Synthesis of hydrazinyl-thiazole ester derivatives, in vitro trypanocidal and leishmanicidal activities.

Aim: To synthesize novel more potent trypanocidal and leishmanicidal agents. Methods: Hantzsch's synthetic strategy was used to synthesize 1,3-thiazole-4-carboxylates and their N-benzylated derivatives. Results: 28 new thiazole-carboxylates and their N-benzylated derivatives were established to test their trypanocidal and leishmanicidal activities. From both series, compounds 3b, 4f, 4g, 4j and 4n exhibited a better or comparable trypanocidal profile to benznidazole. Among all tested compounds, 4n was found to be the most potent and was better than benznidazole. Conclusion: Further variation of substituents around 1,3-thiazole-4-carboxylates and or hydrazinyl moiety may assist in establishing better and more potent trypanocidal and leishmanicidal agents.

Chagas disease and leishmaniasis are neglected tropical diseases. Herein, 28 1,3-thiazoles have been synthesized from thiosemicarbazones in a rapid, efficient and cost-effective manner. In vitro assays were performed against intracellular amastigotes of Trypanosoma cruzi (T. cruzi) and promastigotes and intracellular amastigote forms of Leishmania infantum (L. infantum) and Leishmania amazonensis (L. amazonensis). Some of the 1,3-thiazole-4-carboxylates inhibited the amastigote form of T. cruzi without affecting macrophage viability, compound 4n being the most potent and better than benznidazole. Our synthesized compounds exhibited promising activity against T. cruzi, thus broadening options for scaffold and lead compound optimization. Concerning the leishmanicidal activity, compound 4g was the best prototype in terms of potency and selectivity. Compounds 4g and 3m showed moderate selectivity and potency against intracellular amastigotes of L. amazonensis and L. infantum, respectively.

Facile Synthesis and DFT Analysis of Novel Thiazole-Based Hydrazones: An Experimental and Theoretical Perspective.

Hydrazone compounds with remarkable nonlinear optical (NLO) properties were found with vast applications due to their cost-effective synthesis and greater stability. Therefore, we synthesized hydrazone scaffolds (TCAH1-TCAH8) by condensation reaction, and their structural confirmation was accomplished with spectroscopic methods (1H-, 13C-NMR, and HRMS). Quantum chemical calculations were also performed at B3PW91/6-311G(d,p) functional of DFT to explore electronic, structural, and chemical properties. To understand the NLO responses of afore-said chromophores, various kinds of analyses such as natural bonding orbitals (NBOs), frontier molecular orbitals (FMOs), UV-vis analysis, and density of states (DOS) were performed. Findings showed that the HOMO-LUMO energy gap in TCAH8 (3.595 eV) was found to be lower than the TCAH1-TCAH7 (4.123-3.932 eV) with a large red shift which leads to a substantial NLO response. Furthermore, strong intramolecular interactions showed the highest stabilization energy (24.1 kcal mol-1) for TCAH8 in the NBO transitions, combined with the least binding energy. The significant NLO response of TCAH4 was explored with ⟨α⟩, ßtot, and ⟨γ⟩ values as 5.157 × 10-23, and 2.185 × 10-29, and 2.753 × 10-34 esu, respectively, among the entitled compounds. The recent findings may inspire scientists to develop extremely effective NLO materials for forthcoming hi-tech applications.

Synthesis of hydrazinylthiazole carboxylates: a mechanistic approach for treatment of diabetes and its complications.

Aim: The deaths of thousands of people and millions affected by diabetes mellitus triggered us to look for alternative possible solutions to cure diabetes and its complications. Materials & methods: A series of hydrazinylthiazole carboxylates (3a-n) was prepared by cyclocondensation reaction of thiosemicarbazones with ethyl 2-chloroacetoacetate. These compounds were screened for antidiabetic potential through α-amylase inhibition, antiglycation and antioxidant assays. Results & conclusion: Most of the compounds exhibited a promising antidiabetic property. Compounds 3e and 3h showed excellent α-amylase and glycation inhibition properties. The hemolytic assay indicated that all compounds are biocompatible. Docking studies carried out on α-amylase target showed correlation between in vitro inhibition and binding energy.

4-Adamantyl-(2-(arylidene)hydrazinyl)thiazoles as potential antidiabetic agents: experimental and docking studies.

Aim: To develop an efficient and cost-effective antidiabetic agent. Methods: A simple and convenient Hantzsch synthetic strategy was used to prepare 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles. Results: Fifteen newly established structures of 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles were tested for their α-amylase, antiglycation and antioxidant activities. Almost all tested compounds showed excellent α-amylase inhibition. Compounds 3a and 3j exhibited the highest potency, with IC50 values of 16.34 ± 2.67 and 16.64 ± 1.12 µM, respectively. Compounds 3c and 3i exhibited comparable antiglycation potential with the standard, aminoguanidine. The antioxidant potential of compound 3g was found to be excellent, with an IC50 value of 28.19 ± 0.2563 µM. The binding interactions of compound 3a (binding energy = -8.833 kcal/mol) with human pancreatic α-amylase identified 3a as a potent α-amylase inhibitor. Conclusion: Enrichment of established structures with more electron-donating functionalities may assist/lead to the development of more potent antidiabetic drugs.

Diabetes is one of the major causes of death in the present era. To combat damaging processes associated with diabetes, called glycation and oxidation, we prepared a series of compounds called 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles. The established structures were tested for their antidiabetic potential. The compounds 4-adamantyl-(2-(4-chlorobenzylidene)hydrazinyl)thiazole and 4-adamantyl-(2-(2-chlorobenzylidene)hydrazinyl)thiazole showed the highest potency. The compounds 4-adamantyl-(2-(4-bromobenzylidene)hydrazinyl)thiazole and 4-adamantyl-(2-(2-hydroxybenzylidene)hydrazinyl)thiazole exhibited comparable antiglycation potential. The antioxidant potential of compound 4-adamantyl-(2-(3-nitrobenzylidene)hydrazinyl)thiazole was found to be excellent. A further test was used to check toxicity and all compounds were found to be biocompatible. We also investigated, through docking studies, the way in which these compounds interact with the human proteins albumin and pancreatic α-amylase.

Synthesis of Fluorinated Hydrazinylthiazole Derivatives: A Virtual and Experimental Approach to Diabetes Management.

A novel series of fluorophenyl-based thiazoles was synthesized following the Hanztsch method. All of the compounds were initially verified with physical parameters (color, melting point, retardation factor (R f)), which were further confirmed by several spectroscopic methods, including ultraviolet-visible (UV-visible), Fourier-transform infrared (FTIR), 1H, 13C, 19F NMR, and high-resolution mass spectrometry (HRMS). The binding interactions of all compounds were studied using a molecular docking simulation approach. Furthermore, each compound was evaluated for its alpha(α)-amylase, antiglycation, and antioxidant potentials. The biocompatibility of all compounds was checked with an in vitro hemolytic assay. All synthesized scaffolds were found biocompatible with minimal lysis of human erythrocytes as compared to the standard Triton X-100. Among the tested compounds, the analogue 3h (IC50 = 5.14 ± 0.03 µM) was found to be a highly potent candidate against α-amylase as compared to the standard (acarbose, IC50 = 5.55 ± 0.06 µM). The compounds 3d, 3f, 3i, and 3k exhibited excellent antiglycation inhibition potential with their IC50 values far less than the standard amino guanidine (IC50 = 0.403 ± 0.001 mg/mL). The antidiabetic potential was further supported by docking studies. Docking studies revealed that all synthesized compounds exhibited various interactions along enzyme active sites (pi-pi, H-bonding, van der Waals) with varied binding energies.

Synthesis of Thiazole-Chalcone Hybrid Molecules: Antioxidant, Alpha(α)-Amylase Inhibition and Docking Studies.

The molecular hybrid approach is very significant to combat various drug-resistant disorders. A simple, convenient, and cost-effective synthesis of thiazole-based chalcones is accomplished, using a molecular hybrid approach, in two steps. The compound 1-(2-phenylthiazol-4-yl)ethanone (3) was used as the main intermediate for the synthesis of 3-(arylidene)-1-(2-phenylthiazol-4-yl)prop-2-en-1-ones (4a-f). Thin layer chromatography was used to testify the formation and purity of all synthesized compounds. Further structural confirmation of all compounds was achieved via different spectroscopic techniques (UV, FT-IR, 1 H- and 13 C-NMR) and elemental analysis. All synthesized compounds were tested for their α-amylase inhibition and antioxidant potential. The cytotoxic property of compounds was also tested with in vitro haemolytic assay. All tested compounds showed moderate to excellent α-amylase inhibition and antioxidant activity. All tested compounds are found safe to use due to their less toxicity when compared to the standard Triton X. The molecular docking simulation study of all synthesized compounds was also conducted to examine the best binding interactions with human pancreatic α-amylase (pdb: 4 W93) using AutodockVina. The molecular docking results authenticated the in vitro amylase inhibition results, i.e., 3-(3-Methoxyphenyl)-1-(2-phenylthiazol-4-yl)prop-2-en-1-one (4e) exhibited lowest IC50 value 54.09±0.11  µM with a binding energy of -7.898 kcal/mol.

Synthesis, characterization and exploration of photovoltaic behavior of hydrazide based scaffolds: a concise experimental and DFT study.

Solar energy being a non-depleting energy resource, has attracted scientists' attention to develop efficient solar cells to meet energy demands. Herein, a series of hydrazinylthiazole-4-carbohydrazide organic photovoltaic compounds (BDTC1-BDTC7) with an A1-D1-A2-D2 framework was synthesized with 48-62% yields, and their spectroscopic characterization was accomplished using FT-IR, HRMS, 1H and 13C-NMR techniques. Density functional theory (DFT) and time dependent DFT analyses were performed utilizing the M06/6-31G(d,p) functional to calculate the photovoltaic and optoelectronic properties of BDTC1-BDTC7via numerous simulations of the frontier molecular orbitals (FMOs), transition density matrix (TDM), open circuit voltage (V oc) and density of states (DOS). Moreover, the conducted analysis on the FMOs revealed efficient transference of charge from the highest occupied to the lowest unoccupied molecular orbitals (HOMO → LUMO), further supported by TDM and DOS analyses. Furthermore, the values of binding energy (E b = 0.295 to 1.150 eV), as well as reorganization energy of the holes (-0.038-0.025 eV) and electrons (-0.023-0.00 eV), were found to be smaller for all the studied compounds, which suggests a higher exciton dissociation rate with greater hole mobility in BDTC1-BDTC7. V oc analysis was accomplished with respect to HOMOPBDB-T-LUMOACCEPTOR. Among all the synthesized molecules, BDTC7 was found to have a reduced band gap (3.583 eV), with a bathochromic shift and absorption maximum at 448.990 nm, and a promising V oc (1.97 V), thus it is regarded as a potential candidate for high performance photovoltaic applications.

Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones.

Cyclization of substituted thiosemicarbazones with α-bromo-4-cyanoacetophenone allows rapid single-step sustainable syntheses of 4-cyanophenyl-2-hydrazinylthiazoles libraries (30 examples, 66-79%). All show anticancer efficacy against HCT-116 and MCF-7 carcinoma cell lines with the majority being more active than cisplatin positive controls. The compounds 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f) and 2-(2-((pentafluorophenyl)methylene)-hydrazinyl)-4-(4-cyanophenyl)thiazole (3a') show optimal GI50 values (1.0 ± 0.1 µM and 1.7 ± 0.3 µM) against MCF-7 breast cancer cells. Against colorectal carcinoma HCT-116 cells, (2-(2-(3-bromothiophen-2-yl)methylene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3b'), 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f), 2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3n) and 2-(2-(1-(4-fluorophenyl)ethylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3w) are the most active (GI50 values: 1.6 ± 0.2, 1.6 ± 0.1, 1.1 ± 0.5 and 1.5 ± 0.8 µM respectively). Control studies with MRC-5 cells indicate appreciable selectivity towards the cancer cells targeted. Significant (p < 0.005) growth inhibition and cytotoxicity effects for the thiazoles 3 were corroborated by cell count and clonogenic assays using the same cancer cell lines at 5 and 10 µM agent concentrations. Cell cycle, caspase activation and Western blot assays demonstrated that compounds 3b' and 3f induce cancer cell death via caspase-dependent apoptosis. The combination of straight forward synthesis and high activity makes the thiazoles 3 an interesting lead for further development.

Synthesis of Arylidenehydrazinyl-4-methoxyphenylthiazole Derivatives: Docking Studies, Probing Type II Diabetes Complication Management Agents.

Thiazole has been a key scaffold in antidiabetic drugs. In quest of new and more effective drugs a simple, efficient, high yielding (67-79 %) and convenient synthesis of arylidenehydrazinyl-4-methoxyphenyl)thiazoles is accomplished over two steps. The synthesis involved the condensation of aryl substituted thiosemicarbazones and 2-bromo-4-methoxyacetophenone in absolute ethanol. The structures of the resulting thiazoles are in accord with their UV/VIS, FT-IR, 1 H-, 13 C-NMR and HRMS data. All compounds were evaluated for alpha(α)-amylase inhibition potential, antiglycation, antioxidant abilities and biocompatibility. The compounds library identified 2-(2-(3,4-dichlorobenzylidene)hydrazinyl)-4-(4-methoxyphenyl)thiazole as a lead molecule against α-amylase inhibition with an IC50 of 5.75±0.02 µM. α-Amylase inhibition is also supported by molecular docking studies against α-amylase. All the obtained thiazoles also showed promising antiglycation activity with 4-(4-methoxyphenyl)-2-{2-[2-(trifluoromethyl)benzylidene]hydrazinyl}thiazole exhibiting the best inhibition (IC50 = 0.383±0.001 mg/mL) compared to control. The tested compounds are also biocompatible at the concentration used i. e., 10 µM.

Synthesis, Characterization, and DFT-Based Electronic and Nonlinear Optical Properties of Methyl 1-(arylsulfonyl)-2-aryl-1H-benzo[d]imidazole-6-carboxylates.

Herein, a series of N-1-sulfonyl substituted derivatives of 2-substituted benzimidazoles (2a-2e) were designed and synthesized via structural tailoring of the acceptor part of donor-π-acceptor schemes, and their nonlinear optic (NLO) characteristics were reported. The structures of 2a-2e were investigated and their characterization was accomplished by employing spectroscopic procedures, i.e., UV-vis, FT-IR, and 1H and 13C NMR. Further, a density functional theory (DFT) approach was used to calculate UV-vis, vibrational, and 1H and 13C NMR techniques; frontier molecular orbitals (FMOs); global reactivity parameters (GRPs); natural bond orbitals (NBOs); optical and vibrational analysis; and nonlinear optics (NLO). The most promising results were obtained for 6-nitro-2-(4-nitrophenyl)-1-(4-nitrophenylsulfonyl)-1H-benzo[d]imidazole among entitled compounds, as it exhibited the highest ⟨α⟩ and ßtot values, showing it is an eye-catching NLO material. This DFT study evokes the interest of researchers regarding the development of benzimidazole-based tempting NLO compounds that could be beneficial in modern hi-tech applications.

Synthesis, crystal structure, Hirshfeld surface investigation and comparative DFT studies of ethyl 2-[2-(2-nitrobenzylidene)hydrazinyl]thiazole-4-carboxylate.

The ethyl 2-[2-(2-nitrobenzylidene)hydrazinyl]thiazole-4-carboxylate (1), a thiazole ester, was synthesized by refluxing 1-(2-nitrobenzylidene)thiosemicarbazide and ethyl bromopyruvate. The compound is characterized by spectrometric, spectroscopic and single crystal (SC-XRD) techniques. Non-covalent interactions that are responsible for crystal packing are explored by Hirshfeld surface analysis. All theoretical calculations were performed by DFT quantum chemical methods using 6-311G(d,p) and cc-pVTZ basis sets and compared. Theoretical harmonic frequencies of ethyl 2-[2-(2-nitrobenzylidene)hydrazinyl]thiazole-4-carboxylate (1) were optimized. Confirmation of hydrogen bonding sites was analyzed by molecular electrostatic potential (MEP) and Mulliken population analysis. The vibrational frequencies of characteristic functional groups and chemical shifts were found in good agreement with experimental assignments. Frontier molecular orbital (FMO) revealed relatively small HOMO-LUMO (highest occupied molecular orbital-lowest unoccupied molecular orbital) gape, which speaks off the nearly planar geometry and extended conjugation, as compared to the substituents with no conjugation possible. It has also been observed that -NO2 substituent plays a vital role for this relatively small HOMO-LUMO gape and overall electronic properties when compared with similar thiazole carboxylates (2-6, Table 6). Ethyl 2-[2-(2-nitrobenzylidene)hydrazinyl]thiazole-4-carboxylate (1) was also evaluated for its anti-oxidant and anti-microbial activities.

Synthesis and in Silico Docking Studies of Ethyl 2-(2-Arylidene-1-alkylhydrazinyl)thiazole-4-carboxylates as Antiglycating Agents.

Ethyl 2-(2-arylidene-1-alkylhydrazinyl)thiazole-4-carboxylates (1a-k) were synthesized by alkylation on HN- of ethyl 2-(2-arylidenehydrazinyl)thiazole-4-carboxylates. The proposed structures (1a-k) are corroborated by spectro-analytical techniques like UV, FT-IR, 1 H-, 13 C-NMR and HR-MS. All synthesized compounds were screened for their antiglycation and antioxidant assays. The in vitro antiglycation results revealed promising activity of compounds 1a, 1b, 1d, 1e, 1f, 1g, 1j and 1k with IC50 values 0.0004±1.097-17.22±0.538 µM when compared to standard, aminoguanidine (IC50 =25.50±0.337 µM). Among all tested compounds 1j and 1k are the best antiglycating agents with IC50 values 1.848±0.646 and 0.0004±1.097 µM, respectively. The in-silico studies also agree with these results where binding energy for 1j and 1k was found to be -9.25 and -8.42 kcal/mol with calculated dissociation constants of 0.16 and 0.67 µM, respectively. The antiglycation results demonstrate the application of these compounds in reducing diabetic complications.

Synthesis, antioxidant, antimicrobial and antiviral docking studies of ethyl 2-(2-(arylidene)hydrazinyl)thiazole-4-carboxylates.

A series of ethyl 2-(2-(arylidene)hydrazinyl)thiazole-4-carboxylates (2a-r) was synthesized in two steps from thiosemicarbazones (1a-r), which were cyclized with ethyl bromopyruvate to ethyl 2-(2-(arylidene)hydrazinyl)thiazole-4-carboxylates (2a-r). The structures of compounds (2a-r) were established by FT-IR, 1H- and 13C-NMR. The structure of compound 2a was confirmed by HRMS. The compounds (2a-r) were then evaluated for their antimicrobial and antioxidant assays. The antioxidant studies revealed, ethyl 2-(2-(4-hydroxy-3-methoxybenzylidene)hydrazinyl)thiazole-4-carboxylate (2g) and ethyl 2-(2-(1-phenylethylidene)hydrazinyl)thiazole-4-carboxylate (2h) as promising antioxidant agents with %FRSA: 84.46 ± 0.13 and 74.50 ± 0.37, TAC: 269.08 ± 0.92 and 269.11 ± 0.61 and TRP: 272.34 ± 0.87 and 231.11 ± 0.67 µg AAE/mg dry weight of compound. Beside bioactivities, density functional theory (DFT) methods were used to study the electronic structure and properties of synthesized compounds (2a-m). The potential of synthesized compounds for possible antiviral targets is also predicted through molecular docking methods. The compounds 2e and 2h showed good binding affinities and inhibition constants to be considered as therapeutic target for Mpro protein of SARS-CoV-2 (COVID-19). The present in-depth analysis of synthesized compounds will put them under the spot light for practical applications as antioxidants and the modification in structural motif may open the way for COVID-19 drug.

The design, synthesis, and in vitro trypanocidal and leishmanicidal activities of 1,3-thiazole and 4-thiazolidinone ester derivatives.

Chagas and leishmaniasis are both neglected tropical diseases, whose inefficient therapies have made them remain the cause for millions of deaths worldwide. Given this, we synthesized 27 novel 1,3-thiazoles and 4-thiazolidinones using bioisosteric and esterification strategies to develop improved and safer drug candidates. After an easy, rapid and low-cost synthesis with satisfactory yields, compounds were structurally characterized. Then, in vitro assays were performed, against Leishmania infantum and Leishmania amazonensis promastigotes, Trypanosoma cruzi trypomastigotes and amastigotes, for selected compounds to determine IC50 and SI, with cytotoxicity on LLC-MK2 cell lines. Overall, 1,3-thiazoles exhibited better trypanocidal activity than 4-thiazolidinones. The compound 1f, an ortho-bromobenzylidene-substituted 1,3-thiazole (IC50 = 0.83 µM), is the most potent of them all. In addition, compounds had negligible cytotoxicity in mammalian cells (CC50 values > 50 µM). Also noteworthy is the examination of the cell death mechanism of T. cruzi, which showed that compound 1f induced necrosis and apoptosis in the parasite. Scanning electron microscopy analysis demonstrated that the treatment of Trypanosoma cruzi trypomastigote cells with the compound 1f at different IC50 concentrations promoted alterations in the shape, flagella and body surface, inducing parasite death. Together, our data revealed a novel series of 1,3-thiazole structure-based compounds with promising activity against Trypanosoma cruzi and Leishmania spp., broadening ways for scaffold optimization.

Crystal structure of (E)-2-(4-chloro-benzyl-idene)-3,4-di-hydro-naphthalen-1(2H)-one: a second monoclinic polymorph.

The title compound, C17H13ClO, is the second monoclinic polymorph to crystallize in the space group P21/c. The first polymorph crystallized with two independent mol-ecules in the asymmetric unit [Bolognesi et al. (1975 ▸). Acta Cryst. A31, S119; Z' = 2; no atomic coordinates available], whereas the title compound has Z' = 1. In the title polymorph, the dihedral angle between the plane of the benzene ring of the tetra-lone moiety and that of the 4-chloro-benzyl ring is 52.21 (11)°. The cyclo-hex-2-en-1-one ring of the tetra-lone moiety has a screw-boat conformation. In the crystal, mol-ecules are liked by pairs of C-H⋯π inter-actions forming inversion dimers. There are no other significant inter-molecular inter-actions present.

Pharmacological justification of use of Solena heterophylla Lour. in gastrointestinal, respiratory and vascular disorders.

BACKGROUND: Solena heterophylla Lour. has traditionally been used in the management of diseases pertaining to gastrointestinal, respiratory and vascular system and present study was undertaken to validate its traditional uses. METHODS: The aqueous ethanolic extract of Solena heterophylla Lour (Sh.Cr) was tested in-vitro on isolated rabbit jejunum, tracheal and aorta preparations. The responses of tissues were recorded using isotonic transducers coupled with PowerLab data acquisition system. RESULTS: The aqueous ethanolic extract of Solena heterophylla Lour (Sh.Cr) (0.03-1.0 mg/ml) on application to spontaneous contractions in isolated rabbit jejunum preparation exerted relaxant effect through decrease in magnitude and frequency of contractions, caused relaxation of K(+)(80 mM)-induced contractions and shifted the Ca(2+) concentration response curves toward right in isolated rabbit jejunum preparations in a manner similar to verapamil (a standard Ca(2+) channel blocker), thus confirming its Ca(2+) channel blocking activity. The Sh.Cr also caused relaxation of carbachol (1 µM)- and K(+)(80 mM)-induced contractions in isolated rabbit tracheal preparations in a manner comparable to dicyclomine. CONCLUSIONS: The observed relaxant effect may be outcome of anti-muscarinic and Ca(2+) channel blocking activities. The Sh.Cr (0.03-1.0 mg/ml) against phenyephrine (1 µM)- and K(+)(80 mM)-induced contractions in isolated rabbit aortic preparations exerted a relaxant effect, possibly through Ca(2+) channel blocking activity. These findings provide a rationale for the folkloric uses of the plant in the management of ailments pertaining to gastrointestinal, respiratory and vascular system.

A facile one-pot synthesis of 2-arylamino-5-aryloxylalkyl-1,3,4-oxadiazoles and their urease inhibition studies.

A one-pot method for the synthesis of structural type urease inhibitors, 2-amino-1,3,4-oxadiazoles, was developed. The structures of the compounds were established using spectroanalytical techniques and unambiguously confirmed by single-crystal X-ray analysis of compound 3o. The synthesized compounds were tested against jack beans urease, and most of the compounds (3c, 3g, 3j, 3k, 3n, 3r-3v) were found more active than the standard. The most potent compound (3u) had an IC50 value of 6.03 ± 0.02 µm as compared to the IC50 value of the standard (thiourea; 22.0 ± 1.2 µm). The prominent urease inhibition activity of these compounds may serve as an important finding in the development of less toxic and more potent antiulcer drugs. The compounds were also investigated against four bacterial strains, and some of the compounds (3g and 3r) were found more potent than the standard drug (ciprofloxacin) against all the tested strains. The MIC value for compound 3g was 0.156 µmol/mL against the tested bacterial strains.

Synthesis, crystal structure and anti-HIV activity of 2-adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles.

Two series of 2-adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles (4a-l and 5a-l) were synthesized by cyclodehydration of adamantan-1-carboxylic acid/adamantylacetic acid with various aryl hydrazides (3a-l) in the presence of POCl(3). The synthesis was supported by spectroanalytical techniques and verified further by crystal structure determination of compounds 4e and 5k. The synthesized compounds were screened for their inhibitory activity against HIV-1 and HIV-2 in MT-4 cells. Compound 5b exhibited a moderate activity in vitro for the replication of both virus types, suggesting for further structural modification as a new lead in the development of an antiviral agent.

Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays.

Diglycose derivatives, consisting of two monosaccharides linked at non-anomeric positions by a bridging nitrogen atom, have been synthesised. Conversion of one of the precursor monosaccharide coupling components into an unsaturated derivative enhances its electrophilicity at the allylic position, facilitating coupling reactions. Mitsunobu coupling between nosylamides and 2,3-unsaturated-4-alcohols gave the 4-amino-pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A palladium-catalysed coupling between an amine and a 2,3-unsaturated 4-trichloroacetimidate gave a 2-amino-pseudodisaccharide as the major product, along with other minor products. Derivatisation of the C=C double bond in pseudodisaccharides allowed the formation of Man(N4-6)Glc and Man(N4-6)Man diglycosides. The amine-linked diglycosides were found to show weak glycosidase inhibitory activity.

Synthesis, QSAR and anti-HIV activity of new 5-benzylthio-1,3,4-oxadiazoles derived from α-amino acids.

2-(1-[(4-Chloro/methylphenylsulfonylamino)alkyl]-5-thioxo-4,5-dihydro-1,3,4-oxadiazoles (4a-e) were synthesized, in four steps, via the sulfonyl derivatives of l-amino acids (l-alanine, l-methionine and l-phenylalanine) 1a-e, the esters 2a-e, the hydrazides 3a-e and finally the cyclization to 4a-e. Alkylation of 4a-e with 1.0 mole eq. of substituted benzyl halides furnished S-benzyl derivatives 5a-t, while 1.1 mole eq. yielded major 5a-t and minor amount of 6a-d. Alternatively, treatment of 4a-e with 2.0 mole eq. of substituted benzyl halides furnished 6a-d only. The structures of 5b and 5l were further confirmed by single crystal X-ray analysis. Compounds 5a-t and 6a-d showed no selective inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 5f and 5j-5q exhibited some inhibitory activity against both types with EC(50) values (>11.50 - >13.00 µg/mL). These results suggest that the structural modifications of these compounds might lead to the development of new antiviral agents. The quantum structure-activity relationship of these novel structural congeners is discussed.