SYNTHESIS AND BIOACTIVITY EVALUATION OF AMOXICILLIN DERIVATIVES

Abstract

The work presented in this thesis consists of “synthesis and bioactivity evaluation of amoxicillin derivatives” which includes the synthesis, optimization, applications and bioactivity evaluation of new metallic derivatives (silver and gold nanoparticles) of amoxicillin and some other beta lactam antibiotics. For a wide spread resistive strains of pathogenic bacteria, there is a need for some new antibacterial agents to treat the patients, infected with such resistive pathogenic bacteria. Here we synthesized new gold and silver derivatives of amoxicillin and some other beta lactam antibiotics like cefuraxime, cephradine, ceftriaxone etc belonging to beta lactam antibiotics family; some of them were penicillins while others are cephalosporins. We synthesized metallic derivatives of amoxicillin in the form of gold and silver nanoparticles and their nano-alloys using NaBH4 and TMA as reducing agents. Reducing agents of different nature (organic and inorganic), NaBH4 and trimethylamine were used for the synthesis of gold and silver nanoparticles to study their effect on sizes and shapes of nanoparticles as well as to avoid the sodium salt formation of amoxicillin and other beta-lactam antibiotics using TMA. It was found that nanoparticles synthesized with NaBH4 were of small size compared to nanoparticles synthesized with TMA. Gold nanoparticles stabilized with amoxicillin were prepared using NaBH4 and TMA as reducing agents. The applications for metallic sensing like Cu, Fe, Co, Ni, Pb, Cd, and Hg etc were studied. Gold nanoparticles stabilized with amoxicillin were fluorescent and were used for the detection of Cu2+ions in water solution. Amoxicillin and gold nanoparticles (AuNPs) stabilized with amoxicillin were screened for enzymes inhibition studies as well antiglycation and results were compared. These AuNPs showed very nice inhibition for urease, carbonic anhydrase and xanthine oxidase enzymes and were found very potent inhibitor for xanthine oxidase enzyme with inhibition of 90% and IC50 value of 2.0±0.01. Amoxicillin showed antiglycation activity while AuNPs were inactive. xv Silver nanoparticles stabilized with amoxicillin were also prepared using NaBH4 and TMA as reducing agents. AgNPs were screened for enzymes inhibition studies and antiglycation activity and results were compared with amoxicillin and it was found that AgNPs were active against urease and xanthine oxidase enzymes while inactive against carbonic anhydrase and no antiglycation activity. Nano-alloys of AgNPs and AuNPs stabilized with amoxicillin were also prepared. These were also screened for enzymes inhibition and antiglycation activity but were inactive. Gold and silver nanoparticles using other stabilizing agents like cefuroxime, cephradine, ceftriaxone and cefixime were also synthesized. Their nano-alloys were also prepared stabilized with the above mentioned antibiotics except cefixime. Their applications for metals sensing like Cu, Fe, Co, Ni, Pb, Cd, and Hg etc. were studied. The metallic sensing application of cefixime was investigated and was found that AgNPs stabilized with cefixime detected Ni ion in water solution while its AuNPs detected Cu ion in water solutions. Cephradine stabilized gold nanoparticles detected Hg and Cd ions in water solution upto micro molar concentration. The comparative bioassays of gold and silver nanoparticles stabilized with cefuroxime, cephradine, ceftriaxone and cefixime as well as their parent compounds were also studied and compared. Cefuroxime and their gold and silver nanoparticles showed best results in case of urease inhibitions. Cefuroxime was also found to be active by inhibiting urease enzymes along with its antibiotic activities. AuNPs stabilized with cefuroxime were also active against carbonic anhydrase enzymes. While its silver and nan-alloys were active by inhibiting in Vitroα-Chymotrypsin enzymes. Cephradine stabilized silver nanoparticles and nano-alloys were active for xanthine oxidase enzyme with an inhibition of 87.9% and 85.9% with IC50 value 6.9±1.5 μg/mL and IC50 value 6.76±0.07 μg/mL respectively. AuNPs and parent compound were inactive against XO enzymes inhibition. AuNPs, AgNPs, nano-alloys and parent compound cephradine were active for urease enzymes inhibition and inactive for antiglycation activity except the parent compound. AuNPs and AgNPs were active for carbonic anhydrase inhibition while Nano-alloys and parent compound were inactive. All were inactive for In Vitroα-Chymotrypsin enzyme inhibition. Ceftriaxone caped gold and silver nanoparticles were active for urease inhibition except its nano- alloy while only AgNPs were active for xanthine oxidase enzyme inhibition and rest of members were inactive. All were inactive for the remaining enzymes as well as antiglycation activity. Cefixime is active against xanthine oxidase enzyme inhibition and antiglycation activity while gold and silver nanoparticles were active for urease enzyme inhibition only.