Recurrent Catatonia and Demyelinating Disorders.

Catatonia, a neuropsychiatric syndrome characterized by psychomotor and behavioral symptoms, can be associated with various underlying conditions, including demyelinating diseases such as multiple sclerosis. This paper presents a case study of a 47-year-old female with recurrent catatonic relapses and an underlying demyelinating disease. The patient exhibited symptoms of confusion, decreased oral intake, and difficulty with movement and speech. Neurological examinations, brain imaging, and laboratory tests were conducted to evaluate the etiology and guide treatment. The patient showed improvement with lorazepam and electroconvulsive therapy (ECT). However, relapses occurred after the abrupt withdrawal of medication. The case study highlights the potential connection between demyelinating diseases and catatonia and emphasizes the importance of considering demyelinating diseases in the workup, treatment, and relapse prevention of catatonia. Further research is needed to explore the mechanisms underlying the relationship between demyelination and catatonia and to investigate how different etiologies may impact the recurrence rates of catatonic episodes.

Late-Onset Bipolar Disorder: Considerations for Diagnosis and Treatment.

Bipolar I disorder is characterized by the presence of at least one manic episode (DSM-5). Despite a decent percentage of individuals being diagnosed later in life, there currently exist no formal treatment guidelines for late-onset bipolar disorder (LOBD), which remains poorly understood. Typically, manic or manic-like episodes in elderly individuals can be thought of as arising from a secondary, physical cause. However, in the absence of a pre-existing neurological disorder - and when laboratory, imaging, and exam findings do not fully support a neurological picture - the determination of a structural versus primary etiology for LOBD becomes challenging. We present the case of Ms. S, a 79-year-old woman with a past psychiatry history of bipolar disorder diagnosed after 2012 and non-contributory past medical history who was admitted to a state mental hospital on a probate court order from local jail secondary to labile mood and physical aggression toward an officer. Initial labs were remarkable for slightly elevated low-density lipoprotein and a B12 at the lower limit of normal. She was started on a regiment oral B12 supplement, valproic acid 500 mg twice daily, haloperidol 5 mg nightly, and diphenhydramine 25 mg nightly. Despite her medication regimen, she continued to display marked mood lability, tangential thought processes, grandiose delusions, and paranoia. A CT head one week into admission revealed bilateral periventricular white-matter hyperintensities with decreased attenuation and chronic white-matter infarcts. She underwent five sessions of electroconvulsive therapy (ECT), with significantly improving Montreal Cognitive Assessment and Young Mania Rating Scale scores. At the time of discharge on day 32, the patient was fully oriented to self and surroundings with good hygiene, a normal rate of speech, euthymic mood, and congruent affect. The case of Ms. S underscores the importance of a thorough workup to rule out secondary causes of mania. In addition, it is a clarion call for revisiting and researching a comprehensive management approach to LOBD, for which serial cognitive assessments and ECTs may play an important role.

CryoEM Structure with ATP Synthase Enables Late-Stage Diversification of Cruentaren†A.

Cruentaren A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentaren A derivatives include a trans-alkene isomer, which was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as several other analogues that retained potent inhibitory activity. Together, these studies provide a foundation for the generation of cruentaren A derivatives as potential therapeutics for the treatment of cancer.

Manassantin A inhibits tumour growth under hypoxia through the activation of chaperone-mediated autophagy by modulating Hsp90 activity.

BACKGROUND: Chaperon-mediated autophagy (CMA) has taken on a new emphasis in cancer biology. However, the roles of CMA in hypoxic tumours are poorly understood. We investigated the anti-tumour effects of the natural product ManA through the activation of CMA in tumour progression under hypoxia. METHODS: The effect of ManA on CMA activation was assessed in mouse xenograft models and cells. The gene expressions of HIF-1α, HSP90AA1, and transcription factor EB (TFEB) were analysed using The Cancer Genome Atlas (TCGA) datasets to assess the clinical relevance of CMA. RESULTS: ManA activates photoswitchable CMA reporter activity and inhibits Hsp90 chaperone function by disrupting the Hsp90/F1F0-ATP synthase complex. Hsp90 inhibition enhances the interaction between CMA substrates and LAMP-2A and TFEB nuclear localisation, suggesting CMA activation by ManA. ManA-activated CMA retards tumour growth and displays cooperative anti-tumour activity with anti-PD-1 antibody. TCGA datasets show that a combined expression of HSP90AA1High/HIF1AHigh or TFEBLow/HIF1AHigh is strongly correlated with poor prognosis in patients with lung cancer. CONCLUSIONS: ManA-induced CMA activation by modulating Hsp90 under hypoxia induces HIF-1α degradation and reduces tumour growth. Thus, inducing CMA activity by targeting Hsp90 may be a promising therapeutic strategy against hypoxic tumours.

Forensic evaluation of mitochondrial DNA heteroplasmy in Gujarat population, India.

BACKGROUND: Owing to its high copy number and its small size, mtDNA analysis is the most reliable choice when biological materials from crime scenes are degraded or have mixed STR profiles. AIM: To examine the occurrence of heteroplasmy along with its frequency and pattern in both HV1 and HV2 regions of the mtDNA among unrelated individuals from India. SUBJECTS AND METHODS: Mitochondrial DNA control region [hypervariable region one (HV1) and hypervariable region two (HV2)] were analysed in blood and buccal tissues of 104 unrelated individuals from the Indian state of Gujarat. RESULTS: A high frequency of point heteroplasmy (PH) and length heteroplasmy (LH) was revealed. PH was detected in 7.69% of the population, with a higher frequency observed in blood than in buccal samples. However, there were no statistically significant differences in PH between the two tissues (Chi-square = 0.552, p ≥ 0.05). A total of six PH positions were detected: three at HV1, and another three at HV2. The studied population showed 46.15% LH in the HV1 and HV2 regions of both tissues. The LH positions observed in the Gujarat population were the same as those previously reported at HV1 np16184-16193 and HV2 np303-315. CONCLUSIONS: Our findings suggest that differences in the pattern of heteroplasmy found in different tissues can complicate the forensic analysis, on the other hand, the probability of a match between the questioned and reference samples increases when the heteroplasmy is identical in both tissues. Variability of PH among persons and even within tissues recommends analysing multiple tissue samples before drawing a conclusion in forensic mtDNA analyses.

Recent Developments and Research Avenues for Polymers in Electric Vehicles.

Plastics have been an indispensable material of choice in automobiles with wide range of applications such as interior, exterior, under the hood, and lighting/wiring applications. The prime motive of inclusion of these materials is increase in fuel efficiency and reduction in carbon footprint by replacing the energy intensive metallic counterparts. The current decade i. e., the 2020s has seen a recent surge in the sales of electronic vehicles. Although these numbers are promising, the growth in the rest of the parts of the world is not encouraging. It is primarily due to the skepticism involving battery life and efficiency, profitability, and environmental footprint when compared to conventional and hybrid vehicles. Also, a more concerted effort is needed in the lagging areas in order to install the required infrastructure. The emergence of plastics in the development and acceptance of e-vehicles is going to be pivotal especially when the efficiency and profitability are considered as they give the required freedom to the engineers for the design and development of various parts and sizes by replacing the bulkier and more dense materials. Also, the research on bionanocomposites has received great interest from the research community due to their versatility in application along with their eco-friendly nature throughout the lifecycle starting from feedstock up to end-of-life treatment. This review paper will be one of its kind to present a critical review of the recent developments of polymers suitable for use in e-vehicles. Also, a comprehensive discussion comprising of newer research areas for polymers in their use for e-vehicles will be presented.

Durum wheat semolina-modified ceramic membranes as novel porous separators for enhanced power generation and wastewater remediation using microbial fuel cell.

This proof-of-concept study describes the enhanced performance efficiency of the dual-chambered microbial fuel cell equipped with the fabricated unmodified ceramic membranes and ceramic membranes modified with 5 % and 10 % (w/w) durum wheat semolina in comparison with the commercially available NafionTM 117 membranes. The chemical oxygen demand removal efficiencies were determined to be 85.6 ± 0.1, 72.1 ± 0.2 and 68.6 ± 0.1 % for microbial fuel cell equipped with 10 % (w/w) semolina-modified, 5 % (w/w) semolina-modified and unmodified ceramic membrane, respectively, which indicated the improved wastewater treatment efficiency with increasing content of semolina. Preliminary studies showed that the 10 % (w/w) semolina-modified ceramic was cost-effective (64 USD/m2) with improved water uptake, good proton mobility, low oxygen diffusion in addition to the enhanced power and current density output. The semolina-modified ceramic membranes have the potential to become a cost-effective alternative for the high-efficiency production of bioelectricity using microbial fuel cells.

Synthesis and Evaluation of Simplified Cruentaren A Analogues.

The 90 kDa heat shock protein (Hsp90) belongs to a group of molecular chaperones that regulate homeostasis via the folding of nascent polypeptides into their biologically active proteins, many of which are involved in cancer development and progression. As a result, inhibition of Hsp90 is an exciting area of research for the treatment of cancer. However, most of the 18 Hsp90 N-terminal inhibitors evaluated in clinical trials exhibited deleterious side effects and toxicities. Cruentaren A is a natural product that manifests potent anticancer activity against various human cancer cell lines via disruption of interactions between Hsp90α and F1FO ATP synthase, which does not induce the pro-survival, heat shock response, a major limitation associated with current Hsp90 inhibitors. However, the development of cruentaren A as a new anticancer agent has been hindered by its complex structure. Herein, we systematically removed the functionalities present in fragment 2 of cruentaren A and incorporated some key structural modifications from previous work, which produced 12 simplified analogues. Our studies determined that all functional groups present in fragment 2 are essential for cruentaren A's anticancer activity.

Design of Biopharmaceutical Formulations Accelerated by Machine Learning.

In addition to activity, successful biological drugs must exhibit a series of suitable developability properties, which depend on both protein sequence and buffer composition. In the context of this high-dimensional optimization problem, advanced algorithms from the domain of machine learning are highly beneficial in complementing analytical screening and rational design. Here, we propose a Bayesian optimization algorithm to accelerate the design of biopharmaceutical formulations. We demonstrate the power of this approach by identifying the formulation that optimizes the thermal stability of three tandem single-chain Fv variants within 25 experiments, a number which is less than one-third of the experiments that would be required by a classical DoE method and several orders of magnitude smaller compared to detailed experimental analysis of full combinatorial space. We further show the advantage of this method over conventional approaches to efficiently transfer historical information as prior knowledge for the development of new biologics or when new buffer agents are available. Moreover, we highlight the benefit of our technique in engineering multiple biophysical properties by simultaneously optimizing both thermal and interface stabilities. This optimization minimizes the amount of surfactant in the formulation, which is important to decrease the risks associated with corresponding degradation processes. Overall, this method can provide high speed of converging to optimal conditions, the ability to transfer prior knowledge, and the identification of new nonlinear combinations of excipients. We envision that these features can lead to a considerable acceleration in formulation design and to parallelization of operations during drug development.

Comparative evaluation of different human dental tissues and alveolar bone for DNA quantity and quality for forensic investigation.

In this study, the efficacy of dental tissues (cementum, dentine and pulp) and alveolar bone as a potential source of DNA was tested in terms of the quality and quantity using nuclear and mitochondrial markers for forensic investigation.This study found dentine as the best source of DNA with only 5.36% imbalanced (PHR<0.7) heterozygous loci. Pulp showed the highest quantity of DNA but exhibited 22.3% imbalanced (PHR<0.7) heterozygous loci. Cementum with highest (46.67%) heterozygote imbalance proved to be the last choice as a source of DNA. Alveolar bone exhibited the second-highest total yield of DNA/mg of tissue. All Global Filer™ STR loci were amplified in 70% samples of fresh alveolar bone whereas for 30% samples, only partial profile was generated along with successful sex determination. All the dental tissues and alveolar bone samples amplified non STR markers (D-loop, Cytochrome Oxidase I, SRY, AMEL). Of the alveolar bones from archival samples, one sample exhibited full STR profile whereas other alveolar bone samples gave partial profiles. This study substantiates alveolar bone as an alternate source of nuclear and mitochondrial DNA.

A systematic evaluation of 'Bidi - a hand-rolled cigarette' as a forensic DNA evidence.

Bidis are small handmade cigarettes consisting of ~0.2 g of tobacco flakes rolled in a dried leaf of 'Tendu' (Diospyros melanoxylon) or Piliostigma racemosum and tied with a thin thread. They have gained worldwide popularity among smokers and are often collected as forensic DNA evidence from crime scenes and processed similarly to cigarette butts. However, bidi's composition and manufacturing process differs distinctly from the cigarette, and hence the optimal processing for DNA analysis should not be assumed to be similar to cigarette butts. In the present study, the methodical evaluation of the bidi for DNA analysis is reported and an additional process of cell elution from bidi stubs prior to DNA extraction is systematically compared with the direct lysis of bidi stubs which is identical to the standard practice in forensic labs for cigarette butts. In terms of cell recovery from bidi stubs, the SDS based Cell Elution Buffer (CEB) proved to be better than Tween20 based CEB. The three components (cell-elute, supernatant, and processed stub) obtained after the cell elution process of smoked bidi stubs showed varying amounts of DNA. The cell-elute and processed stub exhibited high quality DNA, resulting in 90-100% of the samples giving a full STR profile. On the contrary, the directly lysed stubs yielded high quantity but low quality of DNA, resulting in only 40% of the samples with full STR profiles. The cell elution process enables three components namely cell-elute, supernatant and processed stub from the same bidi to be used for forensic DNA analysis, although the cell-elute proved to be the best source of DNA for STR profiling. The current study demonstrates that the additional cell elution process proved to be an essential step prior to DNA extraction procedure for bidi stubs.

An Unusual Case of Chronic Hemoptysis.

CASE PRESENTATION: A 62-year-old African American man was admitted to the hospital with hemoptysis. He had a complicated medical history significant for active tobacco use (>50 pack-year history), coronary artery disease, and heart failure with reduced ejection fraction. He reported intermittent episodes of coughing up streaks of blood in the sputum for the past 3 years. For the past few days before this presentation, he had multiple episodes of coughing up over a tablespoon of only blood. He was not on any anticoagulant agents. There were no risk factors for TB, nor was there a history of fevers, chills, shortness of breath, leg swelling, changes in his urine color and frequency or urgency, or unintended weight loss. On admission, he was noted to be breathing comfortably. Vital signs revealed a temperature of 36.6ºC, BP of 138/70 mm Hg, heart rate of 66 beats/min, respiratory of rate of 18 breaths/min, and a blood oxygen saturation level of 98% on room air. Physical examination was significant for decreased bilateral breath sounds with no wheezing, crackles, or rhonchi. Cardiovascular examination revealed normal cardiac rhythm without murmur, rubs, or gallops. There was no clubbing or edema on his extremities.

Recent development in the discovery of PARP inhibitors as anticancer agents: a patent update (2016-2020).

INTRODUCTION: Discovery of small molecules that impede the activity of single-strand DNA repair enzyme, PARP1, has led to four marketed drugs for the treatment of advanced-stage cancers. Hence, there is a renewed enthusiasm in the PARP inhibitor discovery arena. To reduce nonspecific interactions or potential toxicities, and to understand the role of other minimally explored PARP enzymes, exciting new findings have emerged toward the development of selective inhibitors and targeted chemical biology probes. Importantly, the conventional PARP inhibitor design has evolved in a way that could potentially lead to multienzyme-targeting - a polypharmacological approach against aggressive cancers. AREAS COVERED: This review comprises recent progress made in the development of PARP inhibitors, primarily focused on human cancers. Discovery of novel PARP inhibitors with pan, selective, and multi-target inhibition using in vitro and in vivo cancer models is summarized and critically evaluated. Emphasis is given to patents published during 2016-2020, excluding TNKS 1/2 inhibitors. EXPERT OPINION: The outstanding success demonstrated by the FDA approved PARP inhibitors has fueled further clinical evaluations for expansion of their clinical utilities. The current clinical investigations include new candidates as well as marketed PARP-targeted drugs, both as single agents and in combination with other chemotherapeutics. Recent advances have also unveiled critical roles of other PARPs in oncogenic signal transduction, in addition to those of the well-documented PARP1/2 and TNKS1/2 enzymes. Further studies on lesser-known PARP members are urgently needed for functional annotations and for understanding their roles in cancer progression and other human diseases.

Natural products and other inhibitors of F1FO ATP synthase.

F1FO ATP synthase is responsible for the production of >95% of all ATP synthesis within the cell. Dysregulation of its expression, activity or localization is linked to various human diseases including cancer, diabetes, and Alzheimer's and Parkinson's disease. In addition, ATP synthase is a novel and viable drug target for the development of antimicrobials as evidenced by bedaquiline, which was approved in 2012 for the treatment of tuberculosis. Historically, natural products have been a rich source of ATP synthase inhibitors that help unravel the role of F1FO ATP synthase in cellular bioenergetics. During the last decade, new modulators of ATP synthase have been discovered through the isolation of novel natural products as well as through a ligand-based drug design process. In addition, new data has been obtained with regards to the structure and function of ATP synthase under physiological and pathological conditions. Crystal structure studies have provided a significant insight into the rotary function of the enzyme and may provide additional opportunities to design a new generation of inhibitors. This review provides an update on recently discovered ATP synthase modulators as well as an update on existing scaffolds.

Prussian blue-doped nanosized polyaniline for electrochemical detection of benzenediol isomers.

Simultaneous speciation of benzenediol isomers (BDIs), 1,2-benzenediol (catechol, CC), 1,3-benzenediol (resorcinol, RS), and 1,4-benzenediol (hydroquinone, HQ), was investigated by differential pulse voltammetry (DPV) using a graphite paste electrode (GPE) modified with Prussian blue-polyaniline nanocomposite. The modified GPE showed good stability, sensitivity, and selectivity properties for all the three BDIs. Prussian blue-doped nanosized polyaniline (PBNS-PANI) was synthesized first by using mechanochemical reactions between aniline and ferric chloride hexahydrate as the oxidants and then followed by the addition of potassium hexacyanoferrate(II) in a solid-state and template-free technique. The material was characterized by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS). The DPV measurements are performed in phosphate electrolyte solution with pH 4.0 at a potential range of - 0.1 to 1.0 V. The proposed modified electrode displayed a strong, stable, and continuous three well-separated oxidation peaks towards electrooxidation at potentials 0.20, 0.31, and 0.76 V for HQ, CC, and RS, respectively. The calibration curves were linear from 1 to 350.5 µM for both HQ and CC, while for RS, it was from 2 to 350.5 µM. The limit of detection was determined to be 0.18, 0.01, and 0.02 µM for HQ, CC, and RS, respectively. The analytical performance of the PBNS-PANI/GPE has been evaluated for simultaneous determination of HQ, CC, and RS in creek water, commercial hair dye, and skin whitening cream samples with satisfactory recoveries between 90 and 106%. Overall, we demonstrated that the presence of NS-PANI and PB resulted in a large redox-active surface area that enabled a promising analytical platform for simultaneous detection of BDIs. Graphical abstract.

Angle-Sensitive Photonic Crystals for Simultaneous Detection and Photocatalytic Degradation of Hazardous Diazo Compounds.

Congo Red (CR) and Amido Black 10B (AB-10B) are anionic diazo dyes, which are metabolized to produce a bioaccumulative and persistent carcinogen, benzidine. In this regard, an angle sensitive sensor composed of photonic crystal supported photocatalyst was fabricated for the simultaneous detection and photocatalytic degradation of diazo dyes from aqueous solutions. Reflectance spectroscopy was used in the detection of CR and AB-10B, which was based on the emergence of the incident angle dependent reflection peaks from the TiO2 coated two-dimensional photonic crystal (2D-PhC) surfaces and their subsequent quenching due to the presence of dye molecules whose absorbance peak intensity overlapped the reflection peak intensity of TiO2 at the respective angle. Interestingly, ultraviolet (UV) mediated photocatalytic degradation of CR and AB-10B was achieved using the same TiO2 coated 2D-PhC surfaces. 2D-PhC underneath the TiO2 layer was able to confine and localize the light on the TiO2 coated 2D-PhC surface, which enhanced the light absorption by dye molecules on the TiO2 surface and the photocatalytic efficiency in the degradation of CR and AB-10B. Finally, this proof-of-concept study demonstrated the fabrication of copolymer film based photonic crystal supported photocatalytic device, which can be used for developing miniaturized sensors competent in on-field detection and degradation of pollutants.

TiO2-coated 2D photonic crystals for reflectometric determination of malachite green.

A "detect and destroy" strategy is reported for the spectroscopic determination and photocatalytic degradation of Malachite Green (MG) in aqueous solutions. The intensity of the reflection peak maxima from the TiO2-coated 2D-photonic crystal (PhC) at 633 nm wavelength undergoes a gradual decrease with increasing concentrations of MG. The determination of MG was readily achieved in the nanomolar range due to the quenching of the reflection intensity of the peak, measured using a fiber optic probe. The assay works in the 1.0 nM to 10 µM MG concentration range with a detection limit of 1.3 nM. The same TiO2-coated 2D-PhC surface can photocatalytically degrade MG in aqueous solutions under UV irradiation. The photocatalytic degradation in the presence of TiO2-coated 2D-PhC becomes evident as the blue color of MG changes to colorless with increasing irradiation time. The decrease in absorption is detected at 617 nm. It was found that the photocatalytic efficiency of TiO2 was synergistically enhanced in the presence of 2D-PhCs. It is concluded that each component of the TiO2-coated 2D-PhC system plays a key role in the detection and degradation of MG. Graphical abstractSchematic representation for reflectometric detection and photocatalytic degradation of hazardous Malachite Green dye using TiO2-coated two-dimensional photonic crystals.

Trichosporon-Blood Stream Infection.

AIM: Trichosporon species are the major emerging opportunistic pathogen in immunocompromised patients. Its diverse refractoriness to conventional antifungal drugs and association with high mortality rate is worrisome. The present study aims to determine the risk factors, treatment outcome and antifungal susceptibility pattern of Trichosporon species in blood stream infections. MATERIAL AND METHODS: All patients with blood culture positive for Trichosporon species from January 2012 to August 2016 at PD Hinduja National Hospital and research centre were evaluated retrospectively. Species identification and antifungal susceptibility by broth microdilution method for various drugs was determined using Vitek2 compact automated system. RESULTS: 12 patients were found to have Trichosporon blood stream infection. 9 isolates that were speciated all were T. asahii. All patients had central venous catheter and received prior antibiotics. Overall mortality rate was 50%. CONCLUSION: Higher mortality was associated with central venous catheter and voriconazole should be used as drug of choice for treatment. Identification of Trichosporon species along with its sensitivity and proper treatment of patients is of utmost importance.

Electrochemical Detection of Gallic Acid-Capped Gold Nanoparticles Using a Multiwalled Carbon Nanotube-Reduced Graphene Oxide Nanocomposite Electrode.

Recently, a plethora of ecofriendly methods have been developed for the synthesis of AuNPs using a multitude of biogenic agents. Polyphenols from plants are particularly attractive for producing AuNPs because in addition to helping with the synthesis of AuNPs, the polyphenol capping of the NPs can be used as a platform for versatile applications. Polyphenol-capped AuNPs could also make the detection of AuNPs possible, should they be released into the environment. Because polyphenols are redox-active, they can be used as a probe to detect AuNPs using electrochemical techniques. In this work, we have developed an MWCNT-rGO nanocomposite electrode for the sensitive detection of AuNPs capped with gallic acid (GA, a green-tea-derived polyphenol) using differential pulse voltammetry (DPV). The reduction of gallic acid-capped AuNPs was used as the quantification signal, and the calibration curve displayed a detection limit of 2.57 pM. Using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), we have shown that the modification of the electrode surface with an MWCNT-rGO hybrid nanocomposite resulted in a 10-fold increase in current response leading to the sensitive detection of GA-AuNPs compared to unmodified electrodes. We have also demonstrated the applicability of the electrochemical sensor in detecting GA-AuNPs in various analytical matrixes such as human serum and natural creek water (Highland Creek, ON) with good recovery.

Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.

Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC50 = 434 nM) led to a tetrazolyl analogue (51, IC50 = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC50 = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC50 values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC50 values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC50 = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.