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This study presents the synthesis of four series of novel hybrid chalcones (20,21)a-g and (23,24)a-g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28-33)a-g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d-g, 24a-g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e-g, 33a,b,e-g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI50 values between 0.01 and 100 µM and LC50 values in the range of 4.09 µM to >100 µM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 µg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.

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1,4-Diazepine as an active drug component underlies the potency of most psychotic, anticancer, anticonvulsant, and antibacterial drugs in the market and is, therefore crucial in chemotherapeutic treatment in biomedicine. Proper functionalization of this moiety can afford even more potent drugs. As a result of their therapeutic significance, this study aims at precisely giving a comprehensive computational insight into the unexpected initial reactivity of 1,4-diazepine derivatives and mesitonitrile oxide. The initial reaction between mesitonitrile oxide and 1,4-diazepine derivatives proceeds via a (3 + 2) cycloaddition reaction which leads to the formation of a cycloadduct where the mesitonitrile oxide unexpectedly adds across the imine functionality at the expense of the potential olefinic carbon-carbon double bond. Calculations at the density functional theory (DFT) M06/6-311G (d, p) level of theory indicate that the initial (3 + 2) cycloaddition reaction of mesitonitrile oxide (1,3-dipole) and 1,4-diazepine derivatives (dipolarophile) in all cases proceeds to form the cycloadduct where the 1,3-dipole adds preferentially to the imine functionality at the expense of the potential olefinic carbon-carbon double bond. In light of the parent reaction, the most kinetically favored cycloadductP3A had a rate constant of 5.1 × 106 M-1s-1, which is about 12 manifolds faster than the next competing stereoisomer P1A with a rate constant of 4.1 × 105 M-1s-1 and about 1024 faster than the most favored cycloadduct P3B with a rate constant of 7.2 × 10-19 M-1s-1 in the unfavored pathway (Path B). Irrespective of the electronic and steric nature of the electron-donating (EDG) and electron-withdrawing (EWG) substituents placed on the dipolarophile, the selectivities of the reaction were maintained. Rationalization of the potential energy surface depicts that the 1,3-dipole adds across the dipolarophile via an asynchronous concerted mechanism. Rationalization of the HOMO-LUMO energies of the mesitonitrile oxide (1,3-dipole) and the 1,4-diazepine derivatives (dipolarophile) depict that the EDG-substituted dipolarophile react as nucleophiles, whereas the dipole reacts as an electrophile. Conversely, the HOMO-LUMO interaction between the EWG-substituted dipolarophile indicates that the EWG-substituted dipolarophile react as electrophiles, whereas the dipole reacts as a nucleophile. The electrophilic parr function at various reactive sites of the dipolarophile shows that the 1,3-dipole preferentially adds across the local centers with the largest electrophilic NBO or Mulliken spin densities which is consistent with the energetic trend observed. The reactivity of the 1,4-diazepine derivatives and the mesitonitrile oxide showed poor stereoselectivity.

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Thiazolo- and thiadiazolo-[3,2-a][1,3]diazepines and their patented derivatives, tested with diverse CNS pharmacological activities, constitute an important class of compounds for new drug development. Therefore, research efforts were continued to design, synthesize, and evaluate compounds for their ultra-short, short-acting hypnotic, anticonvulsant, and neuromuscular blocking activities. The present review provides a summary of the work accomplished by these heterocycles and their biological evaluation.

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A highly efficient Cu-mediated route for the synthesis of fused [1,2,3]triazolo[1,4]diazepines has been developed by azidation-cyclization of 2-bromo-N-propargylamines in a one-pot fashion. The key highlight of the present work is that the 2-bromo-N-propargylamines are prepared through the A3-reaction of cyclic amines such as isoquinoline and decarboxylative coupling of proline and pipecolinic acid with 2-bromo benzaldehyde and alkyne. As preliminary, these compounds were analyzed for their most probable bioactivity using various in silico tools. The recognized anti-neurodegenerative activity potential was assessed by molecular docking, AChE inhibition activity in erythrocytes and DPPH radical scavenging activity potentials possessed by the compounds. With a relative AChE inhibition activity of 97% (IC50 0.25 ±â€¯0.02 µM), compound 5d identified as the most active compound. Druggability of these compounds also evaluated through Lipinski's filter and other ADMET tools for the betterment of selective execution of in vitro and in vivo activities of the screened compounds cautiously.

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BACKGROUND: 1,4-Diazepines are two nitrogen containing seven membered heterocyclic compounds and associated with a wide range of biological activities. Due to its medicinal importance, scientists are actively involved in the synthesis, reactions and biological evaluation of 1,4-diazepines since number of decades. OBJECTIVE: The primary purpose of this review is to discuss the synthetic schemes and reactivity of 1,4- diazepines. This article also describes biological aspects of 1,4-diazepine derivatives, that can be usefully exploited for the pharmaceutical sector. CONCLUSION: This review summarizes the abundant literature on synthetic routes, chemical reactions and biological attributes of 1,4-diazepine derivatives. We concluded that 1,4-diazepines have significant importance due to their biological activities like antipsychotic, anxiolytic, anthelmintic, anticonvulsant, antibacterial, antifungal and anticancer. 1,4-diazepine derivatives with significant biological activities could be explored for potential use in the pharmaceutical industries.

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AIM AND OBJECTIVE: Benzodiazepines and indole fused heterocycles are pharmacologically significant scaffolds. Trivial work on indole fused benzodiazepine compounds is reported in the literature. Hence, it is imperative to explore the synthesis of indole-fused benzodiazepines that may act as a template for biological studies in the future. Hence, in the present work, the synthesis of indole fused benzodiazepine derivatives was undertaken using multi-phase nano-titania as catalyst under microwave irradiation. MATERIALS AND METHODS: MAOS technique was used to carry out the synthesis of spiro-benzo [1,4]diazepine derivatives in the presence of multiphase nano-titania as a catalyst. Nano-titania was prepared by sol-gel method and characterized by XRD, FT-IR, FESEM, EDS and thermogravimetric techniques. The synthesized spiro-benzo [1,4] diazepine derivatives were identified by physical and spectral methods. RESULTS: Synthesized compounds were obtained in excellent yields in a short span of time. The synthesis was also carried out in the presence of conventional catalysts in addition to nano-titania. Among all the catalysts, the best result was obtained with nano-titania. The amount of nano-titania was optimized to be 0.05g giving 93- 95% yield of products. The study of reusability of nano-titania revealed that it could be reused up to four times with a negligible change in efficiency. CONCLUSION: The paper reports an efficient, cost-effective and environmentally benign approach for the synthesis of spiro-benzo [1,4] diazepine derivatives in the presence of multiphase nano-titania catalyst under microwave irradiation.

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Described herein are our limited structure-activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N(6)-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N(6)-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N(6)-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N(6) and no attachment at N-1, or a combined C-10 at N(6) and a CH2Ph at N-1. Any alkyl chain shorter or longer than C-10 at N(6) with a CH2Ph attached at N-1, would result in decrease of biological activity.

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The tautomeric structure of 4-trifluoromethyl[b]benzo-1,4-diazepine system in solution has been evaluated by means of the calculation of (15)N NMR chemical shifts of individual tautomers in comparison with the averaged experimental shifts to show that the enamine-imine equilibrium is entirely shifted toward the imine form. The adequacy of the theoretical level used for the computation of (15)N NMR chemical shifts in this case has been verified based on the benchmark calculations in the series of the push-pull and captodative enamines together with related azomethynes, which demonstrated a good to excellent agreement with experiment.

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A new series of chalcones 5a-f were synthesized from caffeine-based aldehyde 3 and substituted acetophenones 4a-f. Treatment of compounds 5a-f with hydrazine hydrate led to pyrazolines 6a-f, and their subsequent reaction with acetic anhydride or formic acid afforded the corresponding N-substituted pyrazolines 7a-f and 8a-f respectively. Additionally, the regioselective cyclocondensation reaction of chalcones 5a-f with 4,5-diaminopyrazole 9 afforded the diazepine derivatives 10a-f. Synthesis of the above novel compounds was carried out through a simple procedure involving an easy work-up and mild reaction conditions. In vitro antimalarial activity against Plasmodium falciparum was evaluated for the obtained compounds. Among of them, just pirazoline 6a showed an outstanding growth inhibition percentage 85.2 ± 5.4%, while diazepines 10a-f showed remarkable growth inhibitions in the range of 80.3 ± 13.5 to 94.2 ± 0.2% when were tested at 20 µg/mL. Compounds 5b, 5e, 7c and 7f showed remarkable activities against Leishmania panamensis with growth inhibition of 88.3 ± 1.5, 82.6 ± 2.2, 82.8 ± 1.7 and 87.6 ± 0.5% respectively, at 20 µg/mL. In vitro assays against Trypanozoma cruzi showed that pyrazoline 6d displayed a growth inhibition of 61.9 ± 7.8% at 20 µg/mL while chalcone 5f was considered especially active with a growth inhibition of 9.7 ± 1.5% for a very low concentration of 1.0 µg/mL.

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A new series of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines 6a-g and 7a-g were obtained with high regioselectivity from the reaction of triamino- or tetraaminopyrimidines 4 and 5 with α,ß-unsaturated carbonyl compounds 3a-g based on 2,4-dichlorothiazol-5-carbaldehyde 1. Twelve of the synthesized compounds were selected and tested by US National Cancer Institute (NCI) for their antitumor activity against 60 different human tumor cell lines. Compounds 7d and 7g showed important GI50 ranges of 1.28-2.98 µM and 0.35-2.78 µM respectively under in vitro assays. In addition, 6a-g and 7a-g were tested for antifungal properties against the clinical important fungi Candida albicans and Cryptococcus neoformans. Although these compounds showed moderate activities against C. albicans, the 2-amino derivatives 7a-g and mainly 7a and 7b, showed high activity against standardized and clinical isolates of C. neoformans with MIC50 = 7.8-31.2 µg/mL, MIC80 = 15.6-31.2 µg/mL and MIC100 = 15.6-62.5 µg/mL. In addition, since both compounds were fungicide rather than fungistatic these thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines appear as good candidates for further development not only as antifungal but also as antitumor drugs.

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The photochemical properties and photodynamic activity of three porphyrazines (Pzs) containing annulated diazepine rings, including novel demetalated porphyrazine-possessing bis(styryl)diazepine moieties were investigated. The porphyrazines were evaluated in terms of their electronic absorption and emission properties, their tendency to undergo aggregation and photodegradation, as well as their singlet oxygen generation efficiency. The in vitro photodynamic activity of the porphyrazines and their liposomal formulations were examined by using two oral squamous cell carcinoma cell lines. Magnesium(II) tribenzodiazepinoporphyrazine (1) revealed the highest phototoxic effect in both cell lines used, H413 and HSC-3. Encapsulation of Pz 1 into L-α-phosphatidyl-D,L-glycerol:1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes resulted in a nearly threefold increase in photocytotoxicity relative to that of the solution of Pz 1 (IC50 values of 45 and 129 nM, respectively).

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A new series of tetrahydro-quinazoline and tetrahydro-1H-dibenzo[b,e][1,4]diazepine analogs were synthesized and tested for their DHFR inhibition and in vitro antitumor activity. Compound 35 showed a remarkable DHFR inhibitory potency (IC50, 0.004 µM) which is twenty fold more active than methotrexate (MTX). Compounds 17 and 23 proved to be fifteen fold more active than the known antitumor 5-FU, with MG-MID GI50, TGI, and LC50 values of 1.5, 46.8, 93.3 and 1.4, 17.4, 93.3 µM, respectively. Computer modeling studies allowed the identification that methoxy and methyl substituents, the π-system of the chalcone core, the nitrogen atoms, on the dibenzodiazepine ring as pharmacophoric features essential for activity. These mark points could be used as template model for further future optimization.

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Examples of ring-expanded nucleosides (RENs), represented by general structures 1 and 2, exhibited dual anti-HCV and anti-HIV activities in both cell culture systems and the respective target enzyme assays, including HCV NTPase/helicase and human RNA helicase DDX3. Since HCV is a leading co-infection in late stage HIV AIDS patients, often leading to liver cirrhosis and death, the observed dual inhibition of HCV and HIV by the target nucleoside analogues has potentially beneficial implications in treating HIV patients infected with HCV.

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Guanase is an important enzyme of the purine salvage pathway of nucleic acid metabolism and its inhibition has beneficial implications in viral, bacterial, and cancer therapy. The work described herein is based on a hypothesis that azepinomycin, a heterocyclic natural product and a purported transition state analog inhibitor of guanase, does not represent the true transition state of the enzyme-catalyzed reaction as closely as does iso-azepinomycin, wherein the 6-hydroxy group of azepinomycin has been translocated to the 5-position. Based on this hypothesis, and assuming that iso-azepinomycin would bind to guanase at the same active site as azepinomycin, several analogs of iso-azepinomycin were designed and successfully synthesized in order to gain a preliminary understanding of the hydrophobic and hydrophilic sites surrounding the guanase binding site of the ligand. Specifically, the analogs were designed to explore the hydrophobic pockets, if any, in the vicinity of N1, N3, and N4 nitrogen atoms as well as O(5) oxygen atom of iso-azepinomycin. Biochemical inhibition studies of these analogs were performed using a mammalian guanase. Our results indicate that (1) increasing the hydrophobicity near O(5) results in a negative effect, (2) translocating the hydrophobicity from N3 to N1 also results in decreased inhibition, (3) increasing the hydrophobicity near N3 or N4 produces significant enhancement of inhibition, (4) increasing the hydrophobicity at either N3 or N4 with a simultaneous increase in hydrophobicity at O(5) considerably diminishes any gain in inhibition made by solely enhancing hydrophobicity at N3 or N4, and (5) finally, increasing the hydrophilic character near N3 has also a deleterious effect on inhibition. The most potent compound in the series has a Ki value of 8.0±1.5µM against rabbit liver guanase.

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Precursors of 3-pyridylnitrene and 2- and 4-pyrimidinylcarbenes all afford mixtures of 2- and 3-cyanopyrroles on flash vacuum thermolysis, but 3-cyanopyrroles are the first-formed products. 3-Quinolylnitrenes and 4-quinazolinylcarbenes similarly afford 3-cyanoindoles. 2-Pyrimidinylcarbenes rearrange to 3-pyridylnitrenes, but 4-pyrimidinylcarbenes and 4-quinazolinylcarbenes do not necessarily rearrange to the corresponding 3-pyridylnitrenes or 3-quinolylnitrenes. The ring contraction reactions are interpreted in terms of ring opening of either the nitrenes or the diazacycloheptatetraenes to nitrile ylides.

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Both flash vacuum thermolysis (FVT) and matrix photolysis generate 2-diazomethylpyrazine (22) from 1,2,3-triazolo[1,5-a]pyrazine (24). FVT of 4-azidopyridine (18) as well as of 24 or 2-(5-tetrazolyl)pyrazine (23) affords the products expected from the nitrene, i.e., 4,4'-azopyridine and 2- and 3-cyanopyrroles. Matrix photolyses of both 18 and 24 result in ring expansion of 4-pyridylnitrene/2-pyrazinylcarbene to 1,5-diazacyclohepta-1,2,4,6-tetraene (20). Further photolysis causes ring opening to the ketenimine 27.