New Niflumic Acid Derivatives as EGFR Inhibitors: Design, Synthesis, In silico Studies, and Anti-proliferative Assessment.

BACKGROUND: 1,3,4-oxadizole and pyrazole derivatives are very important scaffolds for medicinal chemistry. A literature survey revealed that they possess a wide spectrum of biological activities including anti-inflammatory and antitumor effects. OBJECTIVES: To describe the synthesis and evaluation of two classes of new niflumic acid (NF) derivatives, the 1,3,4-oxadizole derivatives (compounds 3 and (4A-E) and pyrazole derivatives (compounds 5 and 6), as EGFR tyrosine kinase inhibitors in silico and in vitro. METHODS: The designed compounds were synthesized using conventional organic synthesis methods. The antitumor activities of the new NF derivatives against HepG2 hepatocellular carcinoma and A549 non-small cell lung cancer cell lines were assessed in vitro via MTT assay, flow cytometry, RT-PCR, as well as via molecular docking studies. RESULTS: The cytotoxicity results indicated that the newly synthesized NF derivatives were cytotoxic against the two cancer cell lines, with compound 6 being the most cytotoxic, achieving the lowest IC50 concentration. Furthermore, compound 6 targeted EGFR tyrosine kinase leading to cell cycle arrest at the G2/M cell cycle phase and induction of apoptosis. The in vitro biological investigation results matched those of the molecular docking analysis. In conclusion, the new NF derivatives, specifically compound 6, exhibited favorable pharmacokinetic features and are promising EGFR tyrosine kinase inhibitors. CONCLUSION: A series of niflumic acid derivatives (3, 4A-E, 5, and 6) were successfully created, and FT-IR, ^{1H, ₁₃CNMR, and HRMS were used to confirm their chemical structures. According to molecular docking studies, compounds 3, 5, and 6 have the highest docking scores (ΔG), and most tested compounds have a good pharmacokinetic profile. Results of compound 6 in vitro antitumor activities showed that it is a promising EGFR tyrosine kinase inhibitor.}

Design, Synthesis, in silico and in vitro Evaluation of New Combretastatin A-4 Analogs as Antimitotic Antitumor Agents.

BACKGROUND: Combretastatin A-4 (CA-4) binds ß-tubulin at the colchicine-binding site preventing tubulin from polymerizing into microtubules. CA-4 and cis combretastatin analogs isomerize to the trans form resulting in decreased cytotoxicity and anti-tubulin activity. However, the excellent anti-cancer potential and relatively simple molecular structure of CA-4 provide an encouraging starting point for the development of new, more stable and more potent anti-tubulin compounds. OBJECTIVE: This study aimed to synthesize a new series of compounds derived from 4-(3,4,5- trimethoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives (compounds 10-12) with substituted phenyl group at C5 of the triazole ring (B-ring) as analogs of CA-4, with different alkyl and aryl side chain substituents at the triazole moiety, resulting in the permanent cis configuration of the two phenyl rings. Moreover, the anti-cancer activities of the new compounds were assessed. METHODS: Chemical synthesis was carried out by conventional organic methods. The newly synthesized CA-4 analogs were characterized by FT-IR, 1HNMR, 13CNMR, and HR-MS(ESI) techniques. Molecular docking studies, including docking score (ΔG), ADMET, DFT, and molecular similarities, were performed. The anti-proliferative activity of the new compounds against three human cancer cell lines (A549, Hep G2, and HCT-116) and the normal cell line WI-38 was evaluated using the MTT assay, and their ability to inhibit tubulin polymerization, and consequently, their effects on cell cycle progression and induction of apoptosis were assessed. RESULTS: Molecular docking studies showed that compounds 11b and 11d exhibited the highest docking scores (-13.30 and -14.01 Kcal/mol, respectively) into the colchicine-binding site, scores very close to the reference drug colchicine (-13.50 Kcal/mol), and that hydrogen bonding and hydrophobic interaction are essential for binding. The most active cytotoxic compound, 11b, had potent IC50 values against the three human cancer cell lines (3.83, 10.20, and 10.67 µM against Hep G2, HCT- 116, and A549, respectively) while exhibiting low cytotoxicity against non-cancer-human WI-38, suggesting that compound 11b targets rapidly growing cancer cells. Moreover, compound 11b exhibited potent anti-tubulin activity which was comparable to CA-4. Targeting microtubules caused cell cycle arrest at the G2/M phase resulting in the induction of apoptosis. CONCLUSION: These findings indicate that compound 11b is a promising ß-tubulin-binding compound with antimitotic action that has the potential to treat cancer.

Modern versus Traditional Endodontic Access Cavity Designs.

By creating a precise access cavity (AC) and finishing the pulp chamber, less invasive endodontic therapy attempts to improve conventional endodontic therapy. The cingulum, oblique ridge, and roof of the pulp chamber, which all play a vital role in functional activity, might be preserved to increase fracture resistance. To reduce tooth structure loss, endodontic new ACs have recently been created. The preparation of the conservative access opening had advanced to a new level with the advent of microscopes and improved root canal equipment. The conservation of the cervical dentin is the most essential factor in preserving the restored tooth's normal function and lifespan. In recent years, minimally invasive endodontics has posed a challenge to the traditional method.

Acute childhood leukemias and exposure to magnetic fields generated by high voltage overhead power lines - a risk factor in Iran.

Many investigators have studied the effects of Extremely Low Frequency-Magnetic Fields generated by ordinary and domestic power lines, as a risk factor in acute leukaemias of children, but there are limited information available regarding very high voltage overhead power lines. Children in developing countries sometimes live very close to such structures and we have registered several patients with acute leukaemias appearing in clusters. In the present study we have analyzed 60 consecutively diagnosed patients with acute leukaemias, and 59 matched controls in a provincial capital city in North-Western Iran. After provision of consent, a detailed form was filled in, and a visit to the present (or previous) residential areas of both groups was arranged. The locations of the very high voltage power lines (123, 230, 400 kilo volts), were noted in each area, if present, and their distances from the houses under study were detected. The expected intensities of the Magnetic Fields (B) were calculated having the mean intensity of the electrical current and other line characteristics, by means of relevant equations. Fourteen patients in the case group (23.5%) were living near the high voltage power lines in distances < or = 500 meters. (Mean B = 0.6 microTeslas, microT). In the control group at the same distance, the figure was 2 children (3.3%) (Mean B = 0.35 microT). Statistically, the likelihood of leukaemia was increased considerably in this distance (Odds ratio (OR) = 8.67, 95% Confidence Interval (CI) = 1.74- 58.4, P value= 0.001). On the other hand 15 pts (25 %) in the leukaemia group were experiencing Magnetic fields above 0.45 microT in comparison to 5 in the control group ( 8.5% )(OR = 3.60, 95% CI = 1.11-12.39, P = 0.01). More children in developing countries like Iran live close to very high voltage lines, and they experience relatively more harmful effects from the Magnetic Fields, in comparison with children in developed countries. Residence near very high voltage overhead power lines, in distances < or = 500 meters, and Magnetic Fields >0.45 microT, should be considered a risk factor for the pathogenesis of acute leukaemias in children.

A Unique Case of Empyema Secondary to Amoebic Liver Abscess.

An amoebic liver abscess is an extraintestinal manifestation of amoebiasis that can present with complaints such as right upper quadrant pain and fever. It might not necessarily be associated with abdominal complaints and can have many other atypical presentations. It may present with lung diseases, cardiac diseases, or brain abscesses. We present a case of a patient with empyema secondary to amoebic liver abscess whose diagnosis was delayed due to an unusual presentation. A combination of radiology, serology, and therapeutic interventions led to the accurate management of the patient.

Core Measures for Congestive Heart Failure in a Tertiary Care Setting in Pakistan.

PURPOSE:  Heart failure presents a huge burden for individual patients and the healthcare system as a whole. This study aims to assess the adherence to these core measures as identified by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO)/ American Heart Association (AHA) by physicians of Pakistan. MATERIALS AND METHODOLOGY:  We conducted a cross-sectional study in Shifa International Hospital, Islamabad, Pakistan from the period of April 2013 to April 2016. Patients with a primary diagnosis of heart failure were drawn from a coding section of hospital's record department. Data was evaluated to assess how strictly doctors were following core measures identified by JCAHO/AHA for the given diagnosis. Inclusion criteria for this study were patients ≥ 17 years of age and patients with a primary diagnosis of heart failure according to New York Heart Association (NYHA) classification. Patients with congenital anomalies and structural heart wall problems, like sarcoidosis, hemochromatosis, and amyloidosis, were excluded from the study. RESULTS:  Mean ejection fraction (EF) was found to be 27.23 ± 11.72 percent. Symptoms assessment of heart failure was done in 16/421 (3.8%) patients according to NYHA classification and in 405/421 (96.2%) patients according to outpatient-based heart failure assessment based on physician's experience other than NYHA classification. Left ventricle ejection fraction (LVEF) was assessed in 411/421 (97%) patients. Out of these, 336/411 (81.7%) patients had EF < 40%. Mean EF was found to be significantly higher in females as compared to males (p < 0.001). Three hundred and thirty-six out of 411 (81.7%) patients with EF < 40% needed angiotensin converting enzyme inhibitors (ACEi) and beta-blocker (BB) prescriptions. ACEi were prescribed only to 230/336 (68.7%) patients and 248/336 (73.8%) patients were given BB with documented contraindication to ACEi and BB in 7.36% and 17% patients, respectively. There was no significant association between gender and mean duration of hospitalization (p = 0.411). No significant association was found between EF ≤ 40% and mean duration of hospitalization (p = 0.426). CONCLUSION:  We found that symptom assessment of congestive heart failure (CHF) patients, according to NYHA guidelines, are strikingly low. Also, a significant percentage of patients who need ACEi and BB are not prescribed the required medications despite echocardiography showing low left ventricular function.

Detection of hemophilia a carriers in Azeri Turkish population of Iran: usefulness of HindIII and BclI markers.

Hemophilia A (HA) is an inherited X-linked coagulation disorder caused by the deficiency of factor VIII (FVIII). Linkage analysis is a common indirect method for the detection of female carriers in families with HA. In the current study, 173 patients from 30 unrelated families with HA were recruited from the Azeri Turkish population of northwest Iran and analyzed for BclI and HindIII markers by polymerase chain reaction-restriction fragment length polymorphism. We investigated the potential of using these markers for the detection of mutation in carriers through linkage analysis, which would be of tremendous use in prenatal diagnosis. Among the tested women, 47% and 35% were found to be heterozygous for BclI and HindIII polymorphic markers, respectively. The BclI and HindIII markers were informative for the detection of 63% and 17% potential carriers, respectively, demonstrating the effectiveness of the BclI marker for the detection of HA carriers among the Azeri Turkish population.