Adnan A. Bekhit

Design and synthesis of some substituted 1H-pyrazolyl-thiazolo[4,5-d]pyrimidines as anti-inflammatory-antimicrobial agents

The synthesis of two novel series of structurally related 1H-pyrazolyl derivatives of thiazolo[4,5-d]pyrimidines is described. All the newly synthesised compounds were examined for their in vivo anti-inflammatory activity in two different bioassays namely; cotton pellet-induced granuloma and carrageenan-induced paw edema in rats. The in vitro inhibitory activity of the most active compounds towards human COX-1 and COX-2 enzymes was also estimated. In addition, the ulcerogenic effects and acute toxicity (LD(50)) values of these compounds were determined. The same compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, as an example of Gram negative bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and Candida albicans as a representative of fungi. The results revealed that compounds 5a, 9a, 9b, 10b and 12a exhibited anti-inflammatory activity comparable to that of indomethacin in both local and systemic in vivo animal models with no or minimal ulcerogenic effects (0-10%) and high safety margin (LD(50) > 500 mg kg(-1)). In addition, most of them displayed appreciable antibacterial activities when compared with ampicillin, especially against S. aureus. Compounds 9a and 12a are the most distinctive derivatives identified in the present study because of their remarkable in vivo and in vitro anti-inflammatory activity in addition to their pronounced antibacterial activities comparable to ampicillin against Gram positive and -negative bacteria. Therefore, they are considered as successful dual anti-inflammatory-antimicrobial candidates.

Design and Synthesis of Some Oxadiazolyl, Thiadiazolyl, Thiazolidinyl, and Thiazolyl Derivatives of 1H‐Pyrazole as Anti‐inflammatory Antimicrobial Agents

Four series of 1H‐pyrazole derivatives have been synthesized. The first series was prepared by cyclization of the intermediate 3‐(5‐bromo‐2‐thienyl)‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde aroylhydrazone 4a—c with acetic anhydride to afford the corresponding oxadiazoline derivatives 5a—c. The other series were prepared by the cyclization of the intermediate 3‐(5‐bromo‐2‐thienyl)‐1‐phenyl‐4‐substituted thiocarbamoylhydrazonomethyl‐1H‐pyrazole 6a—c with acetic anhydride, ethyl bromoacetate or phenacyl bromide giving rise to 3‐(5‐bromo‐2‐thienyl)‐1‐phenyl‐4‐[3‐acetyl‐5‐(N‐substituted acetamido)‐2,3‐dihydro‐1,3,4‐thiadiazol‐2‐yl]‐1H‐pyrazoles 7a—c, 3‐(5‐bromo‐2‐thienyl)‐1‐phenyl‐4‐(3‐substituted‐4‐oxothiazolidin‐2‐ylidenehydrazonomethyl)‐1H‐pyrazoles 8a—c, or 3‐(5‐bromo‐2‐thienyl)‐1‐phenyl‐4‐(3‐substituted‐4‐phenyl‐2,3‐dihydrothiazol‐2‐ylidenehydrazonomethyl)‐1H‐pyra zoles 9a—c respectively. Some of these compounds showed antiinflammatory, antibacterial or antifungal activities comparable to that of Proquazone, Ampicillin, or Clotrimazole respectively.

Synthesis and biological evaluation of some thiazolylpyrazole derivatives as dual anti-inflammatory antimicrobial agents

The synthesis of a novel series of 4-thiazolylpyrazolyl derivatives is described in the present report. All the newly synthesized compounds were examined for their anti-inflammatory activity using cotton pellet-induced granuloma and carrageenan-induced rat paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), ulcerogenic effect and acute toxicity were also determined. Furthermore, all compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, Staphylococcus aureus and Candida albicans. A docking pose for compounds 8b, 10a and 10b separately in the active site of the human COX-2 enzyme and DNA-gyrase B was also obtained. The results revealed that compounds 8b, 10a and 10b exhibited good anti-inflammatory activity with no or minimal ulcerogenic effect and good safety margin. Compounds 10a and 10b were found to be the most potent anti-inflammatory agents in the present study. Meanwhile, 10a and 10b displayed higher selective inhibitory activity towards COX-2 compared to indomethacin. Moreover, compounds 10a and 10b exhibited promising antibacterial against both E. coli and S. aureus. Docking studies for 8b, 10a and 10b with COX-2 (PDB ID: 1CX2) and DNA-gyrase B (PDB ID: 1EI1) showed good binding profile.

Pyrazoles as Promising Scaffold for the Synthesis of Anti-Inflammatory and/or Antimicrobial Agent: A Review

There has been a considerable interest in the development of novel compounds with anti-inflammatory and /or antimicrobial activities. Several economical and social merits have been prospected for compounds with dual effects. Pyrazoles are an important class of compounds for new drug development that attracted much attention. Several pyrazole derivatives have been synthesized as target structures and evaluated for their biological activities. This review describes the synthesis and the development of new pyrazoles that possess anti-inflammatory and /or antimicrobial activities. The cytotoxicity of the reported compounds indicate good safety associated with many of the pyrazole derivatives, however, the need for standardized method for cytotoxicity evaluation is required for better understanding of the compounds safety and the safety-structure relationships.

Synthesis and antitumor evaluation of new polysubstituted thiazole and derived thiazolo[4,5-d]pyrimidine systems

The synthesis of three categories of compounds containing the 1H‐pyrazole ring linked to some dihydrothiazoles, thiazolidinones, and thiazolo[4, 5‐d]pyrimidines through different linkages is described. Nine of the newly synthesized target compounds were selected by the NCI for in‐vitro antitumor screening. Four compounds, namely 4a, 4b, 13, and 14, exhibited a broad spectrum of antitumor activity against most of the tested tumor cell lines. Compound 4a, 3‐phenyl‐4‐amino‐5‐(3, 5‐dimethyl‐1‐phenyl‐1H‐pyrazole‐4‐methylidenehydrazinocarbonyl)thiazole‐2(3H)‐thione proved to be the most active antitumor agent in the present study with GI50, TGI, and LC50 MG‐MID values of 3.93, 41.7, and 91.2 μM, respectively. The same compound also exhibited high selectivity towards CNS SNB‐75 and Ovarian IGROV1 cancer cell lines at both the GI50 and TGI levels. Compound 4b, 3‐(4‐chlorophenyl)‐4‐amino‐5‐(3, 5‐dimethyl‐1‐phenyl‐1H‐pyrazole‐4‐methylidenehydra‐zinocarbonyl) thiazole‐2(3H)‐thione showed nearly the same pattern of activity as 4a but to a lesser extent. Compounds 13 and 14 displayed moderate antitumor activity against most of the tested tumor cell lines with GI50 MG‐MID values range of 20.4—80.6 μM and TGI MG‐MID values of 55.5—95.5 μM.

A Novel COX‐2 Inhibitor Pyrazole Derivative Proven Effective as an Anti‐Inflammatory and Analgesic Drug

The introduction of new COX-2 inhibitors with high efficacy and enhanced safety profile would be a great achievement in the development of anti-inflammatory drugs. This study was designed to screen and assess the anti-inflammatory and analgesic activities as well as some of the expected side effects of some pyrazole derivatives, newly synthesized as potential COX-2 inhibitors at the Faculty of Pharmacy, Alexandria University and compared to indomethacin and celecoxib. Twelve compounds were screened for their anti-inflammatory activity using carrageenan-induced paw oedema and cotton pellet granuloma tests. On the basis of their apparent anti-inflammatory activity, four compounds with different substitutions were selected for the evaluation of their analgesic activity using the formalin-induced hyperalgesia and hot-plate tests. Compound AD 532, ((4-(3-(4-Methylphenyl)-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide)), showed very promising results. In the single-dose and subchronic toxicity studies, compound AD 532 showed no ulcerogenic effect and produced minimal effects on renal function. Furthermore, compound AD 532 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It is concluded that compound AD 532 appears to be a promising and safe option for the management of chronic inflammatory conditions. This study recommends more in-depth investigation into the therapeutic effects and toxicity profile of this compound including its cardiovascular toxicity.

Synthesis of new series of quinoxaline based MAO-inhibitors and docking studies

A series of 2-benzyl-3-(2-arylidenehydrazinyl)quinoxalines 3, 4-benzyl-1-aryl-[1,2,4]triazolo[4,3-a]quinoxalines 4 and phenyl(1-aryl-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)methanones 5 analogues were synthesized and investigated for their monoamine oxidase (MAO) inhibitory property. The inhibition profile was found to be competitive for compounds 3k, 3m, 5f and 5n with MAO-A selectivity. Observation of the docked positions of these compounds revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. The structural features of the new compounds have been determined from the microanalytical, IR, (1)H, (13)C NMR spectral studies and X-ray crystalography.

Antifungal and antiviral products of marine organisms

Marine organisms including bacteria, fungi, algae, sponges, echinoderms, mollusks, and cephalochordates produce a variety of products with antifungal activity including bacterial chitinases, lipopeptides, and lactones; fungal (-)-sclerotiorin and peptaibols, purpurides B and C, berkedrimane B and purpuride; algal gambieric acids A and B, phlorotannins; 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol, spongistatin 1, eurysterols A and B, nortetillapyrone, bromotyrosine alkaloids, bis-indole alkaloid, ageloxime B and (-)-ageloxime D, haliscosamine, hamigeran G, hippolachnin A from sponges; echinoderm triterpene glycosides and alkene sulfates; molluscan kahalalide F and a 1485-Da peptide with a sequence SRSELIVHQR; and cepalochordate chitotriosidase and a 5026.9-Da antifungal peptide. The antiviral compounds from marine organisms include bacterial polysaccharide and furan-2-yl acetate; fungal macrolide, purpurester A, purpurquinone B, isoindolone derivatives, alterporriol Q, tetrahydroaltersolanol C and asperterrestide A, algal diterpenes, xylogalactofucan, alginic acid, glycolipid sulfoquinovosyldiacylglycerol, sulfated polysaccharide p-KG03, meroditerpenoids, methyl ester derivative of vatomaric acid, lectins, polysaccharides, tannins, cnidarian zoanthoxanthin alkaloids, norditerpenoid and capilloquinol; crustacean antilipopolysaccharide factors, molluscan hemocyanin; echinoderm triterpenoid glycosides; tunicate didemnin B, tamandarins A and B and; tilapia hepcidin 1-5 (TH 1-5), seabream SauMx1, SauMx2, and SauMx3, and orange-spotted grouper β-defensin. Although the mechanisms of antifungal and antiviral activities of only some of the aforementioned compounds have been elucidated, the possibility to use those known to have distinctly different mechanisms, good bioavailability, and minimal toxicity in combination therapy remains to be investigated. It is also worthwhile to test the marine antimicrobials for possible synergism with existing drugs. The prospects of employing them in clinical practice are promising in view of the wealth of these compounds from marine organisms. The compounds may also be used in agriculture and the food industry.

Synthesis and biological evaluation of some pyrazole derivatives as anti-malarial agents.

Novel series of pyrazole derivatives were synthesized and tested for their in vivo anti‐malarial activity using mice infected with chloroquine sensitive P. berghei at a dose level of 50 µmol/kg. The most active compounds were further tested in vitro against chloroquine resistant (RKL9) strain of P. falciparum. The in vivo anti‐malarial activity study indicated that compounds 2a, 2b, 8a and 8b had mean percent suppression of 85%, 83%, 95% and 97%, respectively at equimolar dose level of the standard drug chloroquine diphosphate. Moreover, compounds 2a, 2b, 8a and 8b showed in vitro IC50 values lower (p < 0.05) than that of the standard drug chloroquine phosphate (0.188 ± 0.003  µM) using the RKL9 strain. Compound 8b was the most active with IC50 of 0.033 ± 0.014  µM. Generally, among the tested compounds, those containing a free carboxylic acid functional group on the pyrazole ring were the most active and this finding was supported by the docking results performed for the active compounds. The acute toxicity studies of the active compounds revealed that they have a good safety profile.

Synthesis of some pyrazolyl benzenesulfonamide derivatives as dual anti-inflammatory antimicrobial agents

Four series of pyrazolylbenzenesulfonamide derivatives were synthesized and evaluated for their anti-inflammatory activity using cotton pellet induced granuloma and carrageenan-induced rat paw edema bioassays. Moreover, COX-1 and COX-2 inhibitory activity, ulcerogenic effect and acute toxiCIT000y were also determined. Furthermore, the target compounds were screened for their in-vitro antimicrobial activity against Eischerichia coli, Staphylococcus aureus and Candida albicans. Compounds 4-(3-Phenyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9a and 4-(3-Tolyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9b were not only found to be the most active dual anti-inflammatory antimicrobial agents in the present study with good safety margin and minimal ulcerogenic effect but also exhibited good selective inhibitory activity towards COX-2. A docking pose for 9a and 9b separately in the active site of the human COX-2 enzyme was also obtained. Therefore, these compounds would represent a fruitful matrix for the development of dual anti-inflammatory antimicrobial candidates with remarkable COX-2 selectivity.