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SYNTHESIS AND BIOLOGICAL TESTING OF NEW 1-ADAMANTYL DERIVATIVES

Pharmacological Properties of Adamantane Derivatives Antiviral Activities Antimicrobial Activities Anti-inflammatory Activity CNS Activities 11  -HSD1 Inhibitory Activity Miscellaneous Activities

Antiviral Adamantane Derivatives Anti-Influenza and Anti-Herpes viruses

Anti-HIV Derivatives

Antimicrobial Adamantane Derivatives

Anti-inflammatory Adamantane Derivatives

CNS Activities Anti-Parkinsonian Activity The high lipophilicity of the adamantane derivatives enables them to pass through the blood brain barriers leading to the existence of high levels of these derivatives in the central nervous system The therapeutic efficacy of amantadine in the symptomatic treatment of Parkinson's disease was discovered in 1969 Amantadine is known to increase the synthesis, release and uptake of dopamine in the striatum Amantadine was found to act as blocker of brain monoamineoxidase A and as non-competitive N-methyl-D-aspartate (NMDA)-receptor antagonist thereby influencing the dopamine transmission

11  -HSD1 Inhibitory Activity

Pharmacological Properties of 1,2,4-Triazoles 1,2,4-Triazoles (s-triazoles) and their fused heterocyclic derivatives are known for their diverse pharmacological activities. The most interesting of these are the anti- inflammatory, analgesic, antibacterial, antifungal and other activities.

Anti-inflammatory 1,2,4-triazole derivatives

Antimicrobial 1,2,4-triazole derivatives

1,2,4-Triazolo[3,4-b][1,3,4]thiadiazoles

Pharmacological Properties of 1,3,4-Thiadiazoles 1,3,4-Thiadiazole-2-sulphonamides were early known as carbonic anhydrase inhibitors which are clinically useful in the treatment of various diseases such as glaucoma, epilepsy, congestive heart failure, mountain sickness, gastric and duodenal ulcers and other neurological disorders Antibacterial, antifungal and anti-inflammatory activities were also reported for several 1,3,4-thiadiazole derivatives

1,3,4-Thiadiazoles as Carbonic Anhydrase Inhibitors

Antimicrobial 1,3,4-Thiadiazoles

RESEARCH OBJECTIVES

NMR data of compound 145b

NMR data of compound 146e

NMR data of compound 149c

NMR data of compound 150j

NMR data of compound 151e

NMR data of compound 151o

NMR data of compound 152i

NMR data of compound 154c

NMR data of compound 155b

NMR data of compound 157

NMR data of compound 164a

BIOLOGICAL TESTING In vitro antimicrobial testing (all new compounds) In vivo acute anti-inflammatory testing in rats (26 compounds) Oral acute toxicity of compounds 151l and 159 in mice.

Antimicrobial Activity The primary screening was carried out using the agar disc-diffusion method using Müller-Hinton agar medium for measuring the growth inhibitory activity against the standard strains of the Gram-positive bacteria: Staphylococcus aureus IFO 3060, Bacillus subtilis IFO 3007, Micrococcus luteus IFO 3232, the Gram-negative bacteria Escherichia coli IFO 3301, Pseudomonas aeuroginosa IFO 3448 and the yeast-like pathogenic fungus Candida albicans IFO 0583 The minimal inhibitory concentration (MIC) for the most active compounds against the same microorganism used in the primary screening was carried out using the microdilution susceptibility method in Müller- Hinton Broth and Sabouraud Liquid Medium

Diameter of Growth Inhibition Zone (mm)Ar/R Comp. No. C APAECMLBSSA C6H5C6H5 145a FC 6 H 4 145b FC 6 H 4 145c ClC 6 H 4 145d BrC 6 H 4 145e C6H5C6H5 146a FC 6 H 4 146b FC 6 H 4 146c ClC 6 H 4 146d BrC 6 H 4 146e NH CH 3 NH149a CH 3 CH 2 NH149b CH 3 (CH 2 ) 3 NH149c CH 2 =CH-CH 2 NH149d C 6 H 5 CH 2 NH149e NT Gentamicin NT Ampicillin 21NT Clotrimazole

Diameter of Growth Inhibition Zone (mm)R Comp. No. C APAECMLBSSA H 150a F 150b F 150c Cl 150d Cl 150e Br 150f OH 150g OH 150h CH 3 150i OCH 3 150j OCH 3 150k NO 2 150l NO 2 150m (CH 3 ) 2 N 150n ,6-F 2 150o Cl,6-F 150p ,6-Cl 2 150q ,4-Cl 2 150r ,4-Cl 2 150s ,4-(CH 3 O) 2 150t ,4-(NO 2 ) 2 150u NO 2,4,5- (CH 3 O) 2 150v

Diameter of Growth Inhibition Zone (mm)R Comp. No. C APAECMLBSSA CH 3 151a C2H5C2H5 151b COOC 2 H 5 151c C6H5C6H5 151d FC 6 H 4 151e CF 3 C 6 H 4 151f CH 3 OC 6 H 4 151g C 6 H 5 CH 2 151h CH 3 151i C2H5C2H5 151j COOC 2 H 5 151k C6H5C6H5 151l FC 6 H 4 151m CF 3 C 6 H 4 151n CH 3 OC 6 H 4 151o C 6 H 5 CH 2 151p NT Gentamicin NT Ampicillin 21NT Clotrimazole

Diameter of Growth Inhibition Zone (mm)R Comp. No. C APAECMLBSSA H 152a F 152b Cl 152c CH 3 152d OH 152e OH 152f OCH 3 152g ,6-F 2 152h Cl,6-F 152i ,6-Cl 2 152j ,4-Cl 2 152k ,4-Cl 2 152l ,4-(CH 3 O) 2 152m NO 2,4,5-(CH 3 O) 2 152n NT Gentamicin NT Ampicillin 21NT Clotrimazole

Diameter of Growth Inhibition Zone (mm)R/X Comp. No. C APAECMLBSSA H 154a F 154b Cl 154c NO 2 154d CH 3 155a CH 3 CH 2 155b C6H5C6H5 155c NT Gentamicin NT Ampicillin 21NT Clotrimazole

Diameter of Growth Inhibition Zone (mm)X Comp. No. C APAECMLBSSA H 164a F 164b Cl 164c NT Gentamicin NT Ampicillin 21NT Clotrimazole

Minimal Inhibitory Concentration (MIC,  g/ml) Comp. No. C APAECMLBSSA ND a ND 4 145b ND 12145e ND h ND 4 150o ND 2 151n ND 4 152a ND 2 152e 8ND 12152f ND m ND20.5ND 153 ND ND ND 4 164b ND 2 164c ND Gentamicin ND Ampicillin 2ND Clotrimazole

Anti-inflammatory Testing The acute anti-inflammatory activity of 26 representative compounds was determined in vivo following the carrageenan-induced paw oedema method in rats The selection of the representative compounds and dose levels were made after carrying out pilot experiments which showed the absence of anti-inflammatory activity in compounds 146a-e, 148 and 149a-e The compounds were tested at 20 and 40 mg/kg dose levels

Mean % Reduction of paw oedemaR/XComp. No. 40 mg/kg20 mg/kg ,4-(CH 3 O) 2 150t C6H5C6H5 151d CH 3 OC 6 H 4 151g C2H5C2H5 151j C6H5C6H5 151l FC 6 H 4 151m H152a Cl152c OH152e ,4-Cl 2 152l C2H5C2H5 155b Indomethacin (5 mg/kg)

Oral Acute Toxicity Testing (gm/kg) LD 50 (95% Confidence limit)LD 84 LD 50 LD 16 Comp. No ( ) l 2.52 ( )

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