ABSTRACT
We report the synthesis and characterisation of a novel series of triazole benzenesulfonamide derivatives, which incorporate the general pharmacophore associated with carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesised compounds were tested in vitro against four human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I, hCA II, hCA IV and hCA IX. The obtained results showed that the tumour-associated hCA IX was the most sensitive to inhibition with the synthesised derivatives, with the triazolo-pyridine benzenesulfonamides 14, 16 and 17 being the most effective inhibitors. Some selected compounds were chosen for a single dose anti-proliferative activity testing against a panel of 57 human tumour cell lines and show some anti-proliferative activity ex vivo.
Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Sulfonamides/pharmacology , Triazoles/pharmacology , Carbonic Anhydrases/drug effects , Carbonic Anhydrases/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Isoenzymes/drug effects , Isoenzymes/metabolism , Spectrum Analysis/methods , Sulfonamides/chemistry , Triazoles/chemistry , BenzenesulfonamidesABSTRACT
In this work, novel series of pyran, thiophene and thienopyrimidine derivatives based on 2-acetamide-thiadiazole scaffold were designed and synthesized for evaluation as selective COX-2 inhibitors in-vitro and investigated in-vivo as anti-inflammatory and analgesic agents against carrageenan-induced rat paw oedema model in irradiated rats, since its well-known that ionizing radiation plays an important role in exaggerating the inflammatory responses and in enhancing the release of inflammatory mediators in experimental animals. Toxicological studies were carried out to evaluate the ulcerogenic activity, acute toxicity and kidney and liver functions for the most potent compounds. In order to understand the binding mode of the synthesized compounds into the active site of COX-2, docking study was performed. Most of the tested compounds showed high inhibitory ability to COX-2. Among them, thiadiazole derivatives bearing thiophene and thienopyrimidine moieties were the most active derivatives, compound 26 showed extremely high selectivity index (SI) of >555.5µM which is nearly two folds better than celecoxib (>277.7µM), in addition to compounds 3, 16, 17, 21 and 26 with SI in the range of >308.6- >384.6µM. The 4-chlorothieno[2.3-d]pyrimidine derivative of thiadiazole 21 showed the highest anti-inflammatory activity in this study having 24.49% of oedema compared to celecoxib (18.61%) in addition to compounds 17 and 26 with 24.70 and 25.40% of oedema, respectively, while the thiadiazol-2-acetamide derivative 2 was the most potent analgesic compound with the highest nociceptive threshold (85.72g) very close to that of celecoxib (90.23g). These compounds showed high safety margin on gastric mucosa with no ulceration effect. Also the most active in-vivo anti-inflammatory compounds 17, 21 and 26 were found to be non-toxic in experimental rats with normal kidney and liver functions. Docking study of the synthesized compounds showed similar orientation as celecoxib within the active site of COX-2 enzyme and similar ability to emerge deeply in the additional pocket and binding with Arg513 and His90 the key amino acids responsible for selectivity.
Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Thiadiazoles/pharmacology , Animals , Male , RatsABSTRACT
New quinoline derivatives 6, 7 and 19, pyrimidoquinoline derivatives 8-16 and triazolopyrimidoquinoline derivatives 17 and 18 bearing a bromo-substituent were synthesized starting from 3-(4-Bromophenylamino)-5,5-dimethylcyclohex-2-enone 3. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 9, 11, 17 and 18 showed IC(50) values (36.4, 39.7, 39.02 and 36.4 µM, respectively) comparable to that of the reference drug doxorubicin (IC(50) = 32.02 µM). On the other hand, compound 6, 14 and 19 exhibited better activity than doxorubicin with IC(50) values of 8.5, 23.5 and 23.7 µM. Additionally, the most potent compounds 6, 14 and 19 were evaluated for their ability to enhance the cell killing effect of γ-radiation.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Quinolones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Cell Line, Tumor , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Female , Gamma Rays , Humans , Inhibitory Concentration 50 , Quinolones/chemical synthesis , Quinolones/chemistry , Radiation-Sensitizing Agents/chemical synthesis , Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/pharmacologyABSTRACT
Novel quinazolines 4-11, 15 and triazoloquinazolines 12-14 bearing biologically active sulfonamide moieties were synthesized. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against liver cancer cell line (HEPG2). Some of the screened compounds exhibited interesting cytotoxic activity compared to doxorubicin as a reference drug. The most active compounds 13 and 15 were selected and evaluated for their ability to enhance the cell killing effect of gamma-radiation, compound 15 was superior to doxorubicin in radiation combination therapy.
