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)
This material content is developed to serve as a GUIDE for students to conduct academic research
SYNTHESIS AND BIOLOGICAL ACTIVITIES OF PHENYLSULPHONYLAMINOALKANAMIDES
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