Research Of Imidazo[2,1-b]benzothiazoles As New Type Of Potential Antimicrobial Agents

Benzothiazoles are a special type of sulfer and nitrogen conjungated aromatic heterocyles,which enables them to bind with various receptors,enzymes,proteins and signal pathways through non-covalent interactions including hydrogen bonds,electrostatic interaction,cation-?,?-?stacking,ion-dipole hydrophobic effect and so on,and thus exhibiting potentially therapeutic effects for various diseases.The exploitation of these molecules facilitates rapid discovery of biologically active compounds across an extensive range of therapeutic areas over a protractible time phase.Especially,in recent years,imidazo[2,1-b]benzothiazoles,the fascinating members of benzothiazole family have been revealed to be significant heterocycles because of their wide range of pharmacological activities.Recent studies from many laboratories implicate the activity of these scaffolds against many of the most common human diseases,including diabetes,cancers,microbial infections,and an array of neurological syndromes.They demonstrated antihelmintic activity and are vascular endothelial cell proliferation,treating proliferative diseases and modulators of protein kinase.The related researches of which enables it to bind with various receptors,enzymes,proteins and signal pathways through non-covalent interactions including hydrogen bonds,electrostatic interaction,cation-?,?-?stacking,ion-dipole hydrophobic effect and so on,and thus exhibiting potentially therapeutic effects for various diseases have been an extremely active topic.Azoles?imidazoles,triazoles,benzimidaozles,tetrazoles?are a significant class of nitrogen heterocycles with multiple heteroatoms,aromaticity and electron rich properties.The exceptional structure facilitates azole-based derivatives to bind effortlessly through noncovalent interactions like coordination and hydrogen bonds with enzymes and receptors in living organisms,thus imparting diverse applications in the scope of medicinal chemistry.Therefore,this thesis designed and synthesized a series of azolyl imidazo[2,1-b]benzothiazoles and evaluated their antimicrobial activities according to our previous researches on benzothiazoles.The highly active compounds were further studied for the pharmacology,toxicology and pharmacokinetics,and the preliminary antibacterial mechanism was also investigated.The main work was summarized as follows:?1?Preparation of azoalkyl ether imidazo[2,1-b]benzothiazoles:The intended azoalkyl ether imidazo[2,1-b]benzothiazoles II-5-7 were prepared by involving multiple step reactions starting from commercially available benzothiazol-2-amine and/or6-ethoxybenzothiazol-2-amine.Condensationofbenzothiazol-2-amineand6-ethoxybenzothiazol-2-amine and phenacyl bromide in the presence of ethanol at 70 ^oC resulted compounds II-2a-b in 90–92%yield,which was then subjected to hydroxyl methylation using acetic acid and sodium acetate at 60 ^oC producing compounds II-3a-b in yields of 74–76%.?2?Preparation of imidazo[2,1-b]benzothiazole-based fluconozole hybrids:Mannich reaction of imidazo[2,1-b]benzothiazole,N-boc piperizine with formaldehyde in the presence of ethanol and acetic acid for 3-4 h at 70 ^oC produced N-boc-piperizine derivatives III-3a-b in moderate yields of 72.4-75.7%.Compounds III-4a-b were obtained in good yield of 64-66%by the de-boc reaction of III-3a-b in triflouroacetic acid.The target molecules III-5a-l were produced in 48.3-54.6%yields by the ring opening reaction.?3?Preparation of benzimidazole-derived imidazo[2,1-b]benzothiazoles:The intended hybrids were produced from imidiazo[2,1-b]benzothiazole.the compounds IV-3a-b undergoes cyclization with benzene-1,2-diamines at 70 ^oC in good yields to afford compounds IV-4a-b.Alkyl derivatives IV-5a-n and aryl alkyl analogues IV-6a-j were obtained in yields of 73–82%by the reaction of compound IV-4a with different aliphatic or substituted aromatic halides respectively in dry DMF at 60 ^oC using potassium carbonate as a base.?4?Preparation of Schiff base imidazo[2,1-b]benzothiazoles:All target Schiff base imdiazo[2,1-b]benzothiazoleswereefficientlypreparedfromcommercial2-aminobenzothiazole,phenacyl bromide and different secondary amine derivatives.Further V-2a-b undergoes Vielsmeir-hack reaction with phosphorus oxychloride and dimethyl formamide at 50 ^oC in chloroform for 12 h to obtain carbonyl intermediates IV-3a-b.The latter was condensed with different amine derivatives in ethanol under reflux using a catalytic amount of concentrated acetic acid at 80°C using potassium carbonate as the base to afford the target Schiff base imdiazo[2,1-b]benzothiazoles V-4a-b,V-5a-d,V-6a-d,V-7a-b,V-8a-b,and V-9a-d in good yield.?5?All the newly synthesized compounds were characterized by ¹H NMR,¹³C NMR,IR,MS,and HRMS spectra.?6?TheantimicrobialresultsrevealedthatcompoundII-5awith2-methyl-5-nitro-1H-imidazole linked to imidazo[2,1-b]benzothiazole backbone with propyl chain gave stronger antibacterial efficacies and broader bioactive spectrum than norfloxacin and chloromycin with quite low MIC?2?g/mL?.The electrostatic maps revealed that molecule II-5a possessed more negative charged regions on the nitro groupof2-methyl-5-nitro-1H-imidazoleandnitrogenatomsof imidazo[2,1-b]benzothiazole.Compound II-5a as when compared to the clinical drug,and thus this structure through substantial therapeutic potency and low drug-resistance might serve as a hopeful candidate as an anti-MRSA agent.?7?The antifungal evaluation in vitro displayed that compound III-5c exerted superior antifungal potency against A.fumigatus?MIC=4?g/mL?and C.parapsilosisATCC 20019?MIC=4?g/mL?to fluconazole andcomparable inhibitory actions towards C.albicans?MIC=1?g/mL?.This drug-resistance result provided an encouragingly starting point in the discovery of novel antifungal agents to overcome drug resistance.DNA-drug interaction studies showed that compound III-5c could replace NR in the DNA-NR complex thus stipulated that hybrid III-5c could intercalate into calf thymus DNA.?8?The antibacterial assay results suggested that Pentyl derivatives IV-5c and IV-5j gave significant activities with MIC values ranging from 2 to 8?g/mL against S.aureus ATCC 25923,S.aureus ATCC 29213,K.pneumonia,A.baumanii,and E.coli 25922,which is comparatively significant than chloromycin.Molecular docking study compounds IV-5j and IV-6g were docked with the DNA gyrase B.?9?The obtained antimicrobiaol results showed that 6-bromo-naphthalamide compound V-8b with ethoxyl substitution on the 7-position of the imidazo[2,1-b]benzothiazole backbone gave the best antibacterial activities with MIC values of 2–32?g/mL towards the subsequent bacteria.Compound V-8b had potent killing effects against drug-resistant E.coli ATCC 25922.Drug resistance studied showed that the very slowly developing resistance of E.coli ATCC 25922 to6-bromo-naphthalamide Schiff-base bridged imidazo[2,1-b]benzothiazole V-8b even after 11 passages.In this thesis,a library of imidazo[2,1-b]benzothiazole derivatives was constructed,and 95 compounds were synthesized including 72 new compounds.The antimicrobial evaluation indicated that 50 compounds exerted better antibacterial effects against some strains than referece drugs.The higly active compounds were further studied,and the results demonstrated that these compound could rapidly kill bacteria,intercalate into DNA and be transtported by HSA,which indicated that this type of compounds exerted great potentiality in the treatment of microbial infections.