Visible-Light-Responsive Novel Ru(II)-Metallo-Antibiotics with Potential Antibiofilm and Antibacterial Activity.

Growing challenges with antibiotic resistance pose immense challenges in combating microbial infections and biofilm prevention on medical devices. Lately, antibacterial photodynamic therapy (aPDT) is now emerging as an alternative therapy to overcome this problem. Herein, we synthesized and characterized four Ru(II)-complexes, viz., [Ru(ph-tpy)(bpy)Cl]PF6 (Ru1), [Ru(ph-tpy)(dpq)Cl]PF6 (Ru2), [Ru(ph-tpy)(dppz)Cl]PF6 (Ru3), and [Ru(ph-tpy)(dppn)Cl]PF6 (Ru4) (where 4'-phenyl-2,2':6',2″-terpyridine = ph-tpy; 2,2'-bipyridine = bpy; dipyrido[3,2-f:2',3'-h]quinoxaline = dpq; dipyrido[3,2-a:2',3'-c]phenazine = dppz; and Benzo[I]dipyrido[3,2-a:2',3'-c]phenazine = dppn), among which Ru2-Ru4 are novel. Octahedral geometry of the complexes with a RuN5Cl core was evident from the crystal structure of Ru2. Ru1-Ru4 showed an MLCT absorption band in the 450-600 nm region, useful for aPDT performances. Further, optimum triplet excited state energy and excellent photostability of Ru1-Ru4 made them good photosensitizers for aPDT. Ru1-Ru4 demonstrated enhanced antimicrobial activity on visible-light exposure (400-700 nm, 10 J cm-2), confirmed using different antibacterial assays. Mechanistic studies revealed that inhibition of bacterial growth was due to the generation of oxidative stress (via NADH oxidation and ROS generation) upon treatment with Ru2-Ru4, resulting in destruction of the bacterial wall. Ru2 performed best killing performance against both Gram-negative (Escherichia coli) and Gram-positive (Bacillus subtilis) bacteria when exposed to light. Ru2-Ru4, when coated on a polydimethylsiloxane (PDMS) disk, showed long-term reusability and durable antibiofilm properties. Molecular docking confirmed the efficient interaction of Ru2-Ru4 with FabH (regulates fatty acid biosynthesis of E. coli) and PgaB (gives structural stability and helps biofilm formation of E. coli), resulting in probable downregulation. In vivo studies with healthy Wistar rats confirmed the biocompatibility of Ru2. This study shows that these lead complexes (Ru2-Ru4) can be used as potent alternative antimicrobial agents in low concentrations toward bacterial eradication with photodynamic therapy (PDT).

Green Light-Triggered Photocatalytic Anticancer Activity of Terpyridine-Based Ru(II) Photocatalysts.

The relentless increase in drug resistance of platinum-based chemotherapeutics has opened the scope for other new cancer therapies with novel mechanisms of action (MoA). Recently, photocatalytic cancer therapy, an intrusive catalytic treatment, is receiving significant interest due to its multitargeting cell death mechanism with high selectivity. Here, we report the synthesis and characterization of three photoresponsive Ru(II) complexes, viz., [Ru(ph-tpy)(bpy)Cl]PF6 (Ru1), [Ru(ph-tpy)(phen)Cl]PF6 (Ru2), and [Ru(ph-tpy)(aip)Cl]PF6 (Ru3), where, ph-tpy = 4'-phenyl-2,2':6',2″-terpyridine, bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, and aip = 2-(anthracen-9-yl)-1H-imidazo[4,5-f][1,10] phenanthroline, showing photocatalytic anticancer activity. The X-ray crystal structures of Ru1 and Ru2 revealed a distorted octahedral geometry with a RuN5Cl core. The complexes showed an intense absorption band in the 440-600 nm range corresponding to the metal-to-ligand charge transfer (MLCT) that was further used to achieve the green light-induced photocatalytic anticancer effect. The mitochondria-targeting photostable complex Ru3 induced phototoxicity with IC50 and PI values of ca. 0.7 µM and 88, respectively, under white light irradiation and ca. 1.9 µM and 35 under green light irradiation against HeLa cells. The complexes (Ru1-Ru3) showed negligible dark cytotoxicity toward normal splenocytes (IC50s > 50 µM). The cell death mechanistic study revealed that Ru3 induced ROS-mediated apoptosis in HeLa cells via mitochondrial depolarization under white or green light exposure. Interestingly, Ru3 also acted as a highly potent catalyst for NADH photo-oxidation under green light. This NADH photo-oxidation process also contributed to the photocytotoxicity of the complexes. Overall, Ru3 presented multitargeting synergistic type I and type II photochemotherapeutic effects.

Polypyridyl-based Co(III) complexes of vitamin B6 Schiff base for photoactivated antibacterial therapy.

Herein, five novel polypyridyl-based Co(III) complexes of Schiff bases, viz., [Co(dpa)(L1)]Cl (1), [Co(dpa)(L2)]Cl (2), [Co(L3)(L2)]Cl (3), [Co(L3)(L1)]Cl (4), and [Co(L4)(L1)]Cl (5), where dpa (dipicolylamine) = bis(2-pyridylmethyl)amine; H2L1 = (E)-2-((2-hydroxybenzylidene)amino)phenol; H2L2 = (E)-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridin-3-ol; L3 = 4'-phenyl-2,2':6',2''-terpyridine (ph-tpy); and L4 = 4'-ferrocenyl-2,2':6',2''-terpyridine (Fc-tpy), were synthesized and characterized. Complexes 1, 3, and 4 were structurally characterized by single-crystal XRD, indicating an octahedral CoIIIN4O2 coordination core. The absorption bands of these complexes were observed in the visible range with a λmax at ∼430-485 nm. Complex 5 displayed an extra absorption band near 545 nm because of a ferrocene moiety. These absorptions in the visible region reflect the potential of the complexes to act as visible-light antimicrobial photodynamic therapy (aPDT) agents. All of these complexes showed reactive oxygen species (ROS)-mediated antibacterial effects against S. aureus (Gram-positive) and E. coli (Gram-negative bacteria) upon low-energy visible light (0.5 J cm-2, 400-700 nm) exposure. Additionally, 1-5 did not show any toxicity toward A549 (Human Lung adenocarcinoma) cells, reflecting their selective bacteria-killing abilities.

Transition Metal Complexes as Antimalarial Agents: A Review.

In antimalarial drug development research, overcoming drug resistance has been a major challenge for researchers. Nowadays, several drugs like chloroquine, mefloquine, sulfadoxine, and artemisinin are used to treat malaria. But increment in drug resistance has pushed researchers to find novel drugs to tackle drug resistance problems. The idea of using transition metal complexes with pharmacophores as ligands/ligand pendants to show enhanced antimalarial activity with a novel mechanism of action has gained significant attention recently. The advantages of metal complexes include tunable chemical/physical properties, redox activity, avoiding resistance factors, etc. Several recent reports have successfully demonstrated that the metal complexation of known organic antimalarial drugs can overcome drug resistance by showing enhanced activities than the parent drugs. This review has discussed the fruitful research works done in the past few years falling into this criterion. Based on transition metal series (3d, 4d, or 5d), the antimalarial metal complexes have been divided into three broad categories (3d, 4d, or 5d metal-based), and their activities have been compared with the similar control complexes as well as the parent drugs. Furthermore, we have also commented on the potential issues and their possible solution for translating these metal-based antimalarial complexes into the clinic.

Dosing interval of 24hours versus 48hours between mifepristone and misoprostol administration for mid-trimester termination of pregnancy.

OBJECTIVE: To compare the efficacy of a shorter interval (24hours) between misoprostol and mifepristone administration with that of the conventional dosing interval (48hours) for second-trimester termination of pregnancy (TOP). METHODS: This was a prospective randomized, controlled, open-label study of 98 healthy women opting for mid-trimester TOP. The women were randomized to receive 200mg mifepristone orally, followed 24hours (Group 1) or 48hours (Group 2) later by misoprostol (800µg, then 400µg every 3hours). The primary outcome measure was the percentage of successful abortions within 24hours. Secondary outcome measures were the induction-to-abortion interval (measured from misoprostol administration) and the frequencies of complications and adverse effects. RESULTS: The rate of successful abortions was similar with the 24-hour and 48-hour dosing intervals (95.8% and 93.6%, respectively; P=0.38). The mean induction-to-abortion interval was also comparable between the 2 groups (8.6±4.1hours versus 8.7±3.9hours; P=0.37). Nulliparous women and women with a pregnancy duration of 16weeks or more had a longer induction-to-abortion interval in both groups. CONCLUSION: The 24-hour dosing interval between misoprostol and mifepristone administration seems to be as effective as the 48-hour dosing interval for second trimester TOP. Clinical Trial Registry India: CTRI/2011/05/001770.

Effect of a single preoperative dose of sublingual misoprostol on intraoperative blood loss during total abdominal hysterectomy.

OBJECTIVE: To investigate whether use of preoperative misoprostol can reduce blood loss during total abdominal hysterectomy (TAH). METHODS: In a randomized double-blind placebo-controlled trial at a tertiary care hospital in Kolkata, India, between March 2011 and April 2012, women (n=132) undergoing TAH with or without bilateral salpingo-oophorectomy for symptomatic myomas were randomly allocated to receive either 400 µg of misoprostol or placebo 30 minutes before surgery. The primary outcome measure was intraoperative blood loss was. The secondary outcomes were postoperative drop in hemoglobin, need for blood transfusion, and incidence of adverse effects. RESULTS: The 2 groups were similar with regard to demographic and clinical characteristics. There was a significant reduction of blood loss during TAH after sublingual administration of misoprostol compared with placebo before surgery (356 mL vs 435 mL; P=0.049). The mean postoperative hemoglobin concentration was higher (10.5 g/dL vs 9.5 g/dL; P<0.001) and the postoperative drop in hemoglobin was smaller (1.1g/dL vs 1.9 g/dL; P=0.004) in the misoprostol group than in the placebo group. No significant adverse effects occurred in either group. CONCLUSION: The results showed that a single dose of misoprostol administered before abdominal hysterectomy resulted in a significant reduction of blood loss with minimal adverse effects. Clinical Trial Registry India (www.ctri.nic.in): CTRI/2011/091/000216.

Successful pregnancy outcome in a woman with untreated ectopia vesicae: a case report and review of literature.

We report the case of a pregnancy in a 25-year-old woman who was born with ectopia vesicae and split pelvis, but had not undergone any reconstructive or diversion surgery in childhood. Her antenatal period was uneventful and the infant was delivered by cesarean section at term due to breech presentation. The baby had no congenital anomalies. The postoperative period was uneventful and they were discharged from the hospital in a good general condition.

Sublingual misoprostol versus intramuscular oxytocin for prevention of postpartum hemorrhage in low-risk women.

OBJECTIVE: To compare sublingual misoprostol with intramuscular oxytocin for prevention of postpartum hemorrhage (PPH) in low-risk vaginal birth. METHODS: In a prospective, randomized, double-blind trial, 530 women without risk of PPH were randomly allocated to receive either 400 µg of misoprostol sublingually or 10 units of oxytocin intramuscularly within 1minute of delivery. The outcome measures were incidence of PPH, postpartum blood loss, drop in hemoglobin level in 24 hours, need for additional uterotonic drug, incidence of adverse effects, and need for blood transfusion. Student t, χ(2), Mann-Whitney U, and Fisher exact tests were used for comparison. RESULTS: Incidence of postpartum hemorrhage (≥ 500 mL) and postpartum blood loss in the misoprostol group were similar to those in the oxytocin group (6% versus 5.7%, P=0.85; 153 mL versus 146 mL, P=0.36). Shivering and pyrexia were encountered more often in the misoprostol than in the oxytocin group (shivering: 19% versus 0.8%, P<0.001, relative risk [RR] 0.86, 95% confidence interval [CI] 0.82-0.90; pyrexia: 2.3% versus 0%, P=0.03, RR 0.97, 95% CI 0.95-0.99). CONCLUSION: The efficacy of 400 µg of misoprostol administered sublingually was equivalent to that of 10 units of oxytocin given intramuscularly for prevention of PPH in low-risk vaginal delivery.

Rectally administered misoprostol versus intravenous oxytocin infusion during cesarean delivery to reduce intraoperative and postoperative blood loss.

OBJECTIVE: To compare the efficacy of rectally administered misoprostol with intravenous oxytocin infusion in preventing uterine atony and blood loss during cesarean delivery. METHODS: In this prospective, randomized, double-blind trial, 200 women undergoing cesarean delivery who did not have risk factors for postpartum hemorrhage were randomly allocated to receive either 800 microg of rectal misoprostol at the time of peritoneal incision or an intravenous infusion of oxytocin after delivery of the neonate. Primary outcome measures were estimated amount of intraoperative and postoperative (8 hours) blood loss and changes in hemoglobin levels 24 hours after delivery. RESULTS: A total of 96 and 94 women were analyzed in the misoprostol and oxytocin groups, respectively. Intraoperative and postoperative blood loss was significantly lower in the misoprostol group than in the oxytocin group (503 vs 592 mL, P=0.003 and 74 vs 114 mL, P=0.045, respectively). The incidence of shivering was higher in the misoprostol group (8.3% vs 1.1%, P=0.018; RR 7.83; 95% confidence interval, 0.99-61.42). CONCLUSION: Rectal misoprostol appears to be an effective alternative to intravenous oxytocin in preventing blood loss for routine use during cesarean delivery. CLINICAL TRIALS REGISTRATION: CTRI/2009/091/000075.