleic anhydride (1) and thiourea (2) under reflux for 5 h in presence of concentrated hydrochloric acid. The acid (3) was converted to the corresponding acid chloride (4) by refluxing with thionyl chloride SOCl2, in anhydrous 1, 4-dioxan medium for 1h. The synthetic approach for exploration of pathway of conjugation of two heterocyclic rings to have structure containing drug molecule with good synergistic affect towards its biological target due to presence of more heteroatoms as binding sites was achieved. Therefore, the synthesis of bisthiazolidine-2,4-dione analogues and thiazolidine-2,4-dione rhodanine hybrids were synthesized by reaction of acid chloride (4) with Z-arylidene rhodanine / thiazolidinedione derivatives (10-13) by heating in DMF and in presence of anhydrous pyridine as a base to afford the new hybrids (14-17) in good yields. Derivatives (10-13) were synthesized by a Knoevenagel condensation as per previously reported protocolas by the condensation of 2,4-thiazolidinedione 6 and rhodanine 7 with aromatic aldehydes (8-9) . Sodium acetate and glacial acetic acid were used as the catalyst and reaction medium. All the synthesized compounds were elucidated and characterized by IR, 1H NMR and 13C NMR spectroscopy. Further, the acid chloride (4) reacts with the appropriate aryl amines (18a-h) in presence of base such as tri ethylamine by refluxing with 1,4-dioxan for 10 min to 30 min to afford the corresponding acetamide derivatives (19a-h) in good yields. Finally, reactions of the acid chloride (4) with aryl sulfonyl hydrazides (20a-d) under reflux in DMF and in presence of triethylamine as a base afforded the corresponding acyl sulfono hydrazide analogues (21a-d) in good to excellent yields.
Furthermore, in present study, the antimicrobial assay of the novel sulfonohydrazide, acetamide, acetate derivatives were carried out towards reference strains using a serial dilution method to obtain the MIC. None of tested compounds had activity against gram-negative bacteria except 19a and 19b derivatives which showed highest inhibitory activity against all tested microorganisms; Furthermore, most of synthesized compounds exhibited strong antibacterial activity against gram positive bacteria. However, compounds 14, 21a and 17 represented highest activity against Gram-positive bacteria and yeast with lowest activity Gram-negative bacteria E. coli, P. mirabilis, and K. pneumonia. Compounds 19c, 19d, 19e, 19f, and 19g represented moderate activity against all tested microorganisms, Compound 19b have bactericidal activity against S. aureus, E. faecalis, B. subtilis, S. epidermidis S. Typhimurium, E. coli, P. mirabilis, K. pneumonia, and P. aeruginosa. Indeed, showed bacteriostatic action against C. albicans, C. glabrata, C. parapsilosis, B. cereus, and M. luteus. On the other hand, compound 14 showed highly bacteriostatic activity against both S. aureus, B. subtilis, M. luteus reference strains and 19a have bacteriocidal activity against all tested strains except M. luteus, E. coli, and C. parapsilosis.
In conclusion, our initial goal to synthesize new analogues based on 2,4-thiazolidinedione scaffolds could be achieved. This leads to have derivatives with promising anti-microbial activity in vitro compared with the reference drug ciprofloxacin and nystatin. Further optimization of the most active compound for the in vivo study is currently underway in our laboratory.