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A series of 1,2,3-triazol-1-ylbenzenesulfonamide derivatives was designed, synthesized and their ability to inhibit several carbonic anhydrase isoforms was evaluated. The basis of our design is to hybridize the benzenesulfonamide moiety widely used as a zinc-binding group, a triazole ring as spacer with a tail of different substituted aryl moieties. The synthesis of these compounds was achieved using Cu(I)-mediated click chemistry between the azide containing the benzenesulfonamide pharmacophore and various aryl acetylenes or 1,6-heptadiyne through copper-catalyzed [3+2] cycloaddition reaction. The ability the new derivatives to inhibit four human carbonic anhydrase isoforms hCA I, II, IX, and XII was evaluated. All the compounds exhibited good potency and high selectivity towards isoforms hCA I and II more than isoforms hCA IX and XII, especially for the derivatives 3c and 3j that displayed K

The broad spectrum of curcumins beneficial properties has encouraged medicinal researchers to investigate its therapeutic efficacy against diverse diseases. The clinical potential of curcumin is, however limited due to its poor pharmacodynamic/pharmacokinetic properties (such as low solubility, pH instability, poor absorption in circulation, rapid elimination from the body and photochemical degradation). 3,5-Bis(ylidene)-4-piperidone scaffolds are considered a curcumin mimic that exhibit diverse bio-properties. The current review provides a brief overview of these mimics and highlights biological activities relevant to drug development. Funding Agencies|National Research Centre, Egypt [12060101]

Currently, limited therapeutic options are available for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). We have developed a set of pyrazine‐based small molecules. A series of pyrazine conjugates was synthesized by microwave‐assisted click chemistry and benzotriazole chemistry. All the synthesized conjugates were screened against the SAR‐CoV‐2 virus and their cytotoxicity was determined. Computational studies were carried out to validate the biological data. Some of the pyrazine‐triazole conjugates (5 d–g) and (S)‐N‐(1‐(benzo[d]thiazol‐2‐yl)‐2‐phenylethyl)pyrazine‐2‐carboxamide 12 i show significant potency against SARS‐CoV‐2 among the synthesized conjugates. The selectivity index (SI) of potent conjugates indicates significant efficacy compared to the reference drug (Favipiravir)., Antiviral drug development for SARS‐CoV‐2: The design and microwave‐assisted synthesis of pyrazine conjugates are reported. Some of the newly synthesized conjugates show better antiviral activity and selectivity indexes than those of the reference drug. All the lead compounds exhibited low cytotoxicity. Thus, these conjugates could lead to the development of potential drug candidates for SARS‐CoV‐2.

A series of 1''-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3''-piperidine]-2,4''-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

A new series of 1,4,5-trisubstituted triazole-bearing benzenesulphonamide moiety, COX-2 pharmacophore, was designed and synthesized. The synthetic pathway for preparation of the new 1,2,3-triazole derivatives started with the preparation of the two key intermediates: 4-(4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)benzenesulfonamide 3 and 4-(4-(hydrazinecarbonyl)-5-methyl-1H-1,2,3-triazol-1-yl)benzenesulfonamide 13 that were then used to synthesize the new triheterocycles. All the synthesized compounds were virtually screened for their binding interactions with both COX isozymes. Compounds showing similar conformation to that of celecoxib, the co-crystallized ligand, and exhibited reasonable interactions, were then evaluated for their in vitro COX-1 and COX-2 inhibition activity. All the compounds under investigation were found to be active as COX-1 and COX-2 inhibitors. Compounds 11 and 13 showed the highest activity as COX-2 inhibitors with IC50 values of 2.618 and 2.92 µM, respectively. On the other hand, compound 13 showed moderate selectivity toward COX-2 inhibition with selectivity ratio of 6.99. Summing up, as confirmed by in vitro and in silico results, the triazolyl benzenesulfonamide derivative 13-bearing unsubstituted hydrazide moiety can be considered as suitable candidate for further investigation as selective COX-2 inhibitor.

Three sets of isatin-based Schiff bases were synthesized utilizing the molecular hybridization approach. Some of the synthesized Schiff bases show significant to moderate antiproliferative properties against MCF7 (breast), HCT116 (colon), and PaCa2 (pancreatic) cancer cell lines with potency compared to reference drugs 5-fluorouracil (5-FU) and Sunitinib. Among all, compound 17 f (3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)-1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-methylindolin-2-one) exhibits promising antiproliferative properties against the MCF7 cancer cell line with 2.1-fold more potency than Sunitinib. However, among all the synthesized compounds, three (5-methylisatin derivatives) were the most effective against HCT116 in comparison to 5-FU. Compound 17 f exhibited the highest anti-angiogenic effect on the vasculature as it significantly reduced BV from 43 mm to 2 mm in comparison to 5.7 mm for Sunitinib and flow cytometry supports the arrest of the cell cycle at G1/S phases. In addition, compound 17 f also showed high VEGFR-2 inhibition properties against breast cancer cell lines. Robust 2D-QSAR studies supported the biological data.

A series of α-aminophosphonates (3a-3m) bearing the sulfisoxazole moiety was synthesized through one-pot Kabachnik-Fields reaction of sulfisoxazole, diethyl phosphite (DEP) and substituted aldehydes using bismuth (III) triflate [Bi(OTf)3] as a catalyst under microwave reaction conditions. The novel compounds are identified by their spectroscopic data and confirmed by X-ray diffraction studies of diethyl (4-chlorophenyl)(4-(N-(3,4-dimethylisoxazol-5-yl)sulfamoyl)phenylamino) methylphosphonate 3g. The antimicrobial properties of the synthesised agents were examined against a range of bacterial species and C. albicans yeast. Some of the synthesised agents, 3j, 3l and 3m, exhibit potent antimicrobial activities against the five pathogenic microorganisms used in the investigation. Compound 3m is the most promising agents among all the synthesized derivatives, showing a potent and broad-spectrum antibacterial activity. The MIC values are 94.2 and 205.7 µM for 3m and sulfisoxazole, respectively for S. typhi (about 2.1 times potency). The MIC values are 102.8 and 187.0 µM for 3m and sulfisoxazole, respectively for L. monocytogenes. The observed biological properties are explained and supported by QSAR models.

A new set of ibuprofen-quinoline conjugates comprising quinolinyl heterocycle and ibuprofen moieties linked by an alkyl chain were synthesized in good yields utilizing an optimized reaction procedure in a molecular hybridization approach to overcome the drawbacks of the current non-steroidal anti-inflammatory drugs. The synthesized conjugates were screened for their anti-inflammatory, and ulcerogenic properties. Several conjugates were found to have significant anti-inflammatory properties in the carrageenan-induced rat paw edema test without showing any ulcerogenic liability. In addition, most conjugates showed promising peripheral analgesic activity in the acetic acid-induced writhing test as well as central analgesic properties in the in vivo hot plate test. The most promising conjugates were the unsubstituted and 6-substituted fluoro- and chloro-derivatives of 2-(trifluoromethyl)quinoline linked to ibuprofen by a propyl chain. Their anti-inflammatory activity was evaluated against LPS-stimulated inflammatory reactions in RAW264.7 mouse macrophages. In this regard, it was found that most of the conjugates were able to significantly reduce the release and production of nitric oxide in the LPS-stimulated macrophages. The secretion and expression of the pro-inflammatory cytokines IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) were also significantly suppressed.

Graphical abstract Sets of 3-alkenyl-2-oxindoles were synthesized of potential antiproliferative (against PaCa-2 and MCF7cancer cell lines) and promising properties against SARS-CoV-2., Sets of 3-alkenyl-2-oxindoles (6,10,13) were synthesized in a facile synthetic pathway through acid dehydration (EtOH/HCl) of the corresponding 3-hydroxy-2-oxoindolines (5,9,12). Single crystal (10a,c) and powder (12a,26f) X-ray studies supported the structures. Compounds 6c and 10b are the most effective agents synthesized (about 3.4, 3.3 folds, respectively) against PaCa2 (pancreatic) cancer cell line relative to the standard reference used (Sunitinib). Additionally, compound 10b reveals antiproliferative properties against MCF7 (breast) cancer cell with IC50 close to that of Sunitinib. CAM testing reveals that compounds 6 and 10 demonstrated qualitative and quantitative decreases in blood vessel count and diameter with efficacy comparable to that of Sunitinib, supporting their anti-angiogenic properties. Kinase inhibitory properties support their multi-targeted inhibitory activities against VEGFR-2 and c-kit in similar behavior to that of Sunitinib. Cell cycle analysis studies utilizing MCF7 exhibit that compound 6b arrests the cell cycle at G1/S phase while, 10b reveals accumulation of the tested cell at S phase. Compounds 6a and 10b reveal potent antiviral properties against SARS-CoV-2 with high selectivity index relative to the standards (hydroxychloroquine, chloroquine). Safe profile of the potent synthesized agents, against normal cells (VERO-E6, RPE1), support the possible development of better hits based on the attained observations.

As a part of our quest to develop new bioactive bisphosphonic acids, we synthesized a series of bis(α-aminobisphosphonic acids) in good yields (66–78%) as new entities for treating malignant melanoma. The reaction of the Schiff bases, 1,4-pheneylenediimines with the Horner–Emmons–Wadsworth reagent, tetraethyl methylene-1,1-bisphosphonate in DMF/LiOH (aq) solution led exclusively to a meso form of nitrogen-containing tetraphosphonates (NTPs) (bis(α-aminobisphosphonates)). Next, hydrolysis of the ester moieties of the tetraphosphonate products yielded the corresponding tetraphosphonic acids, which treated with MeOH/KOH (aq, 20%) to give the respective NTP-tetrapotassium salts. Prior to synthesis, the suggested structures (and others) were applied to the computer-assisted molecular modeling, PASS program to investigate their prospective biological properties. Cytotoxic properties were later evaluated against five malignant melanoma cell lines that originated from different categories of malignant melanoma primary stage (I/II), histologically advanced stage (III/IV), and metastasized malignancy. Almost all tested compounds showed antitumor activity though on different levels. Three NTP salts were found to have activity in the range of GI50 0.650–5.73 μM vs. control reference GI50: 1.745–6.50 μM. Structure activity relationship is also discussed.

Investigations in the discovery of tyrosinase enzyme inhibitors have the potential to design novel anti-cancer drugs. A variety of novel bivalent pyrazolinyl triazoles 5–7 were synthesized and identified. The bis-acetyl triazole 3 was accomplished via two-step process first by preparation of diazide 2 followed its coupling reaction with acetylacetone in basic medium. The Claisen–Schmidt condensation reaction of 3 with two moles equivalent of benzaldehyde produces the corresponding bis-α, β-unsaturated ketone 4. Treatment of Schiff base 4 with excess hydrazine hydrate in either acetic acid or ethanol/DMF afforded the bis-N-acetylpyrazline 5 or bis-pyrazoline 6, respectively. Finally, treatment of 6 with two derivatives of isothiocyanate analog gives the bis-N-thioamide pyrazolines 7a and 7b. The synthesized compounds were evaluated as anti-tumor candidates against three human cancer cell lines (MCF-7, HepG2, and HCT-116). The bioscreening evaluation showed that compounds 7a and 6 had a significant antineoplastic potencies (IC50: 32.26 and 57.06 µg/mL) against breast MCF-7 and hepatic HepG2 cancerous cell lines, respectively, in relative to the standard drug, 5-fluorouracil. Molecular docking studies of the synthesized compounds were investigated as VEGFR2 TK inhibitors.

Graphical abstract Series of salicylate-curcumin mimics were synthesized of potential antiproliferative (against A431 and HCT116 cell lines) and anti-SARS-CoV-2 properties., Series of piperidone-salicylate conjugates were synthesized through the reaction of 3E,5E-bis(arylidene)-4-piperidones with the appropriate acid chloride of acetylsalicylate in the presence of triethylamine. All the synthesized conjugates reveal antiproliferative properties against A431 (squamous skin) cancer cell line with potency higher than that of 5-fluorouracil. Many of the synthesized agents also exhibit promising antiproliferative properties against HCT116 (colon) cancer cell line, of which 5o and 5c are the most effective with 12.9, 9.8 folds potency compared with Sunitinib. Promising activity is also shown against MCF7 (breast) cancer cell line with 1.19, 1.12 folds relative to 5-fluorouracil. PI-flow cytometry of compound 5c supports the arrest of cell cycle at G1-phase. However, compound 5o and Sunitinib arrest the cell cycle at S-phase. The synthesized conjugates can be considered as multi-targeted tyrosine kinase inhibitors due to the promising properties against VEGFR-2 and EGFR in MCF7 and HCT116. CDOCKER studies support the EGFR inhibitory properties. Compounds 5p and 5i possessing thienylidene heterocycle are anti-SARS-CoV-2 with high therapeutic indices. Many of the synthesized agents show enhanced COX-1/2 properties than aspirin with better selectivity index towards COX-2 relative to COX-1. The possible applicability of the potent candidates discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal (non-cancer, RPE1 and VERO-E6) cells.

According to the biological screening reports, a thiadiazoloquinazoline scaffold constitutes a promising source of inspiration for the synthesis of novel bioactive molecules. The current review art...

Thiazoloquinazoline scaffold constitutes a promising source of inspiration for the synthesis of novel bioactive molecules. The current review article summarizes the most recent synthetic routes toward thiazoloquinazoline derivatives, published between the years 1983 and 2016. According to the position of fusion between thiazole and quinazoline rings, the thiazoloquinazoline derivatives in this review were classified into seven major types.

A series of substituted thiazole-bisphosphonates and relevant bisphosphonic acid counterparts was synthesized from the reaction of 2-chloro-N-(substituted)thiazole acetamides with tetraethyl methylene-1,1-bisphosphonate reagent in the presence of a base. The reactions proceeded smoothly via nucleophilic substitution to give our targets in good to high yields. Among the products, 4 bisphosphonic acids exhibited excellent anticancer activity vs four tested carcinoma cell lines (MCF7, HELA, DU-145, and HCT-116) with GI50 values ranging from 1.8 to 4.8 μMmL−1. According to the prediction results (using PASS program), the same acids and their BP-analogs were also evaluated for their anti-inflammatory properties. The acute carrageenan induced paw edema in rats model was used and the tested compounds showed notable anti-inflammatory potency without toxicity side effects.

Environmentally friendly synthesis of 1,3,2-benzothiazaphosphole-3(2H)-carbothioamide and -diazaphosphole-3(2H)-dicarbothioamide 2-oxides or the carboxamide 2-oxide analogs was reported. The targets were accomplished via a two step process: (1) preparation of the substrates 2-phenyl-2,3-dihydro-1H-1,3,2-benzothiazaphosphole 2-oxide and -1,3,2-benzodiazaphosphole 2-oxide; (2) exploiting these two phospholes in reactions with various saturated and unsaturated isothiocyanates and some isocyanate analogs in dry DMF/pyridine under microwave irradiation thereby isolating the target compounds in 85–95 % yields. Based upon computer-assisted molecular model (CAMM), new compounds were screened for their antidiabetic and antioxidant properties and many of them exhibited moderate to high in vivo and in vitro diabetic and/or antioxidant potencies.

In this study, we report recent investigations of the chemical reactivity of alkyl phosphites, mainly trialkyl and dialkyl phosphites, with molecules containing different nitrogen-containing compounds reported by us and other research groups over the past 25 years. Previous ground-breaking important reports are also considered. The reviewed investigations in this article are grouped according to only the type of the nitrogen-functional groups [amines (primary, secondary, and tertiary amines), imines, amides, thioamides, nitriles, isocyanates, isothiocyanates, oximes, hydrazones, diazo, and azides] and not according to the site of attack or the final products. Furthermore, the present review article focuses on the synthesis of α-amino-, β-amino-, and/or enaminophosphonates. These compounds have important roles in pharmaceutical chemistry.

Based on the prediction results (PASS program), a new series of α-aminophosphonate derivatives and azaphosphones was synthesized and evaluated as antitumor agents against breast-, cervical-, liver, and colon cancer diseases. The analgesic/antiinflammatory properties of the new phosphorylated pyrazoles were also investigated. The study demonstrated an efficient site selective method for making condensation products of phosphonate derivatives in high yields from carbodiimides and different types of HE reagents (74–78%) as well as dialkyl phosphites (54–65%) and hexaalkyltriamidophosphites (80–85%). Their antitumor properties against four carcinoma cell lines representing human-liver (HEPG2), -colon (HCT116), -breast (MCF7), and -cervix (HeLa) were investigated. The results showed that at least two out of the five tested phosphonates exhibited remarkable antitumor activity (IC50: 4.15–6.95 μM mL−1) when compared to the standard drugs (IC50: 5.7–9.3 μM mL−1). Nevertheless, four phosphonate products showed an analgesic capacity >80%, when compared to aspirin (73%) at the same dose of 100 mg kg−1. Furthermore, QSAR results indicated that the fused azaphosphones, thiazolopyrimidine- and pyridine-α-aminophosphonate derivatives (6 of 11 tested compounds), possess inflammatory inhibitory potency (99–117%) when compared to the standard drug (100%) after 360 min.

In this study, we report recent investigations of the chemical reactivity of alkyl phosphites, mainly trialkyl and dialkyl phosphites, with molecules containing different nitrogen-containing compounds reported by us and other research groups over the past 25 years. Previous ground-breaking important reports are also considered. The reviewed investigations in this article are grouped according to only the type of the nitrogen-functional groups [amines (primary, secondary, and tertiary amines), imines, amides, thioamides, nitriles, isocyanates, isothiocyanates, oximes, hydrazones, diazo, and azides] and not according to the site of attack or the final products. Furthermore, the present review article focuses on the synthesis of α-amino-, β-amino-, and/or enaminophosphonates. These compounds have important roles in pharmaceutical chemistry.

The α-hydroxyphosphonate generated from dialkyl phosphites and 1-phenyl-1H-pyrazole-4-carbaldehyde derivative was, in situ, trapped by isothiocyanates, isocyanates or acetic anhydride to produce dialkyl phosphorylmethyl-carbamothioates, -carbamates and/or -methyl acetates in good yields. The reactions were carried out in tetrahydrofuran (THF) in one step at room temperature, using K2CO3 catalyst. Antimicrobial and antineoplastic activities of the synthesized compounds were estimated. The results showed that all new compounds cause moderate to good antibiotic activities. However, phosphorylmethylcarbamothioates exhibited the highest growth inhibition. Furthermore, selected nine new synthesized compounds were evaluated for anticancer activity against eight human tumor cell lines (MCF7, MDA-MB-435, BT-549, IGROVI, SK-OV-3, PX-3, PU-145, and HEPG2). The majority of these compounds revealed moderate to potent activity against MCF7, PU-145, and HEPG2. Among them, two of the phosphorylmethylcarbamothioates showed excellent broad spectrum of anticancer activity with IC50 values ranging from 16.6 to 26.9 and 17.2 to 36.9 μmol L−1, respectively (for 5-fluorouracil IC50: 17.7 to 38.8 μmol L−1). Phosphorylmethyl methylcarbamothioate, in particular was more potent than 5-fluorouracil against all tested human carcinoma cell lines.

The reactions of the highly unstable carbodiimide (III) with different phosphonates are studied and the activities of the products are evaluated.

Carbodiimide that was generated from the condensation reaction of iminophosphorane with phenylisocyanate was allowed to react with different phosphorus nucleophiles. Thus, the in situ resulted heterocumulene reacted with dialkylhydrogenphosphonates in tetrahydrofuran (THF)/FeCl(3) /H(2) O system to give fused pyrrole- (≈14%) and pyrimidinephosphonates (≈57%). On the other hand, with tris-(dialkyl)aminophosphines, the reaction afforded the corresponding hexaalkylphosphinic diamides as a water-sensitive fine powder, quite stable for a few days in a desiccator. When a protonating agent was present in the reaction medium, the reaction was markedly accelerated leading to the formation of the phosphamides. Next, some saturated and unsaturated Horner-Emmons reagents were applied in situ to the same carbodiimide to obtain more phosphorylated N-heterocycles. The analgesic and antiinflammatory activities of the newly synthesized compounds were investigated and showed significant activities. Finally, we further estimated the antitumor activity of five new phosphonates against four carcinoma cell lines.