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Nonsteroidal anti-inflammatory drugs represent one of the most popularly used classes of drugs. However, their long-term administration is associated with various side effects including gastrointestinal ulceration. One of the major reasons of NSAIDs ulcerogenicity is direct damage of the epithelial lining cells by the acidic moieties present in many drugs. Another drawback for this acidic group is its rapid metabolism and clearance through Phase II conjugation. Three series of thiophene and thienopyrimidine derivatives were designed and synthesized as nonacidic anti-inflammatory agents. In vivo testing of their analgesic activity indicated that compounds 2b and 7a-d showed higher PI values than that of the positive control drugs, indomethacin and celecoxib. The latter compounds 2b and 7a-d were subjected to further anti-inflammatory activity testing where they showed comparable percentage edema inhibition to that of indomethacin and celecoxib. Compounds 2b, 7a, 7c, and 7d inhibited PGE2 synthesis by 61.10%-74.54% (71.47% for indomethacin, and 80.11% for celecoxib). The same compounds inhibited the expression of rat mPGES-1 and cPGES3 by 74%-83% (77% for indomethacin, and 82% for celecoxib) and 48%-70% (62% for indomethacin, and 70% for celecoxib), respectively. The stability of the most active compound 2b in Nonenzymatic gastrointestinal fluids and in human plasma was tested. Additionally, studying the metabolic stability of compound 2b in S9 rat liver fraction showed that it displayed a slow in vitro clearance with half-life time 1.5-fold longer than indomethacin. The metabolites of 2b were predicted via UPLC-MS/MS. In silico ADMET profiling study was also included.

Background: Breast cancer is currently the leading cause of worldwide cancer incidence exceeding lung cancer. In addition, breast cancer accounts for 1 in 4 cancer cases and 1 in 6 cancer deaths among women. Cytotoxic chemotherapy is still the main therapeutic approach for patients with metastatic breast cancer. Objective: The aim of the study was to synthesize a series of novel celecoxib analogues to evaluate their anticancer activity against the MCF-7 cell line. Method: Our design of target compounds was based on preserving the pyrazole moiety of celecoxib attached to two phenyl rings, one of them having a polar hydrogen bonding group (sulfonamide or methoxy group). The methyl group of the second phenyl ring was replaced with chlorine or bromine atom. Finally, the trifluoromethyl group was replaced with arylidene hydrazine-1-carbonyl moiety, which is substituted either with fluoro or methoxy group, offering various electronic and lipophilic environments. These modifications were carried out to investigate their effects on the antiproliferative activity of the newly synthesized celecoxib analogues and to provide a valuable structure- activity relationship. Results: Four compounds, namely 4e-h, exhibited significant antitumor activity. Compounds 4e, 4f and 4h showed 1.2-2 folds more potent anticancer activity than celecoxib. Celecoxib analogue 4f showed the most potent anti-proliferative activity. Its anti-proliferative activity seems to associate well with its ability to inhibit BCL-2. Moreover, activation of the damage response pathway of the DNA leads to cell cycle arrest at the G2/M phase and accumulation of cells in the pre-G1 phase, indicating that cell death proceeds through an apoptotic mechanism. Compound 4f exhibited a potent pro-apoptotic effect via induction of the intrinsic mitochondrial pathway of apoptosis. This mechanistic pathway was proved by a significant increase in the expression of the tumor suppressor gene p53, elevation in Bax/BCL-2 ratio, and a significant increase in the level of active caspase-7. Furthermore, compound 4f showed moderate COX-2 inhibitory activity. Conclusion: Celecoxib analogue 4f is a promising multi-targeted lead for the design and synthesis of potent anticancer agents.

The present minireview summarizes the data published during the last decade (2012–2019) on the synthesis of nortopsentin analogs and the effect of the structural modifications on the biological activity of the synthesized analogs as antitumor, antifungal, and antiviral agents.

In this work, 3-amino-4-cyano-2-thiophenecarboxamides 1a-k were used as versatile synthons for the preparation of thieno[3,2-d]pyrimidine-7-carbonitriles 2a-k and 4a-d as well as the unexpectedly prepared thieno[3,4-b]pyridine-7-carboxamides 5a-e. Thus, heating thiophene-2-carboxamides 1a-k in formic acid afforded thieno[3,2-d]pyrimidin-4-ones 2a-k. Alternatively, the reaction of compounds 1a-i with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (TMD) in xylene produced the β-keto amides 3a-i. The latter were cyclized to thienopyrimidine-2,4-diones 4a-d by heating with pyrrolidine in toluene using calcium chloride as a desiccant. While refluxing a mixture of β-keto amide derivatives 3a, 3d, 3e, 3f or 3 h and potassium carbonate in ethanol or in ethylene glycol afforded the thieno[3,4-b]pyridine derivatives 5a-e.

An efficient and atom economic modification of a previously reported synthetic pathway to tetrasubstituted thiophenes is described. The previously published synthetic methodology involved a one pot procedure starting with ketene dithioacetal and an appropriate secondary amine, and subsequent reaction with Na2S and phenacyl bromide. However, the liberated methanethiolate by-product was competed with enethiolate intermediate for phenacyl bromide, which reduced the yield and imposed the necessity to use two molar equivalents of α-haloketone reagent to increase the yield of the target thiophene products. In the present work, the proposed modification consisted in isolation of the intermediate enethiolate derivative, thereby reducing quantity of the α-haloketone to one molar equivalent. Moreover, the reaction conditions were optimized to attain optimum base/solvent combination to improve the yield of the target derivatives. Following our modified procedure, three series of new 3-amino-4-cyanothiophene derivatives were synthesized and isolated in high yields and high purity.

This review summarizes the data published on the methods of preparation of β- keto amides as a versatile synthon for many heterocyclic rings and asymmetric urea derivatives. Based on the starting materials used for the synthesis of β-keto amides, eight methods were reported including β-keto acids and their derivatives, Meldrum’s acid and their derivatives, diketene, 2,6-dimethyl-1,3-dioxin-4-one derivatives (TMD), α-diazo ketones, enamines and enolates, acetamides and their derivatives and reduction of certain Passerini products.

Background: Marine sponges and tunicates have been a wealthy source of cytotoxic compounds such as indole alkaloids. Most of the indole alkaloids show in vitro cytotoxic and antineoplastic activities against a wide range of cancer cell lines. Objective: Three series of bioisosteres of marine indole alkaloids (meridianins) were synthesized and the compounds were tested for their in vitro anti-proliferative activity against HCT-116 cellline. In the design of the targeted analogues, the 2-aminopyrimidine ring of merdianins was replaced with 5-aminopyrazole, pyrazolo[1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings. Results: The cytotoxic screening of the synthesized compounds revealed that pyrazolo[1,5- a]pyrimidines (compounds 9c and 11a) had the most potent cytotoxic activity with IC50 = 0.31 μM and 0.34 μM respectively. Compounds 9c and 11a were further investigated for their kinase inhibitory potencies toward six kinases (CDK5/p25, CK1ð/ε, GSK-3α/β, Dyrk1A, Erk2, and CLK1). They exhibited effective inhibition of GSK-3α/β (IC50 = 0.196 μM and 0.246 μM, respectively) and Erk2 (IC50 = 0.295 μM and 0.376 μM, respectively). Conclusion: Meridianins emerged as promising lead structures that need further development to obtain more selective and potent cytotoxic agents. One of these modifications involved the replacement of 2-aminopyrimidinyl ring of meridianins with other heterocyclic rings. Both pyrazolo[ 1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings showed promising cytotoxic activity compared to the five membered 5-aminopyrazole.

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) designed to be a selective cyclooxygenase-2 (COX-2) inhibitor. It was approved by the U.S. Food and Drug Administration for the treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis. Additionally, celecoxib demonstrated potent antitumor and chemopreventive effects in vitro, in vivo, and in patients. The mechanism of celecoxib's chemopreventive effect is still not fully identified, but it is assumed to be multifactorial. Celecoxib's anticancer activity has been described both as independent of and dependent on its COX-2 inhibitory activity. The current review summarizes the recent advances published between 2000 and 2022 on the structure-based optimization of celecoxib to develop compounds with promising anticancer activity. The structure-activity relationships of celecoxib analogs are discussed, which may be beneficial in the design and development of novel analogs as potent antiproliferative agents in the future.

Series of new celecoxib analogs were synthesized to assess their anticancer activity against the MCF-7 cell line. Four compounds, 3a, 3c, 5b, and 5c, showed 1.4-9.2-fold more potent anticancer activity than celecoxib. The antiproliferative activity of the most potent compounds, 3c, 5b, and 5c, seems to be associated well with their ability to induce apoptosis in MCF-7 cells (18-24-fold). This evidence was supported by an increase in the expression of the tumor suppressor gene p53 (4-6-fold), the elevation in the Bax/BCL-2 ratio, and a significant increase in the level of active caspase-7 (4-7-fold). Moreover, compounds 3c and 5c showed significant cyclooxygenase-2 (COX-2) inhibitory activity. They were also docked into the crystal structure of the COX-2 enzyme (PDB ID: 3LN1) to understand their mode of binding.

Background: The reported binding mode of ibuprofen in the COX-2 binding site indicated that the carboxylic group binds with Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel and does not extend into the pocket. This accounted for the non-selectivity of ibuprofen. Based on this fact, we assumed that extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups carrying H-bonding functions might increase the selectivity and reduce the side effects of ibuprofen while maintaining its analgesic and anti-inflammatory activities. Objective: In this work, four series of ibuprofen derivatives were designed and prepared. The compounds were designed by increasing the length of the carboxylate group along with the incorporation of large hydrophobic groups. Method: Four series of ibuprofen derivatives were synthesized starting from ibuprofen. Their chemical structure was confirmed by spectral data. All the compounds were tested for their COX inhibitory activity. Results : The best COX-2 activity and selectivity were obtained with compounds 5c and 5d, which were subjected to further in vivo testing (carrageenan-induced paw edema, rat serum PGE2, TNF- α and IL-6, hot plate latency test) to investigate their anti-inflammatory and analgesic activities as well as their effects on the gastric mucosa. The anti-inflammatory activity of both compounds was comparable to that of ibuprofen, diclofenac, and indomethacin. Both compounds suppressed the production of PGE2 as well as the rat serum concentrations of both TNF-α and IL-6. This potent antiinflammatory and analgesic behavior was not accompanied by any effect on the gastric mucosa. Docking simulation studies of the two compounds explained the higher selectivity for the COX-2 enzyme. Conclusion: Potent and selective ibuprofen derivatives can be successively obtained by extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups with H-bonding functions.

Background: The oceans cover more than 70% of the earth’s surface, which represents over 95% of the biosphere. Therefore, oceans provide a wealth of marine invertebrates, especially sponges, ascidians, bryozoans and molluscs that produce structurally unique bioactive metabolites such as alkaloids. The bioactive scaffolds of marine alkaloids exhibit cytotoxic activities against human cancer cell lines. Objective: To prepare analogues of the marine alkaloid nortopsentin [having 2,4-bis(3'- indolyl)imidazole scaffold] as cytotoxic agents via structural modification of the core imidazole ring and one of the side indole rings. Methods: Four series of nortopsentin analogues were synthesized in which the imidazole ring was replaced by pyrazole, pyrido[2,3-d]pyrimidinone and pyridine rings. Furthermore, one of the side indole rings was replaced by substituted phenyl moiety. The target compounds were tested for their in vitro cytotoxic activity against HCT-116 cell-line and the most potent compound was subjected to further investigation on its effect on HCT-116 cell cycle progression. Results: The cytotoxic screening of the synthesized compounds revealed that bis-indolylpyridinedicarbonitriles 8a-d exhibited the most potent cytotoxic activity with IC50=2.6-8.8 μM. Compound 8c was further tested by flow cytometry analysis to explore its effect on HCT-116 cell cycle progression that, in turn, indicated its anti-proliferative effect. Conclusion: Marine-derived bis-indole alkaloids (nortopsentins) have emerged as a new class of indole-based antitumor agents. The design of new analogues involved several modifications in order to obtain more selective and potent cytotoxic agents. Indole derivatives bearing a pyridine core displayed more potent cytotoxic activity than those containing pyrido[2,3-d]pyrimidin-4(1H)-one moiety.

Aim: The design and synthesis of chromenopyrimidines as microtubule destabilizing agents. Materials & methods: Novel chromenopyrimidines and chromenotriazolopyrimidines were prepared and evaluated for their cytotoxicity against MCF-7 cell line. The most potent compound was tested for its possible effect on tubulin inhibition, cell cycle distribution, apoptosis initiation and caspase-3 activation. Results: All the prepared compounds showed potent cytotoxic activity. Compound 13 was the most prominent (IC50 = 0.13 μM on tumor cell line MCF-7 and 14.06 μM on mammary epithelial cell line MCF-10A). Compound 13 inhibited tubulin polymerization (IC50 = 8.39 μM), caused cell cycle arrest at G2/M phase (fivefold more than control) and cellular apoptosis. Compound 13 increased the level of active caspase-3, 12-fold compared with control.

Three series of benzothiophene derivatives were designed and synthesized as cytotoxic agents. The compounds were subjected to in vitro antitumor screening at the National Cancer Institute (NCI), Bethesda, MD. The results of the single dose screening indicated that only the benzothieno[3,2-b]pyran series 3a–f exhibited potent and broad spectrum cytotoxic activity and was subjected to five dose cytotoxic screening. The most active compound in this study was 2-amino-6-bromo-4-(4-nitrophenyl)-4H-[1]benzothieno[3,2-b]pyran-3-carbonitrile (3e) with MG-MID GI50, TGI, and LC50 values of 0.11, 7.94 and 42.66 μM, respectively. Compound 3e exhibited broad spectrum anticancer activity against a panel of 59 cell lines. To elucidate the underlying mechanism of compound 3e cytotoxic activity, we examined its effect on cell cycle progression and its ability to induce apoptosis using human colon adenocarcinoma cell line (HCT-116). The effect of compound 3e on the cell cycle progression indicated that exposure of HCT-116 cells to compound 3e for 24 and 48 h, induced a significant disruption in the cell cycle profile including time dependent decrease in cell population at G1 phase with concomitant increase in pre-G and G2/M cell population. Moreover, compound 3e induced time dependent increase in the percentage of early and late apoptotic and necrotic cell population. In conclusion, we were able to successfully design a new series of benzothieno[3,2-b]pyran derivatives with potent cytotoxic activity and their mechanism of cytotoxicity was examined.

Two series of 4-phenyl-5-cyanopyrimidin-6-one derivatives bearing various S-alkyl or S-acyl moieties at position 2 were prepared as cytotoxic agents. All compounds were tested for possible anti-cancer activity on two cell lines (MCF-7 and HCT-116). The MCF-7 cell line was found to be more sensitive than the HCT-116 cell line to the action of the compounds. Compound 8g was the most potent on the MCF-7 cell line with IC50 18.3 nM/mL, whereas its IC50 on the normal cell line (MRC-5) was 64.38 nM/mL, indicating its safety and selectivity towards the MCF-7 cell line. On the other hand, compound 8d was the most potent compound on the HCT-116 cell line with IC50 23.8 nM/mL. Compound 8g was screened against five kinases. The compound showed selective inhibitory activity against pim1 kinase with IC50 11.62 µM.

Three series of 2-arylpyridothieno[3,2-d]pyrimidin-4-ones 3a–j, pyridothienotriazolopyrimidines 6–8 and 4-imino-pyridothieno[3,2-d]pyrimidines 9a,b were prepared to improve the pim-1 inhibitory activity of the previously reported 2-arylpyridothieno[3,2-d]pyrimidin-4-ones. All the test compounds showed highly potent pim-1 inhibition with IC50 in the range of 0.06–1.76 µM. No significant difference was detected between the pim-1 inhibitory activity of the 4-pyrimidinone and the 4-imino (=NH) or the cyclised triazolopyrimidine derivatives. The most active compounds were tested for their cytotoxic activity on MCF7 and HCT116 and showed potent activity on both the cell lines.

Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC50 of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18 μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC50 values.

The present study reported the synthesis of tetrahydrocarbazoles hybridized with dithioate derivatives. Three series were synthesized namely alkyl dithiocarbonates (4a–d), heterocyclic dithiocarbamates (6a–g) and dialkyl dithiocarbamate (7). The synthesized compounds were tested in vitro on human breast adenocarcinoma cell line (MCF7) and the human colon tumor cell line (HCT116). Most of the synthesized compounds exploited potent antitumor activity, especially compound 6f [4-chlorophenylpiperazine derivative], which showed cytotoxic activity against MCF7 superior to doxorubicin with IC50 value of 7.24 nM/mL.

A new series of N-substituted diarylidenepiperidin-4-ones was synthesized and screened for their possible anticancer activity at the NCI Developmental Therapeutic Program. Almost all the synthesized compounds showed more potent antiproliferative activity than curcumin. The most active compound in this study was 3,5-bis(4-bromobenzylidene)-1-propanoylpiperidin-4-one (8a) with MG-MID GI50, TGI, and LC50 values of 0.35, 1.62 and 9.12 µM, respectively. Compound 8a displayed broad spectrum antiproliferative activity with GI50 values below 1 µM in 81% of the tested cell lines and was found to be two folds more potent than EF-24. A detailed study of the structure activity relationship of the N-substitution was also described.

Three series of 5-bromo-thieno[2,3-b]pyridines bearing amide or benzoyl groups at position 2 were prepared as pim-1 inhibitors. All the prepared compounds were tested for their pim-1 enzyme inhibitory activity. Two compounds (3c and 5b) showed moderate pim-1 inhibitory activity with IC50 of 35.7 and 12.71 μM, respectively. Three other compounds (3d, 3g and 6d) showed poor pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on five cell lines [MCF7, HEPG2, HCT116, A549 and PC3]. Compound 3g was the most potent cytotoxic agent on almost all the cell lines tested.

A series of new 1-aryl-4-benzylidenehydrazinyl-3-methylsulphanyl-pyrazolo[3,4- d ]pyrimidines 6a – p was synthesized. The cytotoxic activity of the newly synthesized compounds against human breast cancer cell line, MCF7 was investigated. Most of the test compounds showed potent antitumor activity comparable to that of doxorubicin. The 1-phenyl series ( 6a – i ) exhibited better antitumor activity than 1-(4-methoxyphenyl) series ( 6j – p ). 4-[2-(4-Fluorobenzylidene)hydrazinyl]-3-(methylsulphanyl)-1-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine ( 6d ) was the most active compound in this study with IC 50 equal to 7.5 nM.

A novel series of pyrazolo[1,5- a ]pyrimidine-3-carbonitriles substituted with 7-amino, 7-substituted amino and 5-substituted amino groups was synthesized. Some of the newly synthesized compounds were tested in vitro on human colon tumor cell line (HCT116). Compound 14a displayed the highest activity among the tested compounds with IC 50 that equals to 0.0020 μM.

The synthesis of two series of 1-phenyl and 1 H-pyrazolo[3,4- b]pyridine is described. Thus, reacting 5-amino-1-phenylpyrazole with chalcone analogues gave 4,6-diarylpyrazolo[3,4- b]pyridine derivatives. While, reacting the same starting material with benzylidene derivatives of ethyl cyanoacetate and malononitrile resulted in 4-oxo and 4-aminopyrazolo[3,4- b]pyridine derivatives, respectively. The synthesis of 3-amino-4,6-diarylpyrazolo[3,4- b]pyridines starting from pyridine was also described. Thus, chlorination of 4,6-diarylpyridone derivatives and their subsequent cyclisation with hydrazine hydrate afforded 3-amino-4,6-diarylpyrazolo[3,4 -b]pyridines. Reaction of the latter compounds with acetylacetone, ethyl ethoxymethylenecyanoacetate and chalcone analogue gave the tricyclic pyrido[2′,3′: 3,4]pyrazolo[1,5- a]pyrimidines. The structures of the products were confirmed by spectral data.

The "RAS/BRAF/MEK/ERK" pathway has been associated with human cancers due to the frequent oncogenic mutations identified in its members. In particular, BRAF is mutated at high frequency in many cancers especially melanoma. This mutation leads to activation of the MAPK signaling pathway, inducing uncontrolled cell proliferation, and facilitating malignant transformation. All these facts make BRAF an ideal target for antitumor therapeutic development. Many BRAF inhibitors have been discovered during the last decade and most of them exhibit potent antitumor activity especially on tumors that harbor BRAF(V600E) mutations. Some of these compounds have entered clinical trials and displayed encouraged results. The present review highlights the progress in identification and development of BRAF inhibitors especially during the last five years.

Novel pyrazolo[3,4-d]pyrimidine derivatives (IV) are synthesized and screened for their cytotoxic activity against the human breast cancer cell line MCF7.

Cancer is considered as one of the most serious health problems. Despite the presence of many effective chemotherapeutic agents, their severe side effects together with the appearance of mutant tumors limit the use of these drugs and increase the need for new anticancer agents. Eg5 represents an attractive target for medicinal chemists since Eg5 is overexpressed in many proliferative tissues while almost no Eg5 is detected in nonproliferative tissues. Many Eg5 inhibitors displayed potent anticancer activity against some of the mutant tumors with limited side effects. The present review provides an overview about the progress in the discovery of Eg5 inhibitors especially from 2009 to 2012 as well as the clinical trials conducted on some of these inhibitors.

Title derivatives (III) are obtained upon cyclocondensation of benzimidazole derivative (I) with aryl and heteroaryl aldehydes (II).

A series of novel 5-aryl-3-cyclopropyl-4,5-dihydropyrazole derivatives 2a–p were synthesized via cyclization of chalcones 1a–h with thiosemicarbazide or semicarbazide HCl and evaluated as anti-inflammatory/antioxidant agents. The structures were confirmed by elemental analyses and spectral data. The free radical scavenging activity toward superoxide was determined. Their effect on hepatocytes viability and nitric oxide (NO) production in LPS-stimulated macrophages was also determined. The results showed that compounds 2e and 2n demonstrated the highest free-radical scavenging and anti-inflammatory activities, thus can be useful in the prevention of oxidative stress and inflammation-related disorders.

All the synthesized title compounds are tested for their in vitro effect on human breast adenocarcinoma cell line (MCF7).

The synthesis of two series of 1-phenyl and 1H-pyrazolo[3,4-b]pyridine is described. Thus, reacting 5-amino-1-phenylpyrazole with chalcone analogues gave 4,6-diarylpyrazolo[3,4-b]pyridine derivativ...

A series of new pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines with different substituents at position 3 were synthesized. The effect of the newly synthesized compounds was tested in vitro on human breast adenocarcinoma cell line (MCF7). Some of the synthesized compounds exploited potent antitumor activity, especially the 3-amino derivative 12 which displayed the highest activity among the test compounds with IC50 equal to 3.74 μg/mL.

A series of new 6-arylpyrazolo[3,4-d]pyrimidin-4-ones and 6-alkylpyrazolo[3,4-d]pyrimidin-4-ones were synthesized. Some of the newly synthesized compounds were tested in vitro on human colon tumor cell line (HCT116). Most of the test compounds exploited potent antitumor activity, especially compound 10a which displayed the highest activity among the test compounds with IC50 equal to 0.47 μg/mL