In silico screening, synthesis, and antimalarial evaluation of PABA substituted 1,3,5-triazine derivatives as Pf-DHFR inhibitors.

OBJECTIVES: Drug resistance in malaria parasites necessitates the development of new antimalarial drugs with unique mechanisms of action. In the present research work, the PABA conjugated 1,3,5-triazine derivatives were designed as an antimalarial agent. METHODS: In this present work, a library of two hundred-seven compounds was prepared in twelve different series such as [4A (1-23), 4B(1-22), 4C(1-21), 4D(1-20), 4E(1-19), 4F(1-18), 4G(1-17), 4H(1-16), 4I(1-15), 4J(1-13), 4K(1-12) and 4L(1-11) ] respectively using different primary and secondary aliphatic and aromatic amines. Ten compounds were ultimately selected through in silico screening. They were synthesized by conventional and microwave-assisted methods followed by in vitro antimalarial evaluations performed in chloroquine-sensitive (3D7) and resistant (DD2) strains of P. falciparum. RESULTS: The docking results showed that compound 4C(11) had good binding interaction with Phe116, Met55 (-464.70 kcal/mol) and Phe116, Ser111 (-432.60 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. Furthermore, in vitro, antimalarial activity results indicated that compound 4C(11) showed potent antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain of P. falciparum along with IC50 (14.90 µg mL-1) and (8.30 µg mL-1). CONCLUSION: These PABA-substituted 1,3,5-triazine compounds could be exploited to develop a new class of Pf-DHFR inhibitors as a lead candidate.

Microwave-assisted synthesis of hybrid PABA-1,3,5-triazine derivatives as an antimalarial agent.

The present manuscript deals with the development of novel p-aminobenzoic acid (PABA) associated 1,3,5-triazine derivatives as antimalarial agents. The molecules were developed via microwave-assisted synthesis and structures of compounds were ascertained via numerous analytical and spectroscopic techniques. The synthesized compounds were also subjected to ADMET analysis. In a docking analysis, the title compounds showed high and diverse binding affinities towards wild (-162.45 to -369.38 kcal/mol) and quadruple mutant (-165.36 to -209.47 kcal/mol) Pf-DHFR-TS via interacting with Phe58, Arg59, Ser111, Ile112, Phe116. The in vitro antimalarial activity suggested that compounds 4e, 4b, and 4h showed IC50 ranging from 4.18 to 8.66 µg/ml against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum. Moreover, compounds 4g, 4b, 4e, and 4c showed IC50 ranging from 8.12 to 12.09 µg/ml against chloroquine-resistant (Dd2) strain. In conclusion, our study demonstrated the development of hybrid PABA substituted 1,3,5-triazines as a novel class of Pf-DHFR inhibitor for antimalarial drug discovery.

1,3,5-Triazine: A versatile pharmacophore with diverse biological activities.

1,3,5-Triazine and its derivatives have been the epicenter of chemotherapeutic molecules due to their effective biological activities, such as antibacterial, fungicidal, antimalarial, anticancer, antiviral, antimicrobial, anti-inflammatory, antiamoebic, and antitubercular activities. The present review represents a summarized report of the crucial biological activities possessed by substituted 1,3,5-triazine derivatives, with special attention to the most potent compounds.

"TB - Mindedness"-the only way to beat "the great mimicker": A case series with atypical presentation of female genital tuberculosis.

BACKGROUND: Incidence of Tuberculosis (TB) cases in India reported in 2019 is 193 per 1 lakh population [National Tuberculosis Elimination Plan (NTEP)]. In India, annual extra pulmonary TB burden is 20-25%, of which 4% of cases are of urogenital origin (Revised National TB Control Programme, 2019; World Health Organization, 2019). The Ministry of Health and Family Welfare has made a target of eliminating tuberculosis by 2025 under the NTEP by the process of identification, notification and treatment of cases. Tuberculosis being a leading cause of infertility in developing countries, employing best clinical practices and being "TB-minded" will also save the patient of enormous anxiety and uncertainity and also decrease the time gap between clinical presentation and diagnosis to optimize fertility outcome. METHODOLOGY: A prospective cohort study of cases presenting with unusual findings and ultimately being diagnosed as genital tuberculosis was conducted in the gynaecology OPD, AIIMS, New Delhi, from November 2020 to November 2021 (1 year). Patients were investigated judiciously, diagnosis made and followed up for their response to anti tuberculosis therapy (ATT). RESULTS: This data comprises of conglomerate of ten cases with unconventional exhibition of genital tuberculosis. 70% of the cases presented with pain lower abdomen not specifically related to menstrual cycle and often confused with IBD. Tubo ovarian mass (70%) mimicking as simple ovarian cyst, ovarian carcinoma or endometriosis was the most common clinical finding we came across.

Comparison of Intraperitoneal Irrigation With Sodium Bicarbonate Versus Normal Saline in Reducing Pain After Operative Laparoscopy: A Randomized Controlled Trial.

Background It has been postulated that sodium bicarbonate can reduce postoperative pain by neutralizing the acidic peritoneal environment created by carbon dioxide. It also prevents phrenic nerve damage and peritoneal irritation. The present study is a randomized controlled trial aimed at studying the effects of sodium bicarbonate in reducing postoperative pain in laparoscopic gynecological surgeries. Materials and methods This was a single-center, prospective, two-arm, double-blinded randomized control trial in which intraperitoneal irrigation with sodium bicarbonate was compared with normal saline in operative laparoscopy. Group I (intervention group) consisted of 40 patients who received intraperitoneal sodium bicarbonate, and Group II (control group) consisted of 40 patients who received normal saline. All procedures were conducted under general anesthesia. Postoperative pain scores were compared between intervention and control groups.  Results The most common indication of laparoscopy was infertility. There was no difference in the duration of surgery between the two arms (p=0.27). The mean value of the visual analog scale (VAS) score at the shoulder tip was found to be significantly reduced in the intervention group at two hours (p=0.02), four hours (p=0.0009), and 12 hours (p=0.0002) after surgery. The mean VAS score at the abdomen and port sites was also found to be significantly reduced in the intervention group in the first 24 hours after surgery (p<0.05). With the increase in the time period from surgery, the mean VAS scores decreased in both intervention and control groups.  Conclusion Intraperitoneal irrigation with sodium bicarbonate is beneficial in reducing postoperative pain in operative laparoscopy. However, multicenter randomized trials with a greater number of participants will be helpful to confirm the findings.

Hybrid PABA-glutamic acid conjugated 1,3,5-triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme.

Despite the successful reduction in the malaria health burden in recent years, it continues to remain a significant global health problem mainly because of the emerging resistance to first-line treatments. Also because of the disruption in malaria prevention services during the COVID-19 pandemic, there was an increase in malaria cases in 2021 compared to 2020. Hence, the present study outlined the in silico study, synthesis, and antimalarial evaluation of 1,3,5-triazine hybrids conjugated with PABA-glutamic acid. Docking study revealed higher binding energy compared to the originally bound ligand WR99210, predominant hydrogen bond interaction, and involvement of key amino acid residues, like Arg122, Ser120, and Arg59. Fourteen compounds were synthesized using traditional and microwave synthesis. The in vitro antimalarial evaluation against chloroquine-sensitive 3D7 and resistant Dd2 strain of Plasmodium falciparum showed a high to moderate activity range. Compounds C1 and B4 showed high efficacy against both strains and a further study revealed that compound C1 is non-cytotoxic against the HEK293 cell line with no acute oral toxicity. In vivo, study was performed for the most potent antimalarial compound C1 to optimize the research work and found to be effectively suppressing parasitemia of Plasmodium berghei strain in the Swiss albino mice model.

Molecular docking and antimalarial evaluation of hybrid para-aminobenzoic acid 1,3,5 triazine derivatives via inhibition of Pf-DHFR.

In this study, a structurally guided pharmacophore hybridization strategy is used to combine the two key structural scaffolds, para-aminobenzoic acid (PABA), and 1,3,5 triazine in search of new series of antimalarial agents. A combinatorial library of 100 compounds was prepared in five different series as [4A (1-22), 4B (1-21), 4 C (1-20), 4D (1-19) and 4E (1-18)] using different primary and secondary amines, from where 10 compounds were finally screened out through molecular property filter analysis and molecular docking study as promising PABA substituted 1,3,5-triazine scaffold as an antimalarial agent. The docking results showed that compounds 4A12 and 4A20 exhibited good binding interaction with Phe58, IIe164, Ser111, Arg122, Asp54 (-424.19 to -360.34 kcal/mol) and Arg122, Phe116, Ser111, Phe58 (-506.29 to -431.75 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. These compounds were synthesized by conventional as well as microwave-assisted synthesis and characterized by different spectroscopic methods. In-vitro antimalarial activity results indicated that two compounds 4A12 and 4A20 showed promising antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum with IC50 (1.24-4.77 µg mL-1) and (2.11-3.60 µg mL-1). These hybrid PABA substituted 1,3,5-triazine derivatives might be used in the lead discovery towards a new class of Pf-DHFR inhibitors.Communicated by Ramaswamy H. Sarma.

Gynaecological Laparoscopic Surgeries in the Omicron Era: Improvising the Management Skills After Lessons Learnt From the Delta Wave.

Background During the peak of the Omicron wave, elective laparoscopic surgeries were restricted; however, semi-emergency and emergency cases were managed despite the limited resources and manpower. We conducted this study to assess the types of gynaecological laparoscopic surgeries performed, the difficulties faced during the Omicron wave, and how we could implement the lessons learnt from the previous Delta wave for better management of gynaecological cases in the Omicron wave. Methodology We conducted a prospective cohort study over a period of three months involving 105 patients who underwent laparoscopic surgeries. Based on the decision regarding surgical incision time, the surgeries were sub-classified into immediate, urgent, and expedited. The surgical outcome and satisfaction rates among the patients were assessed through various parameters. Results Most of the women (81.9%) were pre-menopausal. Diabetes and chronic hypertension were the predominant medical co-morbidities. Three patients had a history of cardiac valve replacement which required switching warfarin to unfractionated heparin in the pre-operative period. Nearly three-fourthsof the study patients were doubly vaccinated against coronavirus disease 2019 (COVID-19) (77; 73.4%). A total of 14 (13.3%) patients had a history of COVID-19 infection in the past two weeks prior to the current admission. Immediate, urgent, and expedited surgeries comprised 11.4%, 22.8%, and 65.8% of total surgeries, respectively. On assessing the ease of pre-operative preparation according to the five-point Likert scale, immediate, urgent, and expedited surgeries were rated with a mean score of two, four, and five, respectively. The mean duration of surgery in the immediate and urgent groups was 37.6 and 44.2 minutes, respectively. The expedited group comprising mostly laparoscopic myomectomies and hysterectomies required an average duration of 92.6 minutes. The mean rating of patient satisfaction measured by the Likert scale was four, five, and five, respectively, in the three subgroups. Pre-operative patient preparation during the Omicron wave was faster, thereby decreasing the decision to incision interval compared to the Delta wave. Conclusions The lessons learnt from the previous Delta wave were used to modify the existing hospital policies in the Omicron wave. More number of vaccinated ground staff, less stringent intubation and extubation protocols during surgery, and lesser duration of post-operative stay helped modify our existing hospital policies for better patient care and satisfaction.

Clinical and Morphological Spectrum of Histoplasmosis on Cytology Along with the Review of Literature.

OBJECTIVE: The aim of the study was to study the clinical and morphological spectrum of histoplasmosis diagnosed by fine needle aspiration cytology (FNAC). STUDY DESIGN: A total of 17 patients diagnosed with histoplasmosis on FNAC were studied over a period of 5 years. The cytology smears were studied and analysed for the cytomorphological spectrum of histoplasmosis. RESULTS: Among the 17 patients studied, the mean age was 51.3 years (range 6-84 years). Male-to-female ratio was 3.25:1 with 4 females and 13 males. The frequent sites of involvement were the lung (5), lymph node (4), adrenal gland (4), and skin (4). The most common cytological patterns were histiocytic collection, followed by granulomas and multinucleated giant cells. Necrosis was noted in only 4 cases. CONCLUSION: Fine needle aspiration is a highly accurate, rapid, and cheap technique for the diagnosis of histoplasmosis due to its distinct morphological features.