New Pyrazole-Clubbed Pyrimidine or Pyrazoline Hybrids as Anti-Methicillin-Resistant Staphylococcus aureus Agents: Design, Synthesis, In Vitro and In Vivo Evaluation, and Molecular Modeling Simulation.

Two hybrid series of pyrazole-clubbed pyrimidines 5a-c and pyrazole-clubbed pyrazoline compounds 6a,b and 7 were designed as attractive scaffolds to be investigated in vitro and in vivo for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. From the results of the in vitro antibacterial screening, compound 5c showed excellent activity (minimal inhibitory concentration, MIC = 521 µM) when compared with that of the reference antibiotic levofloxacin (MIC = 346 µM). The inhibition of the target dihydrofolate reductase (DHFR) enzyme by compounds 4 and 5a-c (IC50 = 5.00 ± 0.23, 4.20 ± 0.20, 4.10 ± 0.19, and 4.00 ± 0.18 µM, respectively) was found to be better than the reference drug trimethoprim (IC50 = 5.54 ± 0.28 µM). Molecular modeling simulation results have justified the order of activity of all the newly synthesized compounds as DHFR enzyme inhibitors, and compound 5c exhibited the best binding profile (-13.6169386 kcal/mol). Hence, the most potent inhibitor of the DHFR enzyme, 5c, was chosen to be evaluated in vivo for its activity in treating MRSA-induced keratitis in rats and that, in turn, significantly (P < 0.0001) reduced infection in rats when compared to MRSA-treated group results.

Novel Adamantane-Linked Isothiourea Derivatives as Potential Chemotherapeutic Agents: Synthesis, Structural Insights, and Antimicrobial/Anti-Proliferative Profiles.

In this study, two adamantane-linked isothiourea derivatives containing a common 4-chlorophenyl substituent coupled with 4-nitrobenzyl or 4-bromobenzyl moieties were synthesized. Both derivatives were characterized, in the solid state and in solution, through a synergistic combination of experimental and in silico techniques, and the results are of great value for the chemical and structural characterization of related compounds. The crystal structures of both derivatives were analyzed in depth, including Hirshfeld surface analysis and lattice energy calculations, revealing a predominant dispersive component of the total energy that stabilizes crystal packing. Both compounds showed potent broad-spectrum antibacterial activity and moderate activity against the pathogenic fungus Candida albicans. In addition, in vitro anti-proliferative activity assays showed that the 4-bromobenzyl analogue displays higher activity than the 4-nitrobenzyl one, with IC50 values under 30 µM against five human cancer cell lines. Our results give evidence of the potential of the adamantane/isothiourea combination to render auspicious scaffolds for new potential chemotherapeutic agents.

X-ray and theoretical investigation of (Z)-3-(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)-S-(4-bromobenzyl)isothioureas: an exploration involving weak non-covalent interactions, chemotherapeutic activities and QM/MM binding energy.

A detailed exploration of crystal packing of two adamantane-isothiourea hybrid derivatives along with a known closely related structure has been performed to delineate the effect of halogen substituents and the role of weak intermolecular interactions in their supramolecular architectures. The adamantane-isothiourea hybrid derivatives used in the present study are (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-phenylisothiourea (1), C24H27BrN2S and (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-(3-chlorophenyl)isothiourea (2), C24H26BrClN2S, characterized by X-ray crystallography. The X-ray structures revealed that the molecular conformation of 1 and 2 are different and stabilized by intramolecular C-H···N interactions. In addition, a short intramolecular H···H contact is formed in 2. The Hirshfeld surface analysis was used to delineate the nature of different intermolecular interactions and their contributions toward crystal packing. The quantitative analysis of strengths of molecular dimers existed in 1 and 2 has been performed using the PIXEL method. The electrostatic potential map clearly revealed nature and strength of σ-holes at Br and Cl atoms. The topological analysis was used to characterize the nature and the strength of various intermolecular interactions including the type I Br···Br contact. Interestingly, all the H-H bonding observed in 1 and 2 show closed-shell in nature. Further, an in-vitro antimicrobial activity studies suggest that the title compounds exhibited potent antibacterial activity against all the tested Gram-positive bacterial strains and Gram-negative Escherichia coli. Compound 2 showed marked anti-proliferative activity against MCF-7 and HeLa cell lines.Communicated by Ramaswamy H. Sarma.

Synthesis, Antimicrobial, and Anti-Proliferative Activities of Novel 4-(Adamantan-1-yl)-1-arylidene-3-thiosemicarbazides, 4-Arylmethyl N'-(Adamantan-1-yl)piperidine-1-carbothioimidates, and Related Derivatives.

The reaction of 4-(adamantan-1-yl)-3-thiosemicarbazide 3 with various aromatic aldehydes yielded the corresponding thiosemicarbazones 4a-g. 1-Adamantyl isothiocyanate 2 was reacted with 1-methylpiperazine or piperidine to yield the corresponding N-(adamantan-1-yl)carbothioamides 5 and 6, respectively. The latter was reacted with benzyl or substituted benzyl bromides to yield the S-arylmethyl derivatives 7a-c. Attempted cyclization of 1,3-bis(adamantan-1-yl)thiourea 8 with chloroacetic acid via prolonged heating to the corresponding thiazolidin-4-one 9 resulted in desulfurization of 8 to yield its urea analogue 10. The thiazolidin-4-one 9 and its 5-arylidene derivatives 11a,b were obtained via microwave-assisted synthesis. The in vitro antimicrobial activity of the synthesized compounds was evaluated against a panel of Gram-positive and Gram-negative bacteria and yeast-like pathogenic fungus Candida albicans. Compounds 7a-c displayed marked broad spectrum antibacterial activities (minimal inhibitory concentration (MIC), 0.5-32 µg/mL) and compounds 4a and 4g showed good activity against Candida albicans. Nine representative compounds were evaluated for anti-proliferative activity towards three human tumor cell lines. Compounds 7a-c displayed significant generalized anti-proliferative activity against all the tested cell lines with IC50 < 10 µM.

Gliclazide.

Gliclazide is a second-generation oral hypoglycemic drug used for the treatment of noninsulin-dependent diabetes mellitus. It belongs to the sulfonylurea class that stimulates insulin secretion from pancreatic ß-cells by inhibiting ATP-dependent potassium channels. Gliclazide also possesses unique antioxidant properties and other beneficial hemobiological effects. This profile represents a comprehensive description of the physical properties, chemical synthesis, spectroscopic characterization (FTIR, 1H NMR, 13C NMR, UV, and single-crystal X-ray), methods of analysis, pharmacological actions, and pharmacokinetic and pharmacodynamic properties of the title drug.

Crystal structure of 3-[(4-benzyl-piperazin-1-yl)meth-yl]-5-(thio-phen-2-yl)-2,3-di-hydro-1,3,4-oxa-diazole-2-thione.

The title 1,3,4-oxa-diazole-2-thione derivative, C18H20N4OS2, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. The 2-thienyl rings in both mol-ecules are rotationally disordered over two orientations by approximately 180° about the single C-C bond that connects it to the oxa-diazole thione ring; the ratios of site occupancies for the major and minor components were fixed in the structure refinement at 0.8:0.2 and 0.9:0.1 in mol-ecules A and B, respectively. The 1,3,4-oxa-diazole-2-thione ring forms dihedral angles of 7.71 (16), 10.0 (11) and 77.50 (12)° (mol-ecule A), and 6.5 (3), 6.0 (9) and 55.30 (12)° (mol-ecule B) with the major and minor parts of the disordered thio-phene ring and the mean plane of the adjacent piperazine ring, respectively, resulting in approximately V-shaped conformations for the mol-ecules. The piperazine ring in both mol-ecules adopts a chair conformation. The terminal benzene ring is inclined towards the mean plane of the piperazine ring with N-C-C-C torsion angles of -58.2 (3) and -66.2 (3)° in mol-ecules A and B, respectively. In the crystal, no inter-molecular hydrogen bonds are observed. The crystal packing features short S⋯S contacts [3.4792 (9) Å] and π-π inter-actions [3.661 (3), 3.664 (11) and 3.5727 (10) Å], producing a three-dimensional network.

Study on molecular structure, spectroscopic behavior, NBO, and NLO analysis of 3-methylbezothiazole-2-thione.

Experimentally observed spectral data (FT-TR and FT-Raman) of 3-methylbezothiazole-2-thione (3MBT2T) were compared with the spectral data obtained by DFT/B3LYP method using 6-311++G(d,p) basis set. UV-Vis spectrum of the title compound was recorded and the electronic properties, such as frontier molecular orbitals and band gap energies were calculated by TD-DFT approach. The molecular properties like dipole moment, polarizability, first static hyperpolarizability, molecular electrostatic potential surface (MEPs), and contour map were calculated to get a better comprehension of the properties of the title molecule. Natural bond orbital (NBO) analysis was applied to investigate the stability of the molecule arising from charge delocalization. Global and local reactivity descriptors were also computed to predict reactivity and reactive sites on the molecule.

Spectroscopic investigation (FT-IR, FT-Raman), HOMO-LUMO, NBO analysis and molecular docking study of 2-[(4-chlorobenzyl)sulfanyl]-4-(2-methylpropyl)-6-[3-trifluoromethyl)-anilino]pyrimidine-5-carbonitrile, a potential chemotherapeutic agent.

FT-IR and FT-Raman spectra of 2-[(4-chlorobenzyl)sulfanyl]-4-(2-methylpropyl)-6-[3-trifluoromethyl)-anilino]pyrimidine-5-carbonitrile were recorded and analyzed. The vibrational wave numbers were computed using DFT quantum chemical calculations. The data obtained from wave number calculations are used to assign vibrational bands obtained in infrared and Raman spectra. Potential energy distribution was done using GAR2PED program. The NH stretching wave number is red shifted by 102 cm(-1) in IR from the computed wave number, which indicates the weakening of the NH bond. The geometrical parameters (DFT) of the title compound are in agreement with the XRD results. NBO analysis, HOMO-LUMO, first hyperpolarizability and molecular electrostatic potential results are also reported. From the MEP map it is evident that the negative electrostatic potential regions are mainly localized over the CN and CF3 groups and are possible sites for electrophilic attack and positive regions are localized around NH group, indicating possible sites for nucleophilic attack. The preliminary docking results suggest that the title compound might exhibit inhibitory activity against GPb and may act as a potential anti-diabetic compound.

Spectroscopic investigation (FT-IR and FT-Raman), vibrational assignments, HOMO-LUMO analysis and molecular docking study of 2-(Adamantan-1-yl)-5-(4-nitrophenyl)-1,3,4-oxadiazole.

FT-IR and FT-Raman spectra of 2-(Adamantan-1-yl)-5-(4-nitrophenyl)-1,3,4-oxadiazole were recorded and analyzed. The vibrational wavenumbers were computed using DFT quantum chemical calculations. The data obtained from wavenumber calculations are used to assign vibrational bands obtained experimentally. The energy barriers of the internal rotations about the C-C bonds connecting the oxadiazole to the adamantane and benzene rings are reported. The geometrical parameters (DFT) of the title compound are in agreement with the XRD results. The calculated HOMO and LUMO energies allow the calculations of atomic and molecular properties and they also showed that charge transfer occurs in the molecule. A detailed molecular picture of the title compound and its interactions were obtained from NBO analysis. As can be seen from the MEP map of the title compound, which regions having the negative potential are over the electro negative atoms, the region having the positive potential are over the phenyl and adamantine rings and the remaining species are surrounded by zero potential. The molecular docking studies reveal that the adamantyl derivative may exhibit C-South African HIV-proteas inhibitory activity.

Synthesis, biological evaluation and molecular modeling study of 2-(1,3,4-thiadiazolyl-thio and 4-methyl-thiazolyl-thio)-quinazolin-4-ones as a new class of DHFR inhibitors.

A new series of 2-(1,3,4-thiadiazolyl- or 4-methyl-thiazolyl)thio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 29, 34, and 39 proved to be the most active DHFR inhibitors with IC50 values range of 0.1-0.6 µM. Compounds 28, 31 and 33 showed remarkable broad-spectrum antimicrobial activity comparable to the known antibiotic Gentamicin. Compounds 26, 33, 39, 43, 44, 50, 55 and 63 showed broad spectrum antitumor activity with GI values range of 10.1-100%. Molecular modeling study concluded that recognition with key amino acid Glu30, Phe31 and Phe34 is essential for binding. ADMET properties prediction of the active compounds suggested that compounds 29 and 34 could be orally absorbed with diminished toxicity.

3-(Adamantan-1-yl)-4-benzyl-1H-1,2,4-triazole-5(4H)-thione.

The title compound, C19H23N3S, is a functionalized triazoline-3-thione derivative. The benzyl ring is almost normal to the planar 1,2,4-triazole ring (r.m.s. deviation = 0.007 Å) with a dihedral angle of 86.90 (7)°. In the crystal, molecules are linked by pairs of N-H⋯S hydrogen bonds, forming inversion dimers that enclose R 2 (2)(8) loops. The crystal packing is further stabilized by weak C-H⋯π inter-actions that link adjacent dimeric units into supra-molecular chains extending along the a-axis direction.

5-Propyl-6-(p-tolyl-sulfan-yl)pyrimidine-2,4(1H,3H)-dione.

In the title pymiridine-2,4-dione derivative, C14H16N2O2S, the dihedral angle between the six-membered rings is 66.69 (10)°. The mol-ecule is twisted about the Cp-S (p = pyrimidine) bond, with a C-S-C-N torsion angle of -19.57 (16)°. In the crystal, adjacent mol-ecules form inversion dimers through pairs of strong N-H⋯O hydrogen bonds, generating an R 2 (2)(8) ring motif. The dimers are connected into chains extending along the c-axis direction through additional N-H⋯O hydrogen bonds.

4-(2-Meth-oxy-phen-yl)piperazin-1-ium 6-chloro-5-isopropyl-2,4-dioxopyrimidin-1-ide.

In the cation of the title salt, C11H17N2O(+)·C7H8ClN2O2 (-), the piperazine ring adopts a distorted chair conformation and contains a positively charged N atom with quaternary character. Its mean plane makes a dihedral angle of 42.36 (8)° with the phenyl ring of its 2-meth-oxy-phenyl substituent. The 2,4-dioxopyrimidin-1-ide anion is generated by deprotonation of the N atom at the 1-position of the pyrimidine-dione ring. Intra-molecular C-H⋯O hydrogen bonds generate S(6) ring motifs in both the cation and the anion. In the crystal, N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds are also observed, resulting in a two-dimensional network parallel to the ab plane. The crystal stability is further consolidated by weak C-H⋯π inter-actions.

Nonclassical antifolates, part 5. Benzodiazepine analogs as a new class of DHFR inhibitors: synthesis, antitumor testing and molecular modeling study.

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.

Nonclassical antifolates, part 4. 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: synthesis, biological evaluation and molecular modeling study.

A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC50 0.03 µM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors.

Melatonin: comprehensive profile.

This chapter includes the aspects of melatonin. The drug is synthesized in the pineal gland starting from tryptophane or synthetically by using indole as starting material. Melatonin has been used as an adjunct to interleukin-2 therapy for malignant neoplasms, as contraceptive, in the management of various forms of insomnia, to alleviate jet lag following long flights, and finally as free radical scavenger and hence as an antioxidant and an anti-inflammatory. The chapter discusses the drug metabolism and pharmacokinetics and presents various method of analysis of this drug such as biological analysis, spectroscopic analysis, and chromatographic techniques of separation. It also discusses its physical properties such as solubility characteristics, X-ray powder diffraction pattern, and thermal methods of analysis. The chapter is concluded with a discussion on its biological properties such as activity, toxicity, and safety.

Nonclassical antifolates, part 3: synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones.

A new series of 2-heteroarylthio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 21, 25, and 39 proved to be active DHFR inhibitors with IC50 range of 0.3-0.8 µM. Compounds 25, 28, 33, 35 and 36 showed broad spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compound 29 showed broad spectrum antitumor activity toward several tumor cell lines with GI values range of 25.8-41.2%. Molecular modeling studies concluded that recognition with key amino acid Arg38 and Lys31 are essential for binding and biological activities. Flexible alignment; electrostatic and hydrophobic mappings revealed that the obtained model could be useful for the development of new DHFR inhibitors.

Substituted thiazoles VII. Synthesis and antitumor activity of certain 2-(substituted amino)-4-phenyl-1,3-thiazole analogs.

A novel series of 2-acetamido- or 2-propanamido-4-(4-substituted phenyl)-1,3-thiazoles (11-34) was designed and synthesized. Compounds were subjected to National Cancer Institute (NCI) in vitro assessment for their antitumor activity, at a single dose of 10 µM. Most of the investigated compounds exhibited broad-spectrum antitumor activity. Compounds 19 and 28 believed to be the most active members in this study, with MG-MID GI(50), TGI, and LC(50) values of 2.8, 11.4, 44.7; and 3.3, 13.1, 46.8, respectively. Compounds 19 and 28 proved to be nine and sevenfold more active than the standard antitumor drug 5-FU, respectively.

Substituted thiazoles VI. Synthesis and antitumor activity of new 2-acetamido- and 2 or 3-propanamido-thiazole analogs.

A novel series of 2-acetamido and 2 or 3-propanamido derivatives of 4- or 5-substituted-thiazoles was designed and synthesized. Structure elucidation of the new synthesized compounds was attained by the use of (1)H &(13)C NMR, and Mass spectrometry. Compounds were subjected to NCI in vitro assessment for their antitumor activity, at a single dose of 10 µM of test compounds. Compounds bearing straight chain substituent or 4-phenyl function proved to be more active than their branched or 4-methyl congeners. Compounds 37, 41 and 42 exhibited broad spectrum antitumor activity. Compounds 23 and 27 proved lethal while compounds 18, 21, 32 and 37 showed remarkable GI values of 75.5, 69.3, 96.2 and 92.7% to the Leukemia CCRF-CEM cell line, respectively.

Substituted thiazoles V. synthesis and antitumor activity of novel thiazolo[2,3-b]quinazoline and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine analogues.

A novel series of thiazolo[2,3-b]quinazoline (14-23, 26 and 27), and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine (34-43, 45 and 46) analogues were designed and synthesized. The obtained compounds were evaluated for their in-vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 22, 38, 40 and 41 showed remarkable broad-spectrum antitumor activity. Compounds 22 and 38 are almost nine fold more active than 5-FU, with GI(50), TGI, and LC(50) values of 2.5, >100, >100; and 2.4, 9.1, 36.2 µM, respectively; while 40 and 41 are almost seven fold more active than 5-FU, with GI(50), TGI, and LC(50) values of 2.9, 12.4, 46.6 and 3.0, 16.3, 54.0 µM, respectively.