A New Avenue for Enhanced Treatment of Hyperuricemia and Oxidative Stress: Design, Synthesis and Biological Evaluation of Some Novel Mutual Prodrugs Involving Febuxostat Conjugated with Different Antioxidants.

Febuxostat (FEB) is the first non-purine xanthine oxidase inhibitor (XOI) used for the treatment of hyperuricemia and gout. The oxidative stress induced by reactive oxygen species (ROS) which accompany purine metabolism by XO, could contribute to cellular damage and several pathological conditions. In this view, the present work addresses the evaluation of combining the hypouricemic effect of FEB and the free radical scavenging potential of various natural antioxidants in a single chemical entity by implementing the "mutual prodrug" strategy. Accordingly, a series of five ester prodrugs containing FEB together with different naturally occurring antioxidants namely, thioctic acid (4), thymol (5), menthol (6), vanillin (7), and guaiacol (8) was synthesized. Prominently, all the chemically conjugated prodrugs (4 - 8) revealed an obvious increase in the hypouricemic and antioxidant potentials when compared with their corresponding promoieties and physical mixtures. Moreover, they showed a potential protective effect against CCl4-induced hepatotoxicity and oxidative stress, together with no cytotoxicity on normal breast cells (MCF10A). Furthermore, the in vitro chemical and enzymatic stability studies of the prodrugs (4 - 8) using a developed HPLC method, verified their stability in different pHs, and rapid hydrolysis in rabbit plasma and liver homogenate to their parent metabolites. Moreover, the prodrugs (4 - 8) showed higher lipophilicity and lower aqueous solubility when compared to the parent drugs. Finally, the obtained merits from the implementation of the mutual prodrug strategy would encourage further application in the development of promising candidates with high therapeutic efficacy and improved safety profiles.

Towards the Development of Dual Hypouricemic and Anti-inflammatory Candidates: Design, Synthesis, Stability Studies and Biological Evaluation of Some Mutual Ester Prodrugs of Febuxostat-NSAIDs.

Treatment of gout involves two basic approaches: reducing the serum uric acid mainly by xanthine oxidase inhibitors (XOIs) and alleviating the intensity of the accompanying acute arthritic inflammation using non-steroidal anti-inflammatory drugs (NSAIDs). Febuxostat (FEB) is the first non-purine XOI approved for the treatment of hyperuricemia and gout. The present study aims at combining the hypouricemic effect of FEB and the anti-inflammatory (AI) properties of NSAIDs in a single entity by adopting the "mutual prodrug" approach. Accordingly, a series of seven ester prodrugs comprising basically FEB together with different NSAIDs namely, diclofenac (4), ibuprofen (5), ketoprofen (6), indomethacin (7), naproxen (8), ketorolac (9) and etodolac (10) was synthesized. All the investigated seven prodrugs (4-10) were equipotent or even superior to their corresponding parent drugs in the hypouricemic and AI activities, together with a gastrointestinal (GI) safety profile. Among this series, the prodrug FEB-DIC (4) showed excellent dual in vivo hypouricemic and anti-inflammatory activity (43.60 % and 15.96 %, respectively) when compared to the parent drugs FEB and diclofenac (36.82 % and 12.10 %, respectively) and its physical mixture (37.28 % and 12.41 %, respectively). Investigation of the in vitro chemical stability and hydrolysis of the prodrug (4) in aqueous and biological samples using a developed HPLC method confirmed its stability in various pHs, whereas rapid hydrolysis to the parent drugs in liver homogenate and human plasma was proven. Finally, it is concluded that the mutual prodrug approach could be successfully used in drug design and development for overcoming undesirable difficulties without losing the desired activities of the parent drugs.

The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats.

Liver Fibrosis can be life-threatening if left untreated as it may lead to serious, incurable complications. The common therapeutic approach is to reverse the fibrosis while the intervention is still applicable. Celecoxib was shown to exhibit some antifibrotic properties in the induced fibrotic liver in rats. The present study aimed to investigate the possible antifibrotic properties in CCl4-induced liver fibrosis in male Sprague-Dawley rats compared to celecoxib of three novel methoxylated pyrazolo[3,4-d]pyrimidines. The three newly synthesized compounds were proved to be safe candidates. They showed a therapeutic effect against severe CCl4-induced fibrosis but at different degrees. The three compounds were able to partially reverse hepatic architectural distortion and reduce the fibrotic severity by showing antioxidant properties reducing MDA with increasing GSH and SOD levels, remodeling the extracellular matrix proteins and liver enzymes balance, and reducing the level of proinflammatory (TNF-α and IL-6) and profibrogenic (TGF-ß) cytokines. The results revealed that the dimethoxy-analog exhibited the greatest activity in all the previously mentioned parameters compared to celecoxib and the other two analogs which could be attributed to the different methoxylation patterns of the derivatives. Collectively, the dimethoxy-derivative could be considered a safe promising antifibrotic candidate.

Febuxostat-based amides and some derived heterocycles targeting xanthine oxidase and COX inhibition. Synthesis, in vitro and in vivo biological evaluation, molecular modeling and in silico ADMET studies.

Various febuxostat derivatives comprising carboxamide functionalities and different substituted heterocycles were synthesized and evaluated for their biological activities as xanthine oxidase (XO) and cyclooxygenase (COX) inhibitors. All the tested compounds exhibited variable in vitro XO inhibitory activities (IC50 values 0.009-0.077 µM), among which the analog 17 has emerged as the most potent derivative (IC50 0.009 µM), representing nearly 3-times the potency of febuxostat (IC50 0.026 µM). The same analogs were further investigated for their in vitro COX-1 and COX-2 inhibitory activity, where fifteen analogs demonstrated recognizable COX-2 inhibitory potential (IC50 values range 0.04 - 0.1 µM), when correlated with celecoxib (IC50 0.05 µM), together with appreciable selectivity indices. Compounds 5a, 14b, 17, 19c, 19e and 21b that showed significant in vitro XO and/ or COX inhibitory potentials were further investigated for their in vivo hypouricemic as well as anti-inflammatory activities. Interestingly, the in vivo results were concordant with the collected in vitro data. Docking of compounds 5a, 14b, 17, 19c, 19e and 21b with the active sites of XO and COX-2 isozymes demonstrated superior binding profile compared with the reported ligands (febuxostat and celecoxib, respectively). Their docking scores were reasonable and cohering to a great extent with their corresponding in vitro IC50 values. Moreover, in silico computation of the predicted pharmacokinetic and toxicity properties (ADMET), together with the ligand efficiency (LE) of the same six compounds suggesting their liability to act as new orally active drug candidates with a predicted high safety profile.

Synthesis of Nucleosides and Non-nucleosides Based 4,6-disubstituted-2-oxo-dihydropyridine-3-carbonitriles as Antiviral Agents.

BACKGROUND: Viral diseases are considered main threats that face the humanity worldwide. The emergence of new viruses like influenza viruses emphasizes the significance of designing novel antiviral drugs. METHOD: The aim of this work is to synthesize a new set of nucleoside and non-nucleoside cyanopyridine, characterized and evaluated for their in vitro antiviral properties against various strains. CONCLUSION: More of the compounds showed variable antiviral potential against a panel of eighteen DNA and RNA viruses. The screening data suggested that the order of activity of the active compounds are in the order of O-glycosyl > O-alkyl > N-alkyl > S-alkyl derivatives. In addition, the 4-fluoro substituted compounds are more effective among the O- and N-alkyl analogs, whereas remarkable antiviral activity was ascribed to the methoxylated O-glycosyl derivatives. Most of the active compounds proved to be more selective towards the inhibition of the replication of DNA rather than the RNA-viruses. The analogs 1a, 2a, 12b, 14b and 16b possessed broad spectrum and noticeable antiviral potential against most of the tested DNA- and RNA-viruses (EC50 ≈ 0.8-20 µM), accompanied with considerably low cytotoxic margin (MCC ≈ 4-20 µM), and comparable with reference standard antiviral agents.

Structure-based development of novel triazoles and related thiazolotriazoles as anticancer agents and Cdc25A/B phosphatase inhibitors. Synthesis, in vitro biological evaluation, molecular docking and in silico ADME-T studies.

Synthesis of twenty nine new 1,2,4-triazoles and some derived thiazolothiadiazoles (structurally-relevant to some reported triazoles with anticancer and/or Cdc25A/B inhibitory activities) is described in this study. The obtained NCI's in vitro antitumor data revealed that five analogs (12, 15, 18, 19 and 22) displayed considerable tumor percentage growth inhibitory activity (GI%), among which the analog 18 possessed a special antitumor potential and spectrum. Additionally, the same five analogs showed a marginal GI effect on the normal breast epithelial cell line MCF-10A indicating higher selectivity towards cancer cells. The same active analogs 12, 15, 18, 19 and 22 were further assessed for their in vitro Cdc25A/B phosphatase inhibitory activity (a possible antitumor target), where 18 and 22 displayed a distinctive inhibitory affinity towards the Cdc25B isozyme (6.7 and 8.4 µM, respectively). Docking of 12, 15, 18, 19 and 22 with the active site of human Cdc25B phosphatase enzyme demonstrated superior binding profile by the top-scoring analog 18 relative to a reported Cdc25 phosphatase ligand. In silico calculations of molecular properties revealed that all of the active compounds comply with Lipinski's RO5 and Veber's criteria for good bioavailability suggesting good drug-likeness upon oral administration with a predicted high safety profile.

Synthesis, Anti-Inflammatory Activity, and COX-1/2 Inhibition Profile of Some Novel Non-Acidic Polysubstituted Pyrazoles and Pyrano[2,3-c]pyrazoles.

The synthesis and evaluation of the anti-inflammatory activity of some structure hybrids comprising basically the 5-hydroxy-3-methyl-1-phenyl-4-substituted-1H-pyrazole scaffold directly linked to a variety of heterocycles and functionalities, or annulated as pyrano[2,3-c]pyrazoles, is described. According to the in vivo results and a comprehensive structure-activity relationship study, five analogs (5, 10, 17, 19, and 27) displayed remarkable anti-inflammatory profiles showing distinctive % protection and ED50 values, especially 10 and 27 (ED50 35.7 and 38.7 µmol/kg, respectively) which were nearly equiactive to celecoxib (ED50 32.1 µmol/kg). Compounds 10, 17, and 27 exhibited distinctive COX-2 inhibition with a noticeable COX-2 selectivity (SI values 7.83, 6.87, and 7.16, respectively), close to that of celecoxib (SI 8.68). Additionally, 5, 10, 17, 19, and 27 proved to be gastrointestinal tract safe (0-20% ulceration) and non-toxic, being well tolerated by the experimental animals up to 250 mg/kg orally and 80 mg/kg parenterally. Collectively, the in vivo ED50 values for the most potent five derivatives agree with their in vitro COX-2 selectivity indices, suggesting their usefulness as selective anti-inflammatory COX-2 inhibitors. The bipyrazole 10 and the pyranopyrazole 27 could be considered as the most active members in this study, being nearly equiactive to celecoxib, besides their obvious selective COX-2 inhibition, high safety margin, and predicted pharmacokinetic (ADME-T) suitability for oral use.

Compounds Containing Azole Scaffolds as Cyclooxygenase Inhibitors: A Review.

There has been considerable interest in azole-containing compounds as promising antiinflammatory agents. Designed compounds with five-membered nitrogen-containing nuclei have demonstrated good anti-inflammatory activity, indicating their potential for the treatment of this highly irritating condition. Pyrazoles, have attracted much more attention than other azoles, however, reports on other azoles demonstrated that they were as effective as pyrazoles. This review describes the different classes of azoles designed as cyclooxygenase inhibitors and the effect of different structural modifications on their activity.

Synthesis of Some 1,4,6-Trisubstituted-2-oxo-1,2-dihydropyridine-3-carbonitriles and Their Biological Evaluation as Cytotoxic and Antimicrobial Agents.

A series of novel 1,4,6-trisubstituted-2-oxo-1,2-dihydropyridine-3-carbonitriles supported with some functionalities reported to contribute to significant chemotherapeutic potential were synthesized and evaluated for their antimicrobial and/or cytotoxic activities. Thirteen compounds exhibited cytotoxic potential against a panel of three human tumor cell lines. Compounds 15, 23, and 24 proved to be the most active agents with a broad spectrum of cytotoxic activity. Analog 24 was considered as the most active cytotoxic agent, being 2.5 times more active than doxorubicin against the colon HT29 carcinoma cell line. Seventeen compounds were able to exert a variable antimicrobial profile, among which analogs 15, 20, 21, 23, and 24 were prominently active. The highest antimicrobial potential was displayed by analog 24, being equipotent to ampicillin against Staphylococcus aureus and Escherichia coli, together with a considerable antifungal activity comparable with clotrimazole. Collectively, compounds 15, 23, and 24 could be considered as possible dual antimicrobial-anticancer candidates.

Microwave-assisted synthesis of certain pyrrolylpyridines, some derived ring systems and their evaluation as anticancer and antioxidant agents.

The synthesis of 18 novel pyrrolylpyridines and some derived bi-, tri- and tetracyclic ring systems using both the conventional heating and MW irradiation techniques is described. Fourteen compounds; 2-9, 10-12, 14, 17 and 18 were evaluated for their antitumor activity according to the National Cancer Institute (NCI), in vitro disease oriented antitumor screening. Distinctive antitumor activity was conjugated with compounds 3 and 7 (R = 3,4-di-OCH3-C6H3). The analogs 3, 6, 7, 9, 10, 11 and 12 which exhibited prominent antitumor activity, were further evaluated for their antioxidant potential using the DPPH radical scavenging assay. The substituted 6-(3,4-dimethoxyphenyl)pyridine-3-carbonitriles 3 and 7 were nearly equipotent to BHT the standard antioxidant utilized in this assay (scavenging activity 31 and 33%, respectively, vs 36%). Accordingly, compounds 3 and 7 can be considered as lead structures for dual antitumor and antioxidant activities.

Synthesis and biological evaluation of pyrazole chalcones and derived bipyrazoles as anti-inflammatory and antioxidant agents.

A series of bipyrazoles functionalized with sulfonamide, N(1),N(3)-disubstituted sulfonylurea, sulfonylthiourea pharmacophores, and some derived thiazolidinone and thiazoline ring systems were synthesized. The structures of the newly synthesized compounds were substantiated by analytical and diverse spectroscopic data. The anti-inflammatory and antioxidant activity of some of the newly synthesized compounds were tested and the results reveled that compounds 14, 16, 20, 24 and 25 proved to be the most active anti-inflammatory agents according to the Carrageenan-induced rat paw edema bioassay. Whereas, the analogs 14, 16 and 24 were able to exhibit good to moderate antioxidant activity in the DPPH radical-scavenging assay. Hence, compounds 14, 16 and 24 can be considered as lead structures for dual anti-inflammatory and antioxidant activities.

Bifunctional ethyl 2-amino-4-methylthiazole-5-carboxylate derivatives: synthesis and in vitro biological evaluation as antimicrobial and anticancer agents.

Thirty thiazole compounds bearing chemotherapeutically-active pharmacophores were synthesized and evaluated for their preliminary in vitro antimicrobial and anticancer activities. Nineteen compounds displayed obvious antibacterial potential, with special bactericidal activity against Gram positive bacteria, whereas, nine analogs showed moderate to weak antifungal activity against Candida albicans. The analog 12f proved to be the most active antimicrobial member identified in this study being comparable to ampicillin and gentamicin sulfate against Staphylococcus aureus and Bacillus subtilis, together with a moderate antifungal activity. Additionally, nine derivatives were tested for their preliminary in vitro anticancer activity according to the current one-dose protocol of the NCI. Compound 9b revealed a broad spectrum of anticancer activity against 29 out of the tested 60 subpanel tumor cell lines. Collectively, compounds 4, 9b, 10b and 12f could be considered as promising dual anticancer antibiotics.

Synthesis and biological evaluation of some novel urea and thiourea derivatives of isoxazolo[4,5-d]pyridazine and structurally related thiazolo[4,5-d]pyridazine as antimicrobial agents.

This study reports the synthesis of some novel isoxazolo[4,5-d]pyridazines and structurally related thiazolo[4,5-d]pyridazines, and their biological evaluation as antimicrobial agents. The proposed compounds were designed to contain pharmacophores such as urea, thiourea, sulfonylurea (thiourea) and some derived functionalities that are believed to contribute to the anticipated biological activities. The results revealed that 25 compounds displayed broad spectrum of antibacterial activity, with greater inhibitory effect on the growth of the tested Gram positive strains compared to Gram negative ones. Moreover, 14 compounds were able to produce appreciable growth inhibitory activity against Candida albicans fungus when compared to Clotrimazole. Most of the tested isoxazolo[4,5-d]pyridazines displayed better antimicrobial profile than their corresponding thiazolo[4,5-d]pyridazine congeners. Four compounds namely, p-(3,7-dimethyl-4-oxo-4H-isoxazolo [4,5-d]pyridazine-5-yl)benzenesulfonylthioureas (11c-d), 3-substituted-2-[p-(3,7-dimethyl-4-oxo-4H-isoxazolo[4,5-d]pyridazine-5-yl)-benzene-sufonylimino]-4-oxothiazolidines (13d) and p-(2,7-dimethyl-4-oxo-4H-thiazolo[4,5-d]pyridazin-5-yl)benzenesulfonylthiourea (24c) were found to be most active antimicrobial members in present study.

Synthesis, in vitro antitumor evaluation and DNA-binding study of novel tetrahydroquinolines and some derived tricyclic and tetracyclic ring systems.

The synthesis of some new tetrahydroquinolines, tetrahydropyrimido[4,5-b]quinolines, and tetrahydropentaazacyclopenta[a]anthracenes structurally related to some DNA intercalators is described. Fifteen compounds were evaluated for their antitumor activity by the National Cancer Institute (NCI), in vitro disease oriented antitumor screening. The most active tricyclic pyrimido[4,5-b]quinolines 3b, 6b, 7b and 8b were further subjected to DNA-binding investigation in an attempt to rationalize their activity. Compound 8b proved to be the most active member in this study as evidenced from its remarkable growth inhibitory potential against some individual cell lines, and its broad spectrum of antitumor activity (GI50, TGI and LC50 values 46.9, 85.3 and 97.4, respectively), together with a good DNA-binding affinity.

Synthesis and characterization of some hydroxypyridone derivatives and their evaluation as antimicrobial agents.

The synthesis, in vitro antimicrobial activities of some novel hydroxy pyridines supported with various pharmacophores is described. Twenty-six out of the tested 58 compounds exhibited variable inhibitory effects on the growth of the tested Gram positive and Gram negative bacteria. The tested compounds revealed better activity against the Gram positive rather than the Gram negative strains. The synthesized hydroxypyridones have shown very significant inhibitory effect against Staphylococcus aureus and Bacillus subtilis. Twelve compounds namely; 5d, 5f, 6a, 6b, 8b, 18b, 18c, 19c, 21d, 22b, 22d and 23d were able to produce appreciable growth inhibitory activity against Candida albicans when compared to Clotrimazole. Among these, 22d proved to be the most potent antifungal agent.

Synthesis and in vitro antitumor and antimicrobial activity of some 2,3-diaryl-7-methyl-4,5,6,7-tetrahydroindazole and 3,3a,4,5,6,7-hexahydroindazole derivatives.

The synthesis of a series of 2,3-diaryl-7-methyl-4,5,6,7-tetrahydroindazole and 3,3a,4,5,6,7-hexahydroindazole derivatives substituted with various biologically-active function groups with anticipated chemotherapeutic activity is described. 4-(7-methyl-3-aryl-3,3a,4,5,6,7-hexahydro-indazol-2-yl)benzenesulfonamides 2a-c, which were employed as key intermediates in this study, were synthesized by cyclocondensation of 6-arylidene-2-methylcyclohexanones 1a-c with 4-hydrazinobenzenesulfonamide hydrochloride. A detailed discussion of the reactions utilized in the preparation of the intermediate and target compounds is reported, and the structures of the newly synthesized compounds were substantiated with IR, (1)H and (13)C NMR spectral data and elementary microanalyses. Twenty of the newly synthesized compounds were selected by National Cancer Institute (NCI), Maryland, USA, to be evaluated for their antitumor activity and the results revealed that six compounds 3c, 4d,e, 5a,d and 8c exhibited broad spectrum of antitumor activity against most of the tested tumor cell lines. In addition, the in vitro antibacterial and antifungal activities of a number of the target compounds were also tested using the Agar-diffusion method. Some of these compounds have shown significant antibacterial and mild to moderate antifungal activities.

3-cyano-8-methyl-2-oxo-1,4-disubstituted-1,2,5,6,7,8-hexahydroquinolines: synthesis and biological evaluation as antimicrobial and cytotoxic agents.

The synthesis, in vitro antimicrobial and cytotoxic activities of some novel hexahydroquinolines supported with various pharmacophores are described. The results revealed that 18 compounds displayed pronounced activity against Staphylococcus aureus and Escherichia coli bacteria beside a moderate antifungal activity. Compound 25 is the most active candidate with equipotency to ampicillin against S. aureus, E. coli and Pseudomonas aeruginosa, together with an obvious antifungal activity. Additionally, 12 compounds showed remarkable cytotoxic efficiency against human colon carcinoma HT29, hepatocellular carcinoma Hep-G2 and Caucasian breast adenocarcinoma MCF7 cell lines. Among these, the analogs 22 and 25 proved to be the most active cytotoxic members. Collectively, the results would suggest that compounds 22 and 25 could be considered as possible dual antimicrobial-anticancer agents.

Synthesis of some pyrazolines and pyrimidines derived from polymethoxy chalcones as anticancer and antimicrobial agents.

The synthesis of a series of certain polymethoxy chalcones and some derived pyrazole, pyrimidine, and thiazolopyrimidine ring structures is reported. Eleven compounds 4, 6, 9, 11, 14-17, 22, 24, and 25 were selected by the National Cancer Institute (NCI) to be screened for their in-vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in-vitro antimicrobial activity. Compounds 4, 6, and 11 were found to possess a significant broad spectrum antitumor potential against most of the tested subpanel tumor cell lines. The pyrazolines 4 and 6 displayed remarkable growth inhibitory activities (GI(50) MG-MID values of 2.10 and 1.38 µM, respectively), together with moderate cytostatic effects (TGI MG-MID values of 47.9 and 42.7 µM, respectively). Meanwhile, the pyrimidin-2-one 11 showed a noticeable overall tumor growth inhibitory activity, together with high cytostatic and cytotoxic efficacies (GI(50) , TGI and LC(50) MG-MID values of 3.39, 17.4, and 61.7 µM, respectively). On the other hand, compounds 3, 4, 13, 15, 19, 20, and 23 were found to be the most active antimicrobial members in this investigation with a broad spectrum of activity. Compound 23 was four times superior to ampicillin against Pseudomonas aeruginosa. The best antifungal activity was demonstrated by compounds 4, 5, and 11 which possessed almost half the activity of clotrimazole against Candida albicans. Collectively, the obtained biological results suggest that compound 4 could be considered as a possible dual antimicrobial-anticancer agent.

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.

Polysubstituted pyrazoles, part 6. Synthesis of some 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazol-3-carbonyl derivatives linked to nitrogenous heterocyclic ring systems as potential antitumor agents.

The synthesis of two novel series of 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazoles linked to either polysubstituted 1H-pyrazole counterparts through a carbonyl bridge, or to some biologically-active nitrogenous heterocycles by an amide linker, is described. Ten of the newly synthesized compounds were selected by the National Cancer Institute (NCI) in vitro disease-oriented antitumor screening to be evaluated for their antitumor activity. The most active six compounds 2, 3, 6, 7, 13 and 14 revealed a significant broad spectrum of antitumor potential against most of the tested subpanel tumor cell lines at the GI(50) and TGI levels, together with a mild cytotoxic (LC(50)) activity. The pyrazolinedione analog 7 displayed remarkable growth inhibition and cytostatic effects (GI(50) and TGI MG-MID values 0.67 and 53.8microM, respectively). Compounds 13 (GI(50), TGI, and LC(50) MG-MID values 0.08, 30.9 and 93.3microM) and 14 (GI(50), TGI, and LC(50) MG-MID values 0.36, 8.78 and 69.3microM, respectively) proved to be the most active antitumor members identified in this study.