Structural modification of olibergin A,an isoflavonoid,from Dalbergia stipulacea Roxb. and its cytotoxicity

Fifteen derivatives were synthesized from olibergin A, a major isoflavonoid isolated from the stems of Dalbergia stipulacea Roxb. All compounds were evaluated for cytotoxicity against HCT-116, HT-29, MCF-7 and vero cell lines using MTT assay. Cytotoxicity results showed 5-hydroxy-7,2′,4′,5′-tetramethoxyisoflavone (5) was the most active with IC₅₀ values of 19.03 ± 0.70, 10.83 ± 1.65, 12.53 ± 0.70 and 13.53 ± 0.84 μM against HCT-116, HT-29, MCF-7 and vero cell lines, respectively. It should be noted that 5-hydroxy-7,2′,4′,5′-tetramethoxyisoflavone (5) showed two times less toxicity against vero cells than the cisplatin standard (IC₅₀ = 6.55 ± 0.81 μM) while 5 and cisplatin exhibited nearly equal cytotoxicity against the MCF-7 cell line. 5,7,2′,4′,5′-Pentamethoxyisoflavanone (10) showed an IC₅₀ value of 30.34 ± 1.15 μM against the HCT-116 cell line and exhibited weak cytotoxicity against normal cells, the vero cell line. In addition, 5,7,4′-trihydroxy-2′,5′-dimethoxyisoflavan oxime (13) demonstrated cytotoxicity against HT-29 cells with an IC₅₀ value of 31.41 ± 1.38 μM and displayed weak activity toward the vero cell line. The information revealed that these compounds were suitable for development to anticancer agents against HCT-116, HT-29 and MCF-7 cell lines.

Fifteen derivatives were synthesized from olibergin A, a major isoflavonoid isolated from the stems of Dalbergia stipulacea Roxb.     

Discovery of pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives as novel CDK2 inhibitors: synthesis,biological and molecular modeling investigations

CDK2 inhibition is an appealing target for cancer treatment that targets tumor cells in a selective manner. A new set of small molecules featuring the privileged pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffolds (4–13) as well as the thioglycoside derivatives (14, 15) were designed, and synthesized as novel CDK2 targeting compounds. The growth of the three examined cell lines was significantly inhibited by most of the prepared compounds. Results revealed that most of the compounds showed superior cytotoxic activities against MCF-7 and HCT-116 with IC₅₀ range (45–97 nM) and (6–99 nM), respectively, and moderate activity against HepG-2 with IC₅₀ range of (48–90 nM) compared to sorafenib (IC₅₀: 144, 176 and 19 nM, respectively). Of these compounds, 14 & 15 showed the best cytotoxic activities against the three cell lines with IC₅₀ values of 45, 6, and 48 nM and 46, 7, and 48 nM against MCF-7, HCT-116 and HepG-2, respectively. Enzymatic inhibitory activity against CDK2/cyclin A2 was achieved for the most potent anti-proliferative compounds. Compounds 14, 13 and 15 revealed the most significant inhibitory activity with IC₅₀ values of 0.057 ± 0.003, 0.081 ± 0.004 and 0.119 ± 0.007 μM, respectively compared to sorafenib (0.184 ± 0.01 μM). Compound 14 displayed potent dual activity against the examined cell lines and CDK2, and was thus selected for further investigations. It exerted a significance alteration in cell cycle progression, in addition to apoptosis induction within HCT cells. Molecular docking simulation of the designed compounds confirmed the good fit into the CDK2 active site through the essential hydrogen bonding with Leu83. In silico ADMET studies and drug-likeness studies using a Boiled Egg chart showed suitable pharmacokinetic properties which helped in structure requirement prediction for the observed antitumor activity.

A new set of pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffolds (4–13) as well as the thioglycoside derivatives (14, 15) were designed, and synthesized as novel CDK2 targeting compounds.     

Design,synthesis, in silico docking,ADMET and anticancer evaluations of thiazolidine-2,4-diones bearing heterocyclic rings as dual VEGFR-2/EGFRT790M tyrosine kinase inhibitors

Fourteen recent thiazolidine-2,4-diones bearing furan and/or thiophene heterocyclic rings have been designed, synthesized and assessed for their anticancer activities against four human tumor cell lines HepG2, A549, MCF-7 and HCT-116 targeting both VEGFR-2 and EGFR tyrosine kinases. Molecular design was carried out to investigate the binding mode of the proposed compounds with VEGFR-2 and EGFR receptors. HepG2 was the most susceptible cell line to the influence of our derivatives. Compounds 5g and 4g revealed the highest activities against HepG2 (IC₅₀ = 3.86 and 6.22 μM), A549 (IC₅₀ = 7.55 and 12.92 μM), MCF-7 (IC₅₀ = 10.65 and 10.66 μM) and HCT116 (IC₅₀ = 9.04 and 11.17 μM) tumor cell lines. Sorafenib (IC₅₀ = 4.00, 4.04, 5.58 and 5.05 μM) and elotinib (IC₅₀ = 7.73, 5.49, 8.20 and 13.91 μM) were used as reference standards. Furthermore, the most active cytotoxic compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were selected to assess their VEGFR-2 inhibitory effects. Derivatives 5g, 4g and 4f were observed to be the highest effective derivatives that inhibited VEGFR-2 at the submicromolar level (IC₅₀ = 0.080, 0.083 and 0.095 μM respectively) in comparison to sorafenib (IC₅₀ = 0.084 μM). As well, compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were additionally assessed for their inhibitory activities against mutant EGFR^T790M. Compounds 5g and 4g could interfere with the EGFR^T790M activity exhibiting stronger activities than elotinib with IC₅₀ = 0.14 and 0.23 μM respectively. Finally, our derivatives 4g, 5f and 5g showed a good in silico calculated ADMET profile. The obtained results showed that our compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFR^T790M inhibitors with higher anticancer activity.

Fourteen recent thiazolidine-2,4-diones bearing furan and/or thiophene heterocyclic rings have been designed, synthesized and assessed for their anticancer activities against four human tumor cell lines HepG2, A549, MCF-7 and HCT-116 targeting both VEGFR-2 and EGFR tyrosine kinases.     

Diastereoselective synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels–Alder reaction and in vitro anticancer studies

The development of concise methods for the synthesis of small functionalised spirocyclic molecules is important in the search of new bioactive molecules. To contribute this, here we represent a diastereoselective oxa-hetero-Diels–Alder reaction for the synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives and studied their in vitro anticancer activities. Using previously less explored cyclic ketone i.e. indane-1,3-dione and 3-vinyl-2H-chromene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between “drug-like” molecules and natural products. Various spiro indanone fused pyrano[3,2-c]chromene derivatives were synthesized regiospecifically bearing a quaternary stereocenter in high yields (up to 85%) with excellent diastereoselectivity in toluene using 4 Å MS as additive under reflux condition at 120 °C. In vitro cytotoxic studies of these compounds against MCF-7 (breast cancer), HCT-116 (colon cancer), H-357 (oral cancer), MD-MB-231(Breast cancer) cell lines were evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide} assay in vitro. The screening results revealed that many of the compounds are showing moderate to high levels of anticancer activities against the tested cancer cell lines and some displayed potent inhibitory activities in comparison to the commercial anticancer drug 5-fluorouracil (5-FU). Among the series, compound 3′c showed most potent cytotoxicity (15.0–27.5 μM) in three cancer cell lines (MCF-7, HCT-116 and MD-MB-231).

Synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels–Alder reaction has been demonstrated and evaluated for their in vitro anticancer activity.     

Synthesis and antiproliferative assay of triazolyl-2,2-dimethyl-3-phenylpropanoates as potential HDAC inhibitors

Recently, histone deacetylase (HDAC) inhibition has gained great importance in cancer treatment. We herein, describe the design, synthesis and biological testing of 16 compounds based on the structure modification of methyl 3-(4-(2-chloroacetamido)phenyl)-3-hydroxy-2,2-dimethylpropanoate (5) and methyl 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate (14) as potent HDACIs. Two series were synthesized based on the structure of 3-(4-(2-chloroacetamido)phenyl)-3-hydroxy-2,2-dimethylpropanoate and 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate. The compounds were tested in vitro for their antiproliferative activity against HeLa cells. The results identified compounds 16b, 16c, 18 (IC₅₀; 11.69, 0.69, 3.39 μM respectively) as potential good inhibitors compared to the standard drug doxorubicin (IC₅₀; 2.29 μM). Those compounds also exhibited promising activity against other cancer cell lines namely; HCT-116, MCF-7, PC3, A549 and therefore were selected as hits for further optimization. The docking experiment results performed on the HDAC-2 crystal structure were in close agreement with the biological testing results which suggest that those compounds potentially work through HDAC inhibition.

Recently, histone deacetylase (HDAC) inhibition has gained great importance in cancer treatment.     

Identification of novel furo[2,3-d]pyrimidine based chalcones as potent anti-breast cancer agents: synthesis,in vitro and in vivo biological evaluation

Various substituted synthetic chalcones demonstrated potent anti-cancer activities. In the current study a series of novel furo[2,3-d]pyrimidine based chalcones were synthesized as potential anticancer agents. Among the different substituted derivatives, two of the halogen bearing chalcones, 5d and 5e, demonstrated potent anti-proliferative activity against an NCI 59 cell line, with mean GI₅₀ values of 2.41 μM and 1.23 μM, respectively. Moreover, both compounds showed pronounced cytotoxic activity (5d; 1.20 ± 0.21, 5e; 1.90 ± 0.32) against the resistant MCF-7 cell line when compared to doxorubicin; 3.30 ± 0.18. Such outcomes provoked the initiation of an in vivo anticancer assessment study, where compound 5e revealed comparable results to doxorubicin.

Various substituted synthetic chalcones demonstrated potent anti-cancer activities.     

Design,synthesis, docking study and anticancer evaluation of new trimethoxyphenyl pyridine derivatives as tubulin inhibitors and apoptosis inducers

Microtubules have become an appealing target for anticancer drug development including mainly colchicine binding site inhibitors (CBSIs). A new series of novel trimethoxypyridine derivatives were designed and synthesized as tubulin targeting agents. In vitro anti-proliferative activities of the tested compounds compared to colchicine against hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116), and breast cancer (MCF-7) was carried out. Most of compounds showed significant cytotoxic activities. Compounds Vb, Vc, Vf, Vj and VI showed superior anti-proliferative activities to colchicine. Where compound VI showed IC₅₀ values of 4.83, 3.25 and 6.11 μM compared to colchicine (7.40, 9.32, 10.41 μM) against HCT 116, HepG-2 and MCF-7, respectively. The enzymatic activity against tubulin enzyme was carried out for the compounds that showed high anti-proliferative activity. Also, compound VI exhibited the highest tubulin polymerization inhibitory effect with an IC₅₀ value of 8.92 nM compared to colchicine (IC₅₀ value = 9.85 nM). Compounds Vb, Vc, Vf, Vj, & VIIIb showed promising activities with IC₅₀ values of 22.41, 17.64, 20.39, 10.75, 31.86 nM, respectively. Cell cycle and apoptosis test for compound VI against HepG-2 cells, indicated that compound VI can arrest cell cycle at G2/M phase, and can cause apoptosis at pre-G1 phase, with high apoptotic effect 18.53%. Molecular docking studies of the designed compounds confirmed the essential hydrogen bonding with CYS241 beside the hydrophobic interaction at the binding site compared to reference compounds which assisted in the prediction of the structure requirements for the detected antitumor activity.

Interaction of compounds VI (IC₅₀ = 8.92 nM) (A) and Vj (IC₅₀ = 10.75 nM) (B) with key amino acids of CBS.     

Cembrane-type diterpenoids from the gum resin of Boswellia carterii and their biological activities

Eight new cembrane-type diterpenoids, boscartins AH–AK (1–8), along with two known ones (9-10), were isolated from the gum resin of Boswellia carterii. Compounds 1–3 were characteristic of high oxidation assignable to three epoxy groups, while compounds 4–8 were characteristic of two epoxy groups. Spectroscopic examination was used to elucidate their structures. All isolates were evaluated for antiproliferative activity against HCT-116 human colon cancer cells, anti-inflammatory activity against nitric oxide (NO) production, and hepatoprotective activity in vitro. All of them showed weak antiproliferative activity (IC₅₀ > 100 μM), 8 exhibited potent inhibitory effects on NO production (IC₅₀ of 14.8 μM), with the others showing weak anti-inflammatory activity (IC₅₀ > 30 μM), and 1 exhibited more potent hepatoprotective activity than the positive control, bicyclol, at 10 μM against the damage induced by paracetamol in HepG2 cells.

Cembrane-type diterpenoids from the gum resin of Boswellia carterii.     

Antiproliferative activity of new pentacyclic triterpene and a saponin from Gladiolus segetum Ker-Gawl corms supported by molecular docking study

A new triterpenoidal saponin identified as 3-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 4)-β-d-xylopyranosyl]-2β,3β,16α-trihydroxyolean-12-en-23,28-dioic acid-28-O-α-l-rhamnopyranosyl-(1 → 4)-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 2)-α-l-arabinopyranoside 1 together with a new oleanane triterpene identified as 2β,3β,13α,22α-tetrahydroxy olean-23,28-dioic acid 2 and 6 known compounds (3–8) have been isolated from Gladiolus segetum Ker-Gawl corms. The structural elucidation of the isolated compounds was confirmed using different chemical and spectroscopic methods, including 1D and 2D NMR experiments as well as HR-ESI-MS. Moreover, the in vitro cytotoxic activity of the fractions and that of the isolated compounds 1–8 were investigated against five human cancer cell lines (PC-3, A-549, HePG-2, MCF-7 and HCT-116) using doxorubicin as a reference drug. The results showed that the saponin fraction exhibited potent in vitro cytotoxic activity against the five human cancer cell lines, whereas the maximum activity was exhibited against the PC-3 and A-549 cell lines with the IC₅₀ values of 1.13 and 1.98 μg mL⁻¹, respectively. In addition, compound 1 exhibited potent activity against A-549 and PC-3 with the IC₅₀ values of 2.41 μg mL⁻¹ and 3.45 μg mL⁻¹, respectively. Interestingly, compound 2 showed the maximum activity against PC-3 with an IC₅₀ of 2.01 μg mL⁻¹. These biological results were in harmony with that of the molecular modeling study, which showed that the cytotoxic activity of compound 2 might occur through the inhibition of the HER-2 enzyme.

A new triterpenoidal saponin 1, a new oleanane triterpene 2, and 6 known compounds (3–8) have been isolated from Gladiolus segetum Ker-Gawl corms.     

Discovery of pyrano[2,3-d]pyrimidine-2,4-dione derivatives as novel PARP-1 inhibitors: design,synthesis and antitumor activity

Poly(ADP-ribose) polymerases-1 (PARP-1) are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death. In this study, we report the synthesis of a novel series of pyrano[2,3-d]pyrimidine-2,4-dione analogues as potential inhibitors against PARP-1. All the newly synthesized compounds were evaluated for their inhibitory activity towards PARP-1 and examined for their anti-proliferative activity against MCF-7 and HCT116 human cancer cell lines. The synthesized compounds showed promising activity where compounds S2 and S7 emerged as the most potent PARP-1 inhibitors with an IC₅₀ value of 4.06 ± 0.18 and 3.61 ± 0.15 nM, respectively compared to that of Olaparib 5.77 nM and high cytotoxicity against MCF-7 with IC₅₀ 2.65 ± 0.05 and 1.28 ± 1.12 μM, respectively (Staurosporine 7.258 μM). Compound S8 remarkably showed the highest cell growth inhibition against MCF-7 and HCT116 with an IC₅₀ value of 0.66 ± 0.05 and 2.76 ± 0.06 μM, respectively. Furthermore, molecular docking of the compounds into the PARP-1 active site was performed to explore the probable binding mode. Finally, most of the synthesized compounds were predicted to have good pharmacokinetics properties in a theoretical kinetic study.

PARP-1 are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death.     

Three new coordination polymers based on bis(4-(4H-1,2,4-triazol-4-yl)phenyl)methane: syntheses,structures, multiresponsive luminescent sensitive detection for antibiotics and pesticides,and antitumor activities

Three novel coordination polymers (CPs), namely, {[Ag₂(L)₂(Mo₄O₁₃)·(CH₃CN)]}_n (1), {[Zn(L)(1,4-bdc)₂·2(1,4-H₂bdc)]}_n (2), {[Cd(L)(1,4-bdc)_0.5]}_n (3) have been synthesized under solvothermal conditions by the reaction of bis(4-(4H-1,2,4-triazol-4-yl)phenyl)methane (L) and varied metal salts. Their structures are determined by single X-ray crystal diffraction, and further characterized by elemental analysis, IR, TGA and PXRD. CP 1 with ammonium molybdate as a secondary ligand displays a 2D network with (2,3,3,3,4)-connected net topology and the point symbol of {4·8²}₆{4·8⁴·10}₂{8}, CP 2 and CP 3 with 1,4-H₂bdc as a secondary ligand demonstrate 3D structures with different topologies. CP 2 exhibits high sensibility and low detection limit in the recognition of antibiotics (NZF, NFT and FZD) and pesticide (DCN) identification. CP 1 demonstrates good anti-tumor activity toward the tested glioma cells. The possible luminescent sensitivity and anti-tumor mechanisms are also discussed.

Three novel coordination polymers (CPs) have been synthesized under solvothermal conditions by the reaction of bis(4-(4H-1,2,4-triazol-4-yl)phenyl)methane (L) and varied metal salts.     

Correction: Two Ln-based metal–organic frameworks based on the 5-(1H-1,2,4-triazol-1-yl)-1,3-benzenedicarboxylic acid ligand: syntheses,structures, and photocatalytic properties

Correction for ‘Two Ln-based metal–organic frameworks based on the 5-(1H-1,2,4-triazol-1-yl)-1,3-benzenedicarboxylic acid ligand: syntheses, structures, and photocatalytic properties’ by Fei Yuan et al., RSC Adv., 2020, 10, 39771–39778, DOI: 10.1039/D0RA07159E.

The authors regret that in the Graphical Abstract of the original article, incorrect figures were included. The Graphical Abstract online has been replaced with an updated version.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Cytotoxic metabolites from the endophytic fungus Chaetomium globosum 7951

The following compounds were isolated from acetate extracts of Chaetomium globosum 7951 solid cultures: demethylchaetocochin C (1) and chaetoperazine A (3), two new epipolythiodioxopiperazine (ETP) alkaloids, a novel pyridine benzamide, 4-formyl-N-(3′-hydroxypyridin-2′-yl) benzamide (6), and three known ETP derivatives (2, 4, and 5). The structures of these compounds were determined using extensive spectroscopic data analysis. Compounds 1–3, and 6, inhibited the growth of MCF-7, MDA-MB-231, H460 and HCT-8 cells with an IC₅₀ of 4.5 to 65.0 μM.

Demethylchaetocochin C and chaetoperazine A, two new epipolythiodioxopiperazine alkaloids, and three known analogs were isolated from Chaetomium globosum 7951. Demethylchaetocochin C significantly inhibits human lung cancer cell growth.     

Three novel polyoxometalate-based inorganic–organic hybrid materials based on 2,6-bis(1,2,4-triazol-1-yl)pyridine

Three novel inorganic–organic hybrid materials [Co(btp)₂(W₅O₁₆)(H₂O)]_n (1), [Cd₃(btp)₆(PW₁₂O₄₀)₂(H₂O)₆·6H₂O]_n (2), and [Ag₃(btp)₂(PMo₁₂O₄₀)·1.5H₂O]_n (3) (btp = 2,6-bis(1,2,4-triazol-1-yl)pyridine) have been hydrothermally synthesized and characterized by IR spectroscopy, single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), elemental analysis and thermal gravimetric analysis (TGA). The most striking structure feature of compound 1 is a 3D polycatenation framework, interpenetrated by a 2D 4-connected sql topology layer and a 3D 6-connected rob topology framework. Compound 2 exhibits a rare meso-helices 3D network with different chiralities crossing coexistence. Compound 3 also holds a 3D framework formed by linking terminal oxygen atoms of [α-PMo₁₂O₄₀]³⁻ anions and silver ions in a 2D metal–organic layer. Compound 1 displays antiferromagnetic behavior. The luminescence, electrochemical and photocatalytic properties of compounds 1–3 have also been investigated. Compound 3 exhibits significant electrochemical activity for the reduction of H₂O₂ while compounds 1 and 2 show efficient photocatalytic activities for the degradation of Rhodamine B (RhB). Furthermore, the three compounds display luminescence behaviors in the solid state.

Three novel inorganic–organic hybrid materials based on 2,6-bis(1,2,4-triazol-1-yl)pyridine have been synthesized with different polyanions and transition metal ions.     

Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells

A series of 24 compounds were synthesized based on structure modification of the model methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as potent HDACIs. Saponification and hydrazinolysis of the model ester afforded the corresponding acid and hydrazide, respectively. The model ester was transformed into the corresponding trichloroacetimidate or acetate by the reaction with trichloroacetonitrile and acetic anhydride, respectively. N-Alkyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropan-amides and methyl-2-[(3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoyl)amino] alkanoates were obtained by the reaction of corresponding acid or hydrazide with amines and amino acid esters via DCC and azide coupling methods. Methyl-3-aryl-3-(4-chlorophenyl)-2,2-dimethylpropanoates were obtained in good yields and short reaction time from the corresponding trichloroacetimidate or acetate by the reaction with C-active nucleophiles in the presence of TMSOTf (0.1 eq.%) via C–C bond formation. The antiproliferative and apoptotic activity were further studied with molecular docking. The 48 post-treatments showed that out of 24 compounds, 12 compounds showed inhibitory actions on HCT-116 cells, we have calculated the inhibitory action (IC₅₀) of these compounds on HCT-116 and we have found that the IC₅₀ values were in between 0.12 mg mL⁻¹ to 0.81 mg mL⁻¹. The compounds (7a & 7g) showed highest inhibitory activity (0.12 mg mL⁻¹), whereas compound 7d showed the lowest inhibitory activity (0.81 mg mL⁻¹). We have also examined inhibitory action on normal and non-cancerous cells (HEK-293 cells) and confirmed that action of these compounds was specific to cancerous cells. The cancerous cells were also examined for nuclear disintegration through staining with DAPI, (4′,6-diamidino-2-phenylindole) is a blue-fluorescent DNA stain, and we have found that there was loss of DAPI staining in the compound treated cancerous cells. The compounds were found to potentially act through the HSP90 and TRAP1 mediated signaling pathway. Compounds 7a and 7g showed the highest selectivity to TRAP1 which explained its superior activity.

A series of 24 compounds were synthesized based on structure modification of the model methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as potent HDACIs.     

Design,synthesis, bio-evaluation,and in silico studies of some N-substituted 6-(chloro/nitro)-1H-benzimidazole derivatives as antimicrobial and anticancer agents

A new series of 6-substituted 1H-benzimidazole derivatives were synthesized by reacting various substituted aromatic aldehydes with 4-nitro-o-phenylenediamine and 4-chloro-o-phenylenediamine through condensation using sodium metabisulfite as the oxidative reagent. The N-substituted 6-(chloro/nitro)-1H-benzimidazole derivatives were prepared from the 6-substituted 1H-benzimidazole derivatives and substituted halides using potassium carbonate by conventional methods as well as by exposure to microwave irradiation. Seventy-six 1H-benzimidazole derivatives have been synthesized in moderate to excellent yields with the microwave-assisted method (40 to 99%). Compounds 1d, 2d, 3s, 4b, and 4k showed potent antibacterial activity against Escherichia coli, Streptococcus faecalis, MSSA (methicillin-susceptible strains of Staphylococcus aureus), and MRSA (methicillin-resistant strains of Staphylococcus aureus) with MIC (the minimum inhibitory concentration) ranging between 2 and 16 μg mL⁻¹ as compared to ciprofloxacin (MIC = 8–16 μg mL⁻¹), in particular compound 4k exhibits potent fungal activity against Candida albicans and Aspergillus niger with MIC ranging between 8 and 16 μg mL⁻¹ compared with the standard drug fluconazole (MIC = 4–128 μg mL⁻¹). In addition, compounds 1d, 2d, 3s, 4b, and 4k also showed the strongest anticancer activity among the synthesized compounds against five tested cell lines with IC₅₀ (half-maximal inhibitory concentration) ranging between 1.84 and 10.28 μg mL⁻¹, comparable to paclitaxel (IC₅₀ = 1.38–6.13 μM). Furthermore, the five most active compounds showed a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile in comparison to ciprofloxacin, fluconazole, and paclitaxel as reference drugs. Molecular docking predicted that dihydrofolate reductase protein from Staphylococcus aureus is the most suitable target for both antimicrobial and anticancer activities, and vascular endothelial growth factor receptor 2 and histone deacetylase 6 are the most suitable targets for anticancer activity of these potent compounds.

The purpose of this study is to synthesize novel N-substituted 6-(chloro/nitro)-1H-benzimidazole derivatives with various substituted aryl groups at position 2 and alkylation at position 1, and evaluate their antimicrobial and anticancer activities.     

Synthesis of novel naphthalene-heterocycle hybrids with potent antitumor,anti-inflammatory and antituberculosis activities

Multitarget-directed drugs (hybrid drugs) constitute an efficient avenue for the treatment of multifactorial diseases. In this work, novel naphthalene hybrids with different heterocyclic scaffolds such as nicotinonitrile, pyran, pyranopyrazole, pyrazole, pyrazolopyridine, and azepine were efficiently synthesized via tandem reactions of 3-formyl-4H-benzo[h]chromen-4-one 1 with different nucleophilic reagents. Analysis of these hybrids using PASS online software indicated different predicted biological activities such as anticancer, antimicrobial, antiviral, antiprotozoal, anti-inflammatory, etc. By focusing on antitumor, anti-inflammatory, and antituberculosis activities, many compounds revealed remarkable activities. While 3c, 3e, and 3h were more potent than doxorubicin in the case of HepG-2 cell lines, 3a–e, 3i, 6, 8, 10, 11, and 12b were more potent in the case of MCF-7. Moreover, compounds 3c, 3h, 8, 10, 3d, and 12b manifested superior activity and COX-2 selectivity to the reference anti-inflammatory Celecoxib. Regarding antituberculosis activity, 3c, 3d, and 3i were found to be the most promising with MIC less than 1 μg mL⁻¹. The molecular docking studies showed strong polar and hydrophobic interactions with the novel naphthalene-heterocycle hybrids that were compatible with experimental evaluations to a great extent.

Novel naphthalene-heterocycle hybrids were synthesized via tandem reactions of 3-formylchromone with different nucleophilic reagents. Various hybrids revealed potent antitumor and anti-inflammatory as well as promising antituberculosis activities.     

Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides and their tautomerism

Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5) were proposed and successfully realized in the synthesis of 20 representative examples. These methods use the same types of starting materials viz. succinic anhydride, aminoguanidine hydrochloride, and a variety of amines. The choice of the pathway and sequence of the introduction of reagents to the reaction depended on the amine nucleophilicity. The first pathway started with the preparation of N-guanidinosuccinimide, which then reacted with amines under microwave irradiation to afford 5. The desired products were successfully obtained in the reaction with aliphatic amines (primary and secondary) via a nucleophilic opening of the succinimide ring and the subsequent recyclization of the 1,2,4-triazole ring. This approach however failed when less nucleophilic aromatic amines were used. Therefore, an alternative pathway, with the initial preparation of N-arylsuccinimides and their subsequent reaction with aminoguanidine hydrochloride under microwave irradiation, was applied. The annular prototropic tautomerism in the prepared 1,2,4-triazoles 5 was studied using NMR spectroscopy and X-ray crystallography.

Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides were proposed and successfully realized in the synthesis of 20 representative examples.     

Design,synthesis and biological evaluation of 1,2,3-triazole based 2-aminobenzimidazoles as novel inhibitors of LasR dependent quorum sensing in Pseudomonas aeruginosa

Bacteria regulate their phenotype, growth and population via a signalling pathway known as quorum sensing. In this process, bacteria produce signalling molecules (autoinducers) to recognize their population density. Inhibiting this quorum sensing signalling pathway is one of the potential methods to treat bacterial infection. 2-Aminobenimdazoles are reported to be the strongest inhibitors of quorum sensing against wild-type P. aeruginosa. 1,2,3-Triazole based acyl homoserine lactones are found to be good inhibitors of the quorum sensing LasR receptor. Hence, in our current study, forty 1,2,3-triazole based 2-aminobenzimdazoles were synthesized and characterized using IR, NMR, MS and elemental analysis. A single crystal was developed for N-(1H-benzo[d]imidazol-2-yl)-2-(4-nonyl-1H-1,2,3-triazol-1-yl)acetamide (6d). All final compounds were screened for in vitro quorum sensing inhibitory activity against Pseudomonas aeruginosa. The quorum sensing inhibitory activity was determined in the LasR expressing P. aeruginosa MH602 reporter strain by measuring green fluorescent protein production. Among the title compounds, N-(1H-benzo[d]imidazol-2-yl)-2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)acetamide (6i) exhibited good quorum sensing inhibitory activity of 64.99% at 250 μM. N-(1H-Benzo[d]imidazol-2-yl)-2-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)acetamide (6p) exhibited the most promising quorum sensing inhibitory activity with 68.23, 67.10 and 63.67% inhibition at 250, 125 and 62.5 μM, respectively. N-(1H-Benzo[d]imidazol-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)acetamide (6o) and N-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)acetamide (7l) also exhibited 64.25% and 65.80% quorum sensing inhibition at 250 μM. Compound 6p, the most active quorum sensing inhibitor, also displayed low cytotoxicity at the tested concentrations (25, 50 and 100 μM) against normal human embryonic kidney cell lines. Finally, a docking study using Schrodinger Glide elucidated the possible putative binding mode of the significantly active compound 6p at the active site of the target LasR receptor (PDB ID: 2UV0).

Out of 40 benzimdazoles, 12 exhibited potent QSI activity against P. aeruginosa6p, most active QSI is docked to LasR and is less toxic against HEK 293 cell line.