Synthetic Methods and Pharmacological Potentials of Triazolothiadiazines: A Review.

This review article examines the synthetic pathways for triazolothiadiazine derivatives, such as triazolo[3,4-b]thiadiazines, triazolo[5,1-b]thiadiazines, and triazolo[4,3-c]thiadiazines, originating from triazole derivatives, thiadiazine derivatives, or thiocarbohydrazide. The triazolothiadiazine derivatives exhibit several biological actions, including antibacterial, anticancer, antiviral, antiproliferative, analgesic, anti-inflammatory, and antioxidant properties. The review article aims to assist researchers in creating new biologically active compounds for designing target-oriented triazolothiadiazine-based medicines to treat multifunctional disorders.

Design, synthesis and docking studies of novel thiazole derivatives incorporating pyridine moiety and assessment as antimicrobial agents.

A novel series of substituted 4,6-dimethyl-2-oxo-1-(thiazol-2-ylamino)-1,2-dihydropyridine-3-carbonitrile derivatives 6, 9, 13, 15, and 17 was synthesized in a good to excellent yield from the reaction of 1-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)thiourea with 2-oxo-N'-arylpropanehydrazonoyl chloride, chloroacetone, α-bromoketones, ethyl chloroacetate, and 2,3-dichloroquinoxaline, respectively. The potential DNA gyrase inhibitory activity was examined using in silico molecular docking simulation. The novel thiazoles exhibit dock score values between - 6.4 and - 9.2 kcal/mol and they were screened for their antimicrobial activities. Compound 13a shown good antibacterial activities with MIC ranged from 93.7-46.9 µg/mL, in addition, it shown good antifungal activities with MIC ranged from 7.8 and 5.8 µg/mL.

New Potential Antimalarial Agents: Design, Synthesis and Biological Evaluation of Some Novel Quinoline Derivatives as Antimalarial Agents.

A novel series of dihydropyrimidines (DHPMs) 4a-j; 2-oxopyran-3-carboxylate 7a,b; 1-amino-1,2-dihydropyridine-3-carboxylate 8; and 1,3,4-oxadiazole derivatives 12 with quinolinyl residues have been synthesized in fairly good yields. The structure of the newly synthesized compounds was elucidated on the basis of analytical and spectral analyses. In vitro antimalarial evaluation of the synthesized quinoline derivatives against Plasmodium falciparum revealed them to possess moderate to high antimalarial activities, with IC50 values ranging from 0.014-5.87 µg/mL. Compounds 4b,g,i and 12 showed excellent antimalarial activity against to Plasmodium falciparum compared with the antimalarial agent chloroquine (CQ).

5-(4-Fluoro-phen-yl)-3-(4-methyl-phen-yl)-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

The central pyrazole ring in the title compound, C17H16FN3S, adopts an envelope conformation with the methine C atom bearing the 4-fluoro-phenyl substituent as the flap atom. Whereas the tolyl ring is slightly twisted out of the least-squares plane through the pyrazole ring [dihedral angle = 13.51 (11)°], the fluoro-benzene ring is almost perpendicular [dihedral angle = 80.21 (11)°]. The thio-amide group is almost coplanar with the N-N bond of the ring [N-N-C-N torsion angle = 1.2 (3)°] and the amine group forms an intra-molecular hydrogen bond with a ring N atom. In the crystal, supra-molecular double layers in the bc plane are formed via N-H⋯S, N-H⋯F and C-H⋯F inter-actions.

Regioselective synthesis and antimicrobial activities of some novel aryloxyacetic acid derivatives.

Reaction of aryloxyacetic acid hydrazides 1a,b with α-haloketones such as hydrazonoyl chlorides 2a,b; phenacyl bromides 6a,b; and 2-chloro-N-(1,3-thiazol-2-yl)acetamide 10 led to the formation N-(4-halophenyl)-2-[2-(aryloxyacetyl)hydrazinylidene]propanehydrazonoyl chloride 3a-d; (ethene-1,2-diyl)bis-2-(naphthalen-2-yloxy)acetohydrazides 9a,b; and 2-[(2-aryloxyacetyl)hydrazinyl)]-N-(1,3-thiazol-2-yl)acetamides 11a,b; respectively. The nucleophilic substitution reaction of 3a-d with thiophenol and sodium benzenesulfinate furnished the corresponding hydrazinylidenepropanehydrazonothioates 4a-d and sulfones 5a-d, respectively. The antimicrobial activities of the synthesized compounds were evaluated. The obtained data indicated that the majority of the tested compounds exhibited antibacterial activity while all those compounds showed antifungal activity. Sulfone 5d showed greater effect with all tested organism than well known antibacterial and antifungal agents with minimal inhibitory concentration (MIC) ranged between 4.125 and 16.5 µg/mL.

Synthesis of 5- and 6-N-heterocyclic methylenebisphosphonate derivatives and evaluation of their cytogenetic activity in normal human lymphocyte cultures.

Methods for the preparation of various aminomethylene bisphosphonates were developed. The required bisphosphonates were obtained by applying tetraethyl methylenebisphosphonate reagent to different types of oxazinones and the relevant Schiff base derivatives. Based on the prediction results (Pass program), we further estimated the sister chromatid exchange frequency and proliferation rate index values of human lymphocyte cultures after the administration of four newly synthesized bisphosphonates in order to evaluate their cytotoxic/cytostatic and possible antineoplastic potency. The results showed that all four bisphosphonates cause a dose-dependent increase in sister chromatid exchange frequency, followed by a decrease in proliferation rate index in both experiments compared to the control.

Elaborating on efficient anti-proliferation agents of cancer cells and anti-inflammatory-based N-bisphosphonic acids.

Methylenebisphosponic acid tetraethyl ester (1) was added to 2-azido-7a-e and 2-chloroquinoline-3-chalcones 10a-e in boiling sodium ethanolate solution to give, via Michael addition, tetrazolo[1,5-a]quinoline-8a-d, 13a and 2-chloroquinoline-based bisphosphonates 11a-d, 14a in E-configuration. Further acid hydrolysis afforded the respective BP-acid analogues E-9a-d, 12a-d, 13b, and 14b in excellent yields. Anti-tumor activity screening for the new BP-acids at a dose of 10 µM utilizing 44 different human tumor cell lines representing breast, ovary, prostate, lung, and CNS cancer as well as leukemia and melanoma was carried out. Eight of ten tested compounds exhibited remarkable anti-tumor activity against breast and prostate cancer, and a promising anti-tumor sensitivity toward ovarian cancer and melanoma. Conversely, there was only scattered activity against leukemia and no noticeable action of these BP-acids on CNS or lung cancer. Based on the prediction results (PASS program), anti-inflammatory activity of the new acids was also determined in vivo, by the acute carrageenin induced paw edema in rats. Many of these compounds showed anti-inflammatory properties at a dose of 50 mg/kg body weight.

Synthesis and anti-microbial activity of some 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile derivatives.

A new series of 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile such as hydrazide hydrazones 3a-h; ethane-1,2-diaminopyridine 6; phthalimidopyridines 8a,b; hydrazides 10a,b; urea 11a and thiourea 11b were synthesized in a good to excellent yield in step efficient process, using 1-amino-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) as a key intermediate. The antibacterial and antifungal activities of the synthesized compounds were evaluated. The obtained data indicated that the majority of the tested compounds exhibited both antibacterial and antifungal activities, particularly compounds 8a and 8b showed a comparable effect to a well known antibacterial and antifungal agents.

Application of phosphonyl carbanions to highly regioselective synthesis of some diazaphospholes and pyrazolinyl phosphonates.

A series of substituted spiro[3']pyrazolinylphosphonates and spiro[3]diazaphospholes were synthesized via 1:3-dipolar cycloaddition reaction of 2-diazonio-1,3-dioxo-2,3-dihydro-1H-inden-2-ide with phosphonyl carbanions: diethyl-cyanomethylphosphonate, -phosphono-acetates, and -vinylphosphonate. On the other hand, treatment of the diazo substrate with diethyl (thiomethyl)methylphosphonate led to the formation of condensed oxadiazine and spiro[3]diazaphosphole. Some compounds were found to possess antibacterial and antifungal activities.