Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors.

The rapid emergence of resistance to existing frontline antimalarial drugs emphasizes a need for the development of target-oriented molecules with novel modes of action. Given the importance of a plant-like Calcium-Dependent Protein Kinase 1 (PfCDPK1) as a stand-alone multistage signalling regulator of P. falciparum, we designed and synthesized 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) directed towards PfCDPK1. This was accomplished by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a 'click' reaction. The selected CQTrICh-analogs: 7l and 7r inhibited the growth of chloroquine-sensitive 3D7 strain and -resistant RKL-9 isolate of Plasmodium falciparum, with IC50 values of 2.4 µM & 1.8 µM (7l), and 3.5 µM & 2.7 µM (7r), respectively, and showed no apparent hemolytic activity and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. 7l and 7r were found to stably interact with the catalytically active ATP-binding pocket of PfCDPK1 via energetically favourable H-bonds. The interaction was confirmed in vitro by microscale thermophoresis and kinase assays, which demonstrated that the active hybrids interact with PfCDPK1 and inhibit its kinase activity which is presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating their selectivity for the parasite kinase. We report the antiplasmodial potential of novel kinase-targeting bio-conjugates, a step towards developing pan-kinase inhibitors which is a prerequisite for multistage anti-malarial protection.

Synergistic antimicrobial activity, MD simulation studies and crystal structure of natural alcohol motif containing novel substituted cinnamates.

A series of natural alcohols motif containing novel substituted cinnamates were developed and screened against five bacterial strains namely, Enterococcus faecal (E. faecalis), Escherichia coli (E. coli), Bacillus subtilis (B. subtilis), Pseudomonas aeruginosa (P. aeruginosa) and Klebsiella pneumonieae (K. pneumonieae). Among all cinnamates, YS17 was identified with 100% bacterial growth inhibition across the panel, except in E. faecalis with MIC values of 0.25 mg/mL against B. subtilis and P. aeruginosa whereas 0.125, 0.5 and 1 mg/mL against E. coli, K. pneumonieae and E. faecalis, respectively. The growth inhibitory property of YS17 was further validated by disk diffusion, synergistic study and in vitro toxicity assays. Interestingly, YS17 exhibits synergistic effect in combination with the standard drug Ampicillin (AMP). The single crystal structure analysis of YS4 and YS6 was also performed which reconfirmed their proposed structures. Molecular docking visualized significant non-covalent interactions between E. coli MetAP and YS17 and the structural and conformational changes were further analysed using MD simulation studies. Overall, the study provided a suitable core for further synthetic alterations for their optimization as an antibacterial agent. Communicated by Ramaswamy H. Sarma.

Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates.

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity. Among them, QP11, featuring a m-NO2 substitution, demonstrated efficacy against both chloroquine-sensitive and -resistant parasite strains. QP11 selectively inhibited FP2, a cysteine protease involved in hemoglobin degradation, and showed synergistic effects when combined with chloroquine. Additionally, QP11 hindered hemoglobin degradation and hemozoin formation within the parasite. Metabolic stability studies indicated high stability of QP11, making it a promising antimalarial candidate. In vivo evaluation using a murine malaria model demonstrated QP11's efficacy in eradicating parasite growth without neurotoxicity, presenting it as a promising compound for novel antimalarial development.

Structural-activity Relationship of Metallo-aminoquines as Next Generation Antimalarials.

Apicomplexian parasite of the genus Plasmodium is the causative agent of malaria, one of the most devastating, furious and common infectious disease throughout the world. According to the latest World malaria report, there were 229 million cases of malaria in 2019 majorly consist of children under 5 years of age. Some of known analogues viz. quinine, quinoline-containing compounds have been used for last century in the clinical treatment of malaria. Past few decades witnessed the emergence of multi-drug resistance (MDR) strains of Plasmodium species to existing antimalarials pressing the need for new drug candidates. Thus, in those decades bioorganometallic approach to malaria therapy has been introduced which led to the discovery of noval metalcontaining aminoquinolines analogues viz. ferroquine (FQ or 1), Ruthenoquine (RQ or 2) and other related potent metalanalogues. It observed that some metal containing analogues (Fe-, Rh-, Ru-, Re-, Au-, Zn-, Cr-, Pd-, Sn-, Cd-, Ir-, Co-, Cu-, and Mn-aminoquines) were more potent; however, some were equally potent as Chloroquine (CQ) and 1. This is probably due to the intertion of metals in the CQ via various approaches, which might be a very attractive strategy to develop a SAR of novel metal containing antimalarials. Thus, this review aim to summarize the SAR of metal containing aminoquines towards the discovery of potent antimalarial hybrids to provide an insight for rational designs of more effective and less toxic metal containing amonoquines.

Development of Oxadiazole-Sulfonamide-Based Compounds as Potential Antibacterial Agents.

In this work, substituted 1,2,4-oxadiazoles (OX1-OX27) were screened against five bacterial strains, identified to be OX7 and OX11 as growth inhibitors with minimum inhibitory concentration (MIC) values of 31.25 and 15.75 µg/mL, respectively. The growth inhibitory property of OX7 and OX11 was further validated by disk diffusion, growth curve, and time kill curve assays. Both disrupted biofilm formation with 92-100% reduction examined by the XTT assay were further visualized by scanning electron microscopy analysis. These compounds in combination with ciprofloxacin also exhibit synergy against Escherichia coli cells. With insignificant cytotoxic behavior on HEK293 cells, human red blood cells, and Galleria mellonella larvae, OX11 was tested against 28 multidrug resistant environmental isolates of bacteria and showed inhibition of Kluyvera georgiana and Citrobacter werkmanii strains with 32 and 16 µg/mL MIC values, respectively. The synergistic behavior of OX11 with ampicillin showed many fold reductions in MIC values against K. georgiana and Klebsiella pneumoniae multidrug resistant strains. Further, transmission electron microscopy analysis of OX11-treated E. coli cells showed a significantly damaged cell wall, which resulted in the loss of integrity and cytosolic oozing. OX11 showed significant changes in the secondary structure of human serum albumin (HSA) in the presence of OX11, enhancing HSA stability. Overall, the study provided a suitable core for further synthetic alterations and development as an antibacterial agent.

Idiopathic polypoidal choroidal vasculopathy: a review of literature with clinical update on current management practices.

PURPOSE: Polypoidal choroidal vasculopathy is a major cause of visual disability in a vast majority of Asian population due to exudative maculopathy. Although it is a distinctive disease entity with characteristic pathophysiology, genetics, immunology and clinical features, but it is still misdiagnosed as neovascular age related macular degeneration as both the diseases are a part of pachychoroid spectrum and have some similar features. Also, there are varied options for the management of this disease, but there are no clear recommendations. So, a detailed review of the literature has been done along with special attention to the recent therapeutic advances to help the readers get a better understanding of the disease and its current management practices. METHOD: Detailed review of literature regarding polypoidal choroidal vasculopathy was done. The disease pathophysiology, genetics, risk factors, diagnostic modalities along with current treatment guidelines were extensively studied and compiled. RESULT: A comprehensive clinical update on polypoidal choroidal vasculopathy was compiled with special emphasis on the recent diagnostic modalities and treatment guidelines. CONCLUSION: Polypoidal choroidal vasculopathy is a distinct clinical entity which can be diagnosed based on indocyanine green angiography and optical coherence tomography. Treatment includes various options like photodynamic therapy, anti VEGF agents and thermal laser ablation. A review of literature has been done and recent diagnostic modalities with management practices have been compiled for the better understanding of the disease.

Atypical optic neuritis as the presenting feature of testicular malignancy: Rare case report with review of literature.

A 23-year-old male presented with unilateral acute onset, painless, progressive diminution of vision. Initial clinical and radiological findings were consistent with optic neuritis. The patient was started on pulse steroids leading to visual recovery. However, the patient relapsed within one week. Repeat imaging revealed metastatic lesions near the orbital apex. Orbit is an unusual site of metastasis from testicular tumors and only 3 cases of testicular synovial sarcoma with orbital metastasis have been reported. A thorough systemic evaluation should be done in cases of atypical and relapsing optic neuritis to rule out the causes of optic neuritis (ON) masquerade syndrome.

Quinoline Containing Side-chain Antimalarial Analogs: Recent Advances and Therapeutic Application.

The side-chains of quinoline antimalarial agents are the major concern of focus to build novel and efficaciaous bioactive and clinical antimalarials. Bioative antimalarial analogs may play a critical role in pH trapping in the food vacuole of RBC's with the help of fragmented amino acid, thus lead to ß-hematin inhibition. Here, the authors tried to summarize a useful, comprehensive compilation of side-chain modified ACQs along with their synthesis, biophysical and therapeutic applications etc. of potent antiplasmodial agents and therefore, opening the door towards the potential clinical status.

Comparison of topical cyclosporine alone and topical loteprednol with cyclosporine in moderate dry eye in Indian population: A prospective study.

PURPOSE: The purpose of this study is to compare the efficacy of topical cyclosporine (Cs) 0.05% alone and topical Cs 0.05% with loteprednol 0.5% in patients with moderate dry eye. STUDY DESIGN: This was a comparative, prospective, interventional study. PATIENTS AND METHODS: A total of 140 patients diagnosed with moderate dry eyes were randomly divided into two groups. Group A patients received treatment with topical loteprednol 0.5% started as QID dosage for 2 weeks and tapered to BID dosage over the next 6 weeks, topical Cs 0.05% BID and artificial tears. Group B patients received treatment with topical Cs 0.05% BID and artificial tears. All patients were followed over a period of 6 months with ocular surface disease index (OSDI) questionnaire, tear film break up time (TBUT), corneal fluorescein, and lissamine green staining scores. RESULTS: There was a significant difference in the symptoms and signs of dry eye in the group receiving combination of loteprednol 0.5% and Cs 0.05% as compared to the group receiving Cs alone evident by greater reduction in OSDI score, corneal staining, and improvement in TBUT and Schirmer's test values over a follow-up of 6 months. CONCLUSION: Combination therapy with topical loteprednol and Cs is significantly better than topical Cs alone on alleviating symptoms and signs in moderate dry eye patients.

Effect of intravitreal anti-vascular endothelial growth factor on corneal endothelial cell count and central corneal thickness in Indian population.

PURPOSE: To evaluate the effect of intravitreal anti-VEGF on corneal endothelial cell count and central corneal thickness as well as to compare these in phakic and pseudophakic eyes. MATERIAL AND METHODS: The study was conducted in 102 eyes selected, as per selection criteria, over a time period of 18 months. At first patient visit, examination included: 1. Fundus examination. 2. Specular microscopy was done to look for endothelial cell count and Central corneal thickness. At second visit, Injection 0.5 mg/0.05 ml of ranibizumab was administered. Visits at day 1, day 7 and 1 month were done for Endothelial cell density and central corneal thickness was measured by specular microscope. RESULTS: The mean CCT value in pseudophakic group was 502.08 ± 19.91, 501.9 ± 20.31, and 501.72 ± 21.55 on day 1, 7 and 30, respectively. The mean CCT value in phakic group was 506.53 ± 22.61, 505.96 ± 20.12, 505.92 ± 20.3 and 505.69 ± 21.47. The mean value of ECD in pseudophakic eyes on day 1, 7, and 30 were 2284.24 ± 299.86, 2281.39 ± 289.46 and 2284.06 ± 312.65 cells/mm2, respectively. The mean value of ECD in phakic eyes on day 1, 7, and 30 were 2314.51 ± 212.08, 2313.92 ± 212.7 and 2313.63 ± 216.86 cells/mm2, respectively. CONCLUSION: There is no significant change in endothelial cell density, central corneal thickness, coefficient of variation and intraocular pressure before and after intravitreal injection over one month of follow-up. The results are similar between phakic and pseudophakic eyes.

4-Aminoquinoline Antimalarials Containing a Benzylmethylpyridylmethylamine Group Are Active against Drug Resistant Plasmodium falciparum and Exhibit Oral Activity in Mice.

Emergence of drug resistant Plasmodium falciparum including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness. These compounds exhibited significantly improved solubility and decreased lipophilicity and were potent against chloroquine-sensitive (NF54) and -resistant (Dd2 and 7G8) P. falciparum strains with 5/6 having IC50 < 100 nM against the NF54 strain. All inhibited both ß-hematin (synthetic hemozoin) formation and hemozoin formation in the parasite. Parasitemia was reduced by over 90% in P. berghei infected mice in 3/6 derivatives following oral dosing at 4 × 30 mg/kg, with microsomal metabolic stability data suggesting that this could be attributed to highly active metabolites.

Granuloma after sling surgery: an attempt to answer the 'why' and 'what to do next'.

PURPOSE: To review cases of granuloma formation after sling surgery with a view to find out possible aetiological factors and propose a further plan of management MATERIALS AND METHODS: A retrospective analysis of 120 eyes of 108 patients who underwent frontalis sling surgery with silicone rod from Jan 2008 to Dec 2015 was conducted. All patients with severe ptosis and poor levator function who underwent frontalis sling surgery with silicone rod were included in the study irrespective of the cause of ptosis and method of passing the sling. A complete ophthalmic and ptosis examination was done. In all the cases, the prolene suture was tied over the sleeve to tighten it and it was buried along with the silicone rod in forehead pocket. All the cases with granuloma formation were first subjected to a microbiological examination including culture and sensitivity to antibiotics. All the patients were given a trial of antibiotics. RESULTS: We encountered 10 cases of granuloma in 120 eyes of 108 patients operated during this period. The duration between time of surgery and presentation varied from 2 weeks to 4 months. The microbiological examination revealed positive culture in 5 cases. None of the cases responded to the course of antibiotics given for 10 days. The histopathological examination done in 5 cases (2 of them culture positive and 3 of them culture negative) revealed granulomatous inflammation of non-specific type. The sling was explanted in all cases which resulted in prompt resolution of granuloma in 7-10 days. CONCLUSIONS: The granuloma is primarily due to exposure of the sling itself or the sleeve enveloping the sling or the suture tied around the sleeve thereby. They do not respond to antibiotics but respond very well to explantation. These patients can be taken up for re-sling surgery after a waiting period of 3 months.

Modified Krimsky test for irregular scarred corneas.

The measurement of the amount and nature of deviation is the essence of diagnostic workup of a patient with strabismus and also has important therapeutic implications while planning the amount of surgery or prescribing therapeutic prisms. Although Krimsky test is a useful method, it cannot be used to measure deviation in patients with scarred and irregular cornea with an anechoic posterior segment making it difficult to see the corneal reflex. We hereby take the opportunity to present a modification of the original Krimsky test which is extremely helpful in determining the deviation in patients with irregular opaque corneas.

Investigating the Influence of Alkyl Chain Length in Poly(3-alkylthiophene)s Over the Thin Film Morphology by Optical and Electrical Characterization.

This paper studies the influence of alkyl-chain length in poly(3-alkylthiophene)s over the morphology of thin films and electrical parameters of the devices based on it. Regioregular poly(3-hexylthiophene) and poly(3-octylthiophene) were chosen as the semiconducting materials for the study. The morphological variations were studied by absorption spectroscopy, photoluminescence spectroscopy and X-ray diffraction study. The absorption and photoluminescence showed decreased coplanarity of main chain in poly(3-octylthiophene) over poly(3-hexylthiophene) and which was later confirmed using X-ray diffraction studies which clearly showed increased interchain spacing in case of poly(3-octylthiophene). The schottky diodes fabricated using these materials showed decreased mobility in poly(3-octylthiophene) based diodes as measured by space-charge limiting current method and photo-induced charge carrier extraction by linearly increasing voltage technique. Moreover, we observed a negative field dependence of mobility at room temperature in both the devices and attributed this to the presence of dominant positional disorder in poly(3-alkylthiophene)s. Furthermore, the photocurrent dependence on electric field too showed inferior mobility of poly(3-octylthiophene) based diodes.

Potent phosphatidylinositol 3-kinase inhibitors and their biology.

The Phosphoinositide 3-kinase (PI3k) is an important regulator of intracellular signalling pathways, like cell proliferation, migration, survival, and angiogenesis upon activation by growth factor or receptors. The PI3k's pathway is frequently up-regulated in human cancers, thus inhibition of PI3k's is a promising approach for cancer therapy. Many potent PI3k's inhibitors have been reported so far and few of them are in clinical trial like GDC-0941, BGT-226, AZD-6482 and others are natural products etc.

In vitro antimalarial activity, ß-haematin inhibition and structure-activity relationships in a series of quinoline triazoles.

A novel series of quinoline triazole amide analogues (38-51) has been synthesized. Analogues 38-44 had a Cl substituent at the 7-position of the quinoline ring, while 45-51 had a CN substituent at this position. Compounds 40, 45 and 49 were found to be the most active in the series against the Plasmodium falciparum chloroquine-sensitive D10 strain, with IC50 values in the range of 349-1247 nM, with 40 and 45, but not 49 also exhibiting similar activity against the chloroquine-resistant K1 strain of parasite. Quinoline triazoles 40 and 44 were the most active ß-haematin inhibitors, with 50% inhibitory concentrations of 14.7 and 8.9 µM respectively. In vitro antimalarial activity of the 7-Cl bearing analogues 38-44 exhibited a strong linear dependence of log(1/IC50) on log P. Thus, the more lipophilic, the more active it was found be. The 7-CN series 45-51 showed no such dependence. The resistance index (IC50 K1/IC50 D10) also exhibited a linear dependence on log P, with a substantially steeper slope in the case of the 7-Cl series. The findings demonstrate the feasibility of producing hydrophilic analogues with strong activity and low cross-resistance with chloroquine.

Recent developments in enediyne chemistry.

The enediynes are known for highly potent anticancer, antimicrobial, as well as cytotoxic activities. The discovery of enediynes from natural sources was achieved in late 1980s. They are presently of high interest, because they exert their biological action due to their ability to form a diradical, which abstracts H-atoms from the DNA backbone, thus causing cell death. Nowadays, the major works are dedicated to the syntheses of enediynes. This review covers recent developments in enediyne chemistry of the last few decades. It is subdivided in six chapters dealing with the discussion of the chemistry and biological significances of enediynes, and the factors responsible for a better activation of enediynes and potent biological evaluations.

Synthesis and anticancer activity of 13-membered cyclic enediynes.

We herein describe the synthesis of 15 novel 13-membered cyclic enediyne derivatives using simple and straightforward approach. Representative examples were screened for their anticancer activities on 60 different human tumor cell lines representing various histologies viz. leukemia, melanoma, and cancers of lung, colon, kidney, ovary, breast, prostate, and central nervous system. The enediyne derivatives with halogen substitutions, especially fluorides were found to be active against most of the cell lines. The initial results indicates marginal to good inhibition for the growth of tumor cells for several cell lines, which shows the potential of these class of compound towards anticancer application.

Quinoline antimalarials containing a dibemethin group are active against chloroquinone-resistant Plasmodium falciparum and inhibit chloroquine transport via the P. falciparum chloroquine-resistance transporter (PfCRT).

A series of 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains were shown to inhibit synthetic hemozoin formation. These compounds were equally active against cultures of chloroquine-sensitive (D10) and chloroquine-resistant (K1) Plasmodium falciparum. The most active compound had an IC(50) value comparable to that of chloroquine, and its potency was undiminished when tested in three additional chloroquine-resistant strains. The three most active compounds exhibited little or no cytotoxicity in a mammalian cell line. When tested in vivo against mouse malaria via oral administration, two of the dibemethin derivatives reduced parasitemia by over 99%, with mice treated at 100 mg/kg surviving the full length of the experiment. Three of the compounds were also shown to inhibit chloroquine transport via the parasite's chloroquine-resistance transporter (PfCRT) in a Xenopus oocyte expression system. This constitutes the first example of a dual-function antimalarial for which the ability to inhibit both hemozoin formation and PfCRT has been demonstrated directly.

The genus Plectranthus in India and its chemistry.

Phytochemical constituents isolated from Indian species of the genus Plectranthus reported up to 2009 are compiled. In India, the genus Plectranthus is found in all the habitats and altitudes, particularly in the Himalaya, the Southern Ghats, and the Nilgiri region. P. amboinicus, P. barbatus, P. caninus, P. mollis, P. coetsa, and P. incanus are the most common species found in India. Phytochemical studies of the genus revealed that Indian Plectranthus species are rich in essential oil, and that the most abundant secondary metabolites are diterpenoids, i.e., labdanes, abietanes, and ent-kauranes, as well as triterpenoids.