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SYNTHESIS AND BIOLOGICAL ACTIVITIES OF PHENYLSULPHONYLAMINOALKANAMIDES

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ABSTRACT

Palladium     catalysed     synthesis     of    substituted     2-[acetyl(phenylsulphonyl)amino]-3- methylbutanamide  (176) is reported. The  intermediate 2-[acetyl(phenylsulphonyl)amino]-3- methybutanamide     (175)     was     obtained     by     the     reaction     between     2-[acetyl (phenylsulphonyl)amino]-3-methybutanoic acid chloride (175) and ammonia. Substituted 2- [acetyl (phenylsulphonyl)amino]-3-methylbutanamides (176a-f) were obtained by coupling 2-[acetyl (phenylsulphonyl)amino]-3-methylbutanamide (175) with various readily available substituted aryl halides via a Buchwald-Hartwig-type  cross coupling protocol. Structures of the synthesized compounds were confirmed using Fourier transform infrared (FT-IR), as well as  proton  and  carbon-13  Nuclear  Magnetic  Resonance  (1HNMR  and  13CNMR).   The antimicrobial  properties  of  the  synthesized  sulphonamides  were  determined  on  Bacillus subtilis,  Salmonella  typhi,  Staphylococcus  aureus,  Pseudomonas  aeruginosa,  Escherichia coli, Klebsiella  pneumonia,  Candida  albican  and Aspergillus  niger   using  agar diffusion technique.  The antimicrobial  activities against some pathogenic  microorganism  have been reported  in this work. Results showed  significant  improvement  in antimicrobial  activities compared with tetracycline and fluconazole used as reference drugs.

CHAPTER ONE

1.0       Introduction

The  sulphonamides  constitute  a  class  of  organosulphur   compounds.  They  are   amide derivatives of sulphonic acids. These compounds contain the RSO2NH2  group.  They are a family  of  broad-spectrum  synthetic  bacteriostatic  antibiotics.  They  are  among  the  most

widely  used  classes  of  antibiotics  in  the  world1,  with  the  general  structural  formula

represented by 1.

R      S     NR1R2

O      1

R = alkyl, aromatic or heteroaromatic groups

R1 , R2 = hydrogen, alkyl, aromatic or heteroaromatic groups

Sulphonamides are known to represent a class of medicinally important compounds which are  extensively  used  as  anticancer2,  antitumour3,  antiviral4,  antimalaria5,   antidiabetic6, antihypertensive7,     antituberculosis8,     antiosteoarthiritis9,     anticataract10,     antidiuretics11, antimigraine12, antiretroviral13, and inhibitors of carbonic anhydrase,  among others. Before the discovery of antibiotics in the 1940s, sulphonamides were the first efficient compounds

used to treat microbial infections. Topical sulphonamides are employed in infections of the eye, mucous membrane and skin. The emergence of resistant bacterial strains replaced the therapeutic use of some of the sulphonamides with other drugs. Mixtures of sulphonamides

with other drugs have also been used in the treatment of various infections15. The mixture of

sulphamethoxazole-trimethoprim  (septran) is often preferred in treating current urinary tract infections  and  especially  for  opportunistic  infections  in  patients  with  AIDS.  Some  of aromatic/heterocyclic   sulphonamides  and  their  derivatives  showed  very  high  inhibitory

activity  against  carbonic  anhydrase16.  Some  of  these  sulpha  drugs  that  have  performed

“healing magic” in world of chemotherapy include:

( Anticancer Drug)

Sulphamonomethoxine

(Diurectic drug)

In addition, sulphonamides are also highly relevant both in the animal world and plant life cycle. In fact, the breaking of cyclic guanosine monophosphate  is retarded by sildenafil, a substituted  guanine  analog,  which  keeps  cut  flowers  fresh  for  another  week  and  also

strengthens plants stems to stand straight even in the midst of storm and wind17. A preserving

effect on fruit vegetables was also found, making sildenafil (9) an agent for the treatment of erectile dysfunction in man. Today, it is marketed under the trade name Viagra which is a

potent drug used in the treatment of erectile dysfunction in man18.

Furthermore,  the  sulphonamide  group  has  been  proved  to  have  remarkable  utility  in medicinal  chemistry  and  expectedly  features  in  the  structure  of  a  number  of  clinically relevant small molecules19. For instance, some currently approved drugs with sulphonamide

structural skeletons include: the antihypertensive agent bosentan (10)20, glibenclamide (11)21,

antidiabetic nonantibiotic glimepiride (12) and the diurectic drug, torasemide (13)22,23.

1.1 Mechanism of Action of Antimicrobial Sulphonamides

Mechanistically,  antimicrobial sulphonamides  compete with p-amino benzoic acid (14)  for incorporation into folic acid (15), which is required for growth by all cells. Since folic acid cannot  cross  bacteria  walls  by diffusion  or  active  transport,  these  organisms must  then synthesize  folic  acid  (15)  from  p-amino  benzoic  acid  (14).  Its  antimicrobial  activity  is explained below.

1.1.1    Synthesis of folic acid24. (15)

Pteridine (16) reacts with p-amino benzoic acid (14) to give pteroic acid (17) which treats with glutamic acid (18) to give folic acid (15)



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