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.

[Hysterosonography]. / Hystérosonographie.

Hysterosonography, which consists in the injection of some cc of saline in the uterine cavity during sonography, allows an exploration of the uterine cavity and of the endometrium. Accuracy of hysterosonography is similar to that of office hysteroscopy. Hysterosonography distinguishes normal cavities from pathologic ones, endometrial atrophy from mucosal anomalies, polyps from myomas. Conversely, endometrial biopsy is still necessary for diagnosis of hyperplasia or cancer. Hysterosonography can also be proposed for first trimester bleedings, trophoblast retention or ectopic pregnancy. In the near future it could be applied to therapeutic goals such as sonographic section of polyps.

Laparoscopy in patients with prior surgery: results of the blind approach.

BACKGROUND AND OBJECTIVES: To compare the complication rate due to blind access laparoscopy between patients with or without a prior history of laparotomy. METHODS: We examined a prospective record of data on laparoscopic surgeries performed from 1992 to 1998. Only cases in which the Veress needle and the first trocar were inserted through the umbilicus were included in this study. Results issued from patients without previous abdominal surgery (Group I) were compared with those arising from women with prior laparotomy (Group II). A statistical analysis was performed using the Chi-square test or Fisher exact test when appropriate. RESULTS: One thousand thirty-three laparoscopies were carried out during the study period, 881 of which began with a blind access through the umbilicus. Two hundred two women (19.3%) had an history of abdominal or pelvic surgery. Eight hundred forty-two patients were included in Group I and 39 in Group II. Failure to penetrate into the peritoneal cavity occurred significantly more frequently in Group II (4/39) than in Group I (1/842, P < 0.0001). The insertion of the Veress needle gave rise to 2 complications in Group I and 0 in Group II (P = 1.0). Transumbilical trocar insertion gave rise to 1 complication in each group (1/841 vs. 1/35, P = 0.11). When all events were considered, incidents or accidents were significantly more frequent in Group II (5/39) than in Group I (4/842)(P < 0.0001). CONCLUSIONS: We recorded a higher rate of incidents/complications due to the Veress needle and trocar insertion in patients with a previous history of laparotomy. An adapted approach should be recommended for these patients.

Saline contrast sonohysterography in the preoperative assessment of benign intrauterine disorders.

OBJECTIVES: To assess the value of saline contrast sonohysterography (SCSH) in the preoperative evaluation of benign intrauterine lesions. DESIGN: Patients presenting with abnormal bleeding related to benign uterine pathologies and scheduled for surgical treatment were prospectively enrolled in a study conducted between 1 January 1996 and 31 December 1997. SCSH was first carried out with the intention of establishing further surgical management (hysterectomy or hysteroscopy). The end point of the study was to compare the surgical option ultimately carried out with the one decided after SCSH. In addition, size and location of intrauterine lesions determined by SCSH were compared with those issued from surgical records. Similarly, pathologic results were juxtaposed to SCSH diagnosis. Statistical analysis used non-parametric and correlation tests. RESULTS: Two hundred and thirty-three patients were included in the study, 39.5% of whom were postmenopausal. SCSH was consistently effective in the choice of the best surgical method, because no hysterectomy was required when an operative hysteroscopy was indicated on SCSH data. Similarly, only one patient treated by hysterectomy (5.8%) could have undergone a more conservative approach. But this patient had a genital prolapse, and thus hysterectomy was a part of the treatment. SCSH correlated well with surgery for the location and size of intrauterine lesions (P < 0.001). SCSH was accurate in the diagnosis of polyps and submucous myomas (sensitivity 85.7%, specificity 95.4%). CONCLUSIONS: SCSH appears an important tool for preoperative assessment of benign intrauterine pathologies. It should be used in the selection of patients that should be scheduled for an operative hysteroscopy.

Perioperative morbidity of gynecological laparoscopy. A prospective monocenter observational study.

BACKGROUND: To study the morbidity rate of gynecological laparoscopy and to the most influential variables. METHODS: We conducted a prospective observational study from January 1st 1992 to December 31st 1998 in a single tertiary care center. It concerned patients who underwent gynecological laparoscopic surgery performed by seniors and residents. We have prospectively recorded patients characteristics, indications for laparoscopy, leading diagnosis, main operative procedures, post-operative course, surgical and anesthetic incidents and accidents. Complications were defined as any event that would modify the usual course of laparoscopy or of the post-operative period. RESULTS: One thousand and thirty-three laparoscopies were included. 80.1% of the procedures were major or advanced laparoscopies. The overall complication rate was 3%, with a laparotomy rate of 1.2%. About half of those complications (54.8%) occurred during the installation of laparoscopy. Veress needle and first trocar insertion accounted for 23.5% of those accidents (0.3% of the procedures) and suprapubic trocar insertion for 76.5%. Hemorrhages constituted almost all of the complications occurring during the operative stage (80%). The risk increased with the level of surgery and decreased with surgeon's experience. Prior abdominal surgery had no significant effect on the overall morbidity rate. Post-operative and anesthetic complications were rare. The overall complication rate as well as the laparotomy rate were stable all along the course of the study. CONCLUSIONS: Complication rate of gynecological laparoscopy is not negligible. Efforts should be made to lower the complications induced by the installation of laparoscopy, especially for secondary trocars.

[Complications of gynecological laparoscopy. Results of a prospective single center study]. / Complications de la coeliochirurgie gynécologique. Résultats d'une étude prospective unicentrique.

Gynaecological laparoscopy is associated with a patient morbidity rate. Half of the complications occur during the installation stage.

Morbidity in laparoscopic gynecological surgery: results of a prospective single-center study.

BACKGROUND: We set out to investigate prospectively the morbidity rate for gynecological laparoscopy patients at a tertiary care center. METHODS: We prospectively recorded data on 743 laparoscopic procedures performed between January 1, 1992 and December 31, 1996. The procedures included 36 diagnostic laparoscopies (4.8%), 115 laparoscopies carried out for minor surgical acts (15.4%), 523 for major surgical acts (70.4%), and 69 for advanced surgical acts (9. 4%). A total of 127 patients had a history of prior laparotomy (17%). All those procedures were performed by young senior surgeons. We defined a complication as an event that had modified the usual course of the procedure or of the postoperative period. For statistical analysis, we used the chi-squared test or Fisher's exact test. RESULTS: Complications occurred in 22 cases; the overall complication rate was 2.9% when all events were considered. One complication (injury of the left primitive iliac artery) was related to insertion of the Veress needle (0.13%). A total of 2,578 trocars were inserted, giving rise to 10 complications (1.3%). Three unintended laparotomies were required for bowel or bladder injuries (0.4%). Finally, the introduction of the laparoscope was responsible for 11 complications (1.4%); this figure represents 50% of all the complications of this series. Eight intraoperative complications (1%) occurred during the laparoscopic surgery (seven severe bleedings and one ureter injury, but no intestinal lesions); laparotomy was required in six of these cases. Three complications occurred during the postoperative stage: one granulomatous peritonitis after intraabdominal rupture of a dermoid cyst, one incisional hernia, and a fast-resolving cardiac arrhythmia. CONCLUSIONS: In our experience, operative gynecological laparoscopy is associated with an acceptable morbidity rate. Moreover, about half of the complications occur during the installation of the laparoscopic procedure, underscoring the usefulness of safety rules.

A worldwide clinical overview of lomefloxacin, a once-daily fluoroquinolone.

Lomefloxacin, an orally active difluorinated quinolone, is active against a wide variety of clinically relevant Gram-negative and Gram-positive organisms. A totoal of 3387 evaluable patients received (both complicated and uncomplicated), acute exacerbations of chronic bronchitis, acute bacterial diarrhea, skin and skin structure infections, or for prophylaxis during urinary tract surgery or instrumentation. In these studies lomefloxacin was compared with oral norfloxacin, ciprofloxacin, trimethoprim/sulfamethoxazole, amoxicillin and cefaclor, and the parenteral agents cefotaxime and cefuroxime. Once-daily oral administration of lomefloxacin was either equally effective or statistically significantly superior in clinical and/or bacteriologic efficacy to comparative agents that were administered two or three times per day (except for prophylaxis studies, in which single doses of each antibiotic were administered preoperatively). The safely of lomefloxacin was assessed in 3246 patients and subjects. Most adverse events were mild to moderate in severity. In general, the incidence of adverse events for patients and subjects receiving lomefloxacin was comparable to that observed in patients treated with comparative drugs. The incidence of adverse events in elderly patients was similar to that observed in younger patients. Concurrent administratopm of the ophylline did not increase the incidence of adverse events. The most common adverse events were related tothe gastrointestinal tract (nausea), the skin and appendages (photosensitivity) and the central nervous system (dizziness). Lomefloxacin, administered orally once daily, is effective and well tolerated in patients with a variety of infections of bacterial origin.

The U.S. clinical experience with lomefloxacin, a new once-daily fluoroquinolone.

Lomefloxacin is a new fluoroquinolone antimicrobial agent that has undergone extensive worldwide clinical evaluation. This report summarizes the safety and efficacy of lomefloxacin in the treatment of uncomplicated urinary tract infections, complicated urinary tract infections, acute exacerbations of chronic bronchitis, and for prophylaxis during urinary tract surgery. The clinical data presented are an overview of all clinical studies conducted in the United States to date. The results have been derived from multiple studies in which patients received lomefloxacin or a comparative agent in either blinded or open-label studies. During the course of the clinical program in the United States, lomefloxacin has been compared with oral norfloxacin, ciprofloxacin, and cefaclor, as well as parenteral cefotaxime. In all instances, the once-daily oral administration of lomefloxacin was either equally effective or statistically significantly superior in clinical and/or bacteriologic efficacy to these comparative agents. In addition, the comparators were administered either two or three times per day, except in the surgical prophylaxis studies, in which single doses of each antibiotic were administered preoperatively. These results attest to the value of the convenience and simplicity of the oral dosing regimen for lomefloxacin. During the course of the clinical program, lomefloxacin was well tolerated, with most adverse events of mild to moderate severity. In general, the incidence of adverse events for patients and subjects receiving lomefloxacin was comparable to that observed in patients treated with comparator drugs. The most common adverse events were related to the gastrointestinal tract (nausea and diarrhea), the skin and appendages (photosensitivity), and the central nervous system (dizziness and headache). A sub-analysis of adverse events in the respiratory studies demonstrated that concomitant administration of lomefloxacin and theophylline does not increase the incidence of adverse events when compared to lomefloxacin alone. An additional sub-analysis also showed that the incidence of adverse events in elderly patients was similar to that in younger patients. The results of the U.S. clinical program indicate that lomefloxacin administered orally once daily is effective and well tolerated in a variety of infections of bacterial origin.